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Garcia-Mouronte E, Naharro-Rodriguez J, Alonso-Mtz de Salinas L, Pérez-González LA, Fernández-Guarino M. Self-Applied Daylight Photodynamic Therapy: A Paradigm Shift? Int J Mol Sci 2025; 26:628. [PMID: 39859342 PMCID: PMC11766313 DOI: 10.3390/ijms26020628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2024] [Revised: 12/31/2024] [Accepted: 01/09/2025] [Indexed: 01/27/2025] Open
Abstract
Photodynamic therapy (PDT) involves the topical application of a photosensitizer and its activation by visible light, leading to the generation of protoporphyrin IX (PpIX) and reactive oxygen species. Daylight photodynamic therapy (dPDT), a variant utilizing natural sunlight as the energy source, enhances procedural flexibility by eliminating the need for specialized equipment. dPDT has been effectively used in dermatology to treat various cutaneous disorders, including neoplastic and infectious diseases. Traditionally, skin preparation and photosensitizer application are performed by trained practitioners, limiting the accessibility of dPDT for broader populations. However, recent studies suggest that these preparatory steps can be managed by patients or caregivers, enabling fully self-applied, home-based dPDT protocols. This review systematically examines the current evidence on self-applied dPDT (SA-dPDT), emphasizing molecular mechanisms and its efficacy in managing premalignant and other cutaneous conditions.
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Affiliation(s)
- Emilio Garcia-Mouronte
- Dermatology Department, Hospital Universitario Ramon y Cajal, Carretera M-607 km 9.1, 28034 Madrid, Spain; (J.N.-R.); (L.A.-M.d.S.); (L.A.P.-G.)
| | | | | | | | - Montserrat Fernández-Guarino
- Dermatology Department, Hospital Universitario Ramon y Cajal, Carretera M-607 km 9.1, 28034 Madrid, Spain; (J.N.-R.); (L.A.-M.d.S.); (L.A.P.-G.)
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Hosik J, Hosikova B, Binder S, Lenobel R, Kolarikova M, Malina L, Dilenko H, Langova K, Bajgar R, Kolarova H. Effects of Zinc Phthalocyanine Photodynamic Therapy on Vital Structures and Processes in Hela Cells. Int J Mol Sci 2024; 25:10650. [PMID: 39408981 PMCID: PMC11476877 DOI: 10.3390/ijms251910650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Revised: 09/24/2024] [Accepted: 10/01/2024] [Indexed: 10/20/2024] Open
Abstract
This work presents results on the efficiency of newly designed zinc phthalocyanine-mediated photodynamic therapy of both tumoral and nontumoral cell models using the MTT assay. Further detailed examinations of mechanistic and cell biological effects were focused on the HELA cervical cancer cell model. Here, ROS production, changes in the mitochondrial membrane potential, the determination of genotoxicity, and protein changes determined by capillary chromatography and tandem mass spectrometry with ESI were analyzed. The results showed that, in vitro, 5 Jcm-2 ZnPc PDT caused a significant increase in reactive oxygen species. Still, except for superoxide dismutase, the levels of proteins involved in cell response to oxidative stress did not increase significantly. Furthermore, this therapy damaged mitochondrial membranes, which was proven by a more than 70% voltage-dependent channel protein 1 level decrease and by a 65% mitochondrial membrane potential change 24 h post-therapy. DNA impairment was assessed by an increased level of DNA fragmentation, which might be related to the decreased level of DDB1 (decrease in levels of more than 20% 24 h post-therapy), a protein responsible for maintaining genomic integrity and triggering the DNA repair pathways. Considering these results and the low effective concentration (LC50 = 30 nM), the therapy used is a potentially very promising antitumoral treatment.
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Affiliation(s)
- Jakub Hosik
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic; (J.H.); (S.B.); (M.K.); (L.M.); (H.D.); (K.L.); (R.B.); (H.K.)
| | - Barbora Hosikova
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic; (J.H.); (S.B.); (M.K.); (L.M.); (H.D.); (K.L.); (R.B.); (H.K.)
| | - Svatopluk Binder
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic; (J.H.); (S.B.); (M.K.); (L.M.); (H.D.); (K.L.); (R.B.); (H.K.)
| | - Rene Lenobel
- Laboratory of Growth Regulators, Faculty of Science, Palacky University and Institute of Experimental Botany of the Czech Academy of Sciences, 77900 Olomouc, Czech Republic;
| | - Marketa Kolarikova
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic; (J.H.); (S.B.); (M.K.); (L.M.); (H.D.); (K.L.); (R.B.); (H.K.)
| | - Lukas Malina
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic; (J.H.); (S.B.); (M.K.); (L.M.); (H.D.); (K.L.); (R.B.); (H.K.)
| | - Hanna Dilenko
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic; (J.H.); (S.B.); (M.K.); (L.M.); (H.D.); (K.L.); (R.B.); (H.K.)
| | - Katerina Langova
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic; (J.H.); (S.B.); (M.K.); (L.M.); (H.D.); (K.L.); (R.B.); (H.K.)
| | - Robert Bajgar
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic; (J.H.); (S.B.); (M.K.); (L.M.); (H.D.); (K.L.); (R.B.); (H.K.)
| | - Hana Kolarova
- Department of Medical Biophysics, Faculty of Medicine and Dentistry, Palacky University, 77900 Olomouc, Czech Republic; (J.H.); (S.B.); (M.K.); (L.M.); (H.D.); (K.L.); (R.B.); (H.K.)
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Lee CK, Wang FT, Huang CH, Chan WH. Dose-dependent effects of silver nanoparticles on cell death modes in mouse blastocysts induced via endoplasmic reticulum stress and mitochondrial apoptosis. Toxicol Res (Camb) 2024; 13:tfae158. [PMID: 39371680 PMCID: PMC11447381 DOI: 10.1093/toxres/tfae158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 08/19/2024] [Accepted: 09/27/2024] [Indexed: 10/08/2024] Open
Abstract
In view of the rapidly expanding medical and commercial applications of silver nanoparticles (AgNPs), their potential health risks and environmental effects are a significant growing concern. Earlier research by our group uncovered the embryotoxic potential of AgNPs, showing detrimental impacts of these nanoparticles on both pre- and post-implantation embryonic development. In the current study, we showed that low (50-100 μM) and high (200-400 μM) dose ranges of AgNPs trigger distinct cell death programs affecting mouse embryo development and further explored the underlying mechanisms. Treatment with low concentrations of AgNPs (50-100 μM) triggered ROS generation, in turn, inducing mitochondria-dependent apoptosis, and ultimately, harmful effects on embryo implantation, post-implantation development, and fetal development. Notably, high concentrations of AgNPs (200-400 μM) evoked more high-level ROS generation and endoplasmic reticulum (ER) stress-mediated necrosis. Interestingly, pre-incubation with Trolox, a strong antioxidant, reduced ROS generation in the group treated with 200-400 μM AgNPs to the level induced by 50-100 μM AgNPs, resulting in switching of the cell death mode from necrosis to apoptosis and a significant improvement in the impairment of embryonic development. Our findings additionally indicate that activation of PAK2 is a crucial step in AgNP-triggered apoptosis and sequent detrimental effects on embryonic development. Based on the collective results, we propose that the levels of ROS generated by AgNP treatment of embryos serve as a critical regulator of cell death type, leading to differential degrees of damage to embryo implantation, post-implantation development and fetal development through triggering apoptosis, necrosis or other cell death signaling cascades.
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Affiliation(s)
- Cheng-Kai Lee
- Department of Obstetrics and Gynecology, Taoyuan General Hospital, Ministry of Health & Welfare, Zhongshan Road, Taoyuan District, Taoyuan City 33004, Taiwan
| | - Fu-Ting Wang
- Rehabilitation and Technical Aid Center, Taipei Veterans General Hospital, Section 2, Shipai Road, Beitou District, Taipei City 11217, Taiwan
| | - Chien-Hsun Huang
- Hungchi Gene IVF Center, Taoyuan District, Daxing West Road, Taoyuan District, Taoyuan City 330012, Taiwan
| | - Wen-Hsiung Chan
- Department of Bioscience Technology and Center for Nanotechnology, Chung Yuan Christian University, Zhongbei Road, Zhongli District, Taoyuan City 32023, Taiwan
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Kobzev D, Semenova O, Aviel-Ronen S, Kulyk O, Carmieli R, Mirzabekov T, Gellerman G, Patsenker L. Sonodynamic Therapy for HER2+ Breast Cancer with Iodinated Heptamethine Cyanine-Trastuzumab Conjugate. Int J Mol Sci 2024; 25:10137. [PMID: 39337633 PMCID: PMC11431973 DOI: 10.3390/ijms251810137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 09/30/2024] Open
Abstract
The first example of sonodynamic therapy (SDT) with a cyanine dye-antibody conjugate is reported. The aim of this study was to evaluate the sonodynamic efficacy of a trastuzumab-guided diiodinated heptamethine cyanine-based sensitizer, 2ICy7-Ab, versus its non-iodinated counterpart, Cy7-Ab, in a human epidermal growth factor receptor 2-positive (HER2+) xenograft model. In addition, the combined sonodynamic and photodynamic (PDT) effects were investigated. A single intravenous injection of 2ICy7-Ab followed by sonication or combined sonication and photoirradiation in mice resulted in complete tumor growth suppression compared with the nontreated control and showed no detectable toxicity to off-target tissues. In contrast, Cy7-Ab provided only a moderate therapeutic effect (~1.4-1.6-fold suppression). SDT with 2ICy7-Ab resulted in a 3.5-fold reduction in tumor volume within 45 days and exhibited 13-fold greater tumor suppression than PDT alone. In addition, 2ICy7-Ab showed more durable sonostability than photostability. The sonotoxicity of the iodinated versus noniodinated counterparts is attributed to the increased generation of hydroxyl radicals, superoxide, and singlet oxygen. We observed no significant contribution of PDT to the efficacy of the combined SDT and PDT, indicating that SDT with 2ICy7-Ab is superior to PDT alone. These new findings set the stage for the application of cyanine-antibody conjugates for fluorescently monitored targeted sonodynamic treatment of cancer.
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Affiliation(s)
- Dmytro Kobzev
- Department of Chemical Sciences, Faculty of Natural Sciences, Ariel University, Ariel 40700, Israel; (D.K.); (O.S.); (O.K.); (G.G.)
| | - Olga Semenova
- Department of Chemical Sciences, Faculty of Natural Sciences, Ariel University, Ariel 40700, Israel; (D.K.); (O.S.); (O.K.); (G.G.)
| | - Sarit Aviel-Ronen
- Adelson School of Medicine, Ariel University, Ariel 40700, Israel;
- Sheba Medical Center, Tel-Hashomer, Ramat Gan 52621, Israel
| | - Olesia Kulyk
- Department of Chemical Sciences, Faculty of Natural Sciences, Ariel University, Ariel 40700, Israel; (D.K.); (O.S.); (O.K.); (G.G.)
| | - Raanan Carmieli
- Department of Chemical Research Support, Weizmann Institute of Science, Rehovot 76100, Israel;
| | | | - Gary Gellerman
- Department of Chemical Sciences, Faculty of Natural Sciences, Ariel University, Ariel 40700, Israel; (D.K.); (O.S.); (O.K.); (G.G.)
| | - Leonid Patsenker
- Department of Chemical Sciences, Faculty of Natural Sciences, Ariel University, Ariel 40700, Israel; (D.K.); (O.S.); (O.K.); (G.G.)
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Alvarez N, Sevilla A. Current Advances in Photodynamic Therapy (PDT) and the Future Potential of PDT-Combinatorial Cancer Therapies. Int J Mol Sci 2024; 25:1023. [PMID: 38256096 PMCID: PMC10815790 DOI: 10.3390/ijms25021023] [Citation(s) in RCA: 61] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 01/05/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Photodynamic therapy (PDT) is a two-stage treatment that implies the use of light energy, oxygen, and light-activated compounds (photosensitizers) to elicit cancerous and precancerous cell death after light activation (phototoxicity). The biophysical, bioengineering aspects and its combinations with other strategies are highlighted in this review, both conceptually and as they are currently applied clinically. We further explore the recent advancements of PDT with the use of nanotechnology, including quantum dots as innovative photosensitizers or energy donors as well as the combination of PDT with radiotherapy and immunotherapy as future promising cancer treatments. Finally, we emphasize the potential significance of organoids as physiologically relevant models for PDT.
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Affiliation(s)
- Niuska Alvarez
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain;
| | - Ana Sevilla
- Department of Cell Biology, Physiology and Immunology, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain;
- Institute of Biomedicine, University of Barcelona (IBUB), 08036 Barcelona, Spain
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Pashootan P, Saadati F, Fahimi H, Rahmati M, Strippoli R, Zarrabi A, Cordani M, Moosavi MA. Metal-based nanoparticles in cancer therapy: Exploring photodynamic therapy and its interplay with regulated cell death pathways. Int J Pharm 2024; 649:123622. [PMID: 37989403 DOI: 10.1016/j.ijpharm.2023.123622] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 11/01/2023] [Accepted: 11/16/2023] [Indexed: 11/23/2023]
Abstract
Photodynamic therapy (PDT) represents a non-invasive treatment strategy currently utilized in the clinical management of selected cancers and infections. This technique is predicated on the administration of a photosensitizer (PS) and subsequent irradiation with light of specific wavelengths, thereby generating reactive oxygen species (ROS) within targeted cells. The cellular effects of PDT are dependent on both the localization of the PS and the severity of ROS challenge, potentially leading to the stimulation of various cell death modalities. For many years, the concept of regulated cell death (RCD) triggered by photodynamic reactions predominantly encompassed apoptosis, necrosis, and autophagy. However, in recent decades, further explorations have unveiled additional cell death modalities, such as necroptosis, ferroptosis, cuproptosis, pyroptosis, parthanatos, and immunogenic cell death (ICD), which helps to achieve tumor cell elimination. Recently, nanoparticles (NPs) have demonstrated substantial advantages over traditional PSs and become important components of PDT, due to their improved physicochemical properties, such as enhanced solubility and superior specificity for targeted cells. This review aims to summarize recent advancements in the applications of different metal-based NPs as PSs or delivery systems for optimized PDT in cancer treatment. Furthermore, it mechanistically highlights the contribution of RCD pathways during PDT with metal NPs and how these forms of cell death can improve specific PDT regimens in cancer therapy.
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Affiliation(s)
- Parya Pashootan
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran; Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Saadati
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran
| | - Hossein Fahimi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Marveh Rahmati
- Cancer Biology Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Raffaele Strippoli
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy; National Institute for Infectious Diseases L. Spallanzani IRCCS, Rome, Italy
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396, Turkey; Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai - 600 077, India
| | - Marco Cordani
- Departament of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University of Madrid, Madrid, Spain; Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, Spain.
| | - Mohammad Amin Moosavi
- Department of Molecular Medicine, Institute of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology, Tehran, P.O Box 14965/161, Iran.
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Thomas-Moore BA, Dedola S, Russell DA, Field RA, Marín MJ. Targeted photodynamic therapy for breast cancer: the potential of glyconanoparticles. NANOSCALE ADVANCES 2023; 5:6501-6513. [PMID: 38024308 PMCID: PMC10662151 DOI: 10.1039/d3na00544e] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 10/15/2023] [Indexed: 12/01/2023]
Abstract
Photodynamic therapy (PDT) uses a non-toxic light sensitive molecule, a photosensitiser, that releases cytotoxic reactive oxygen species upon activation with light of a specific wavelength. Here, glycan-modified 16 nm gold nanoparticles (glycoAuNPs) were explored for their use in targeted PDT, where the photosensitiser was localised to the target cell through selective glycan-lectin interactions. Polyacrylamide (PAA)-glycans were chosen to assess glycan binding to the cell lines. These PAA-glycans indicated the selective uptake of a galactose-derivative PAA by two breast cancer cell lines, SK-BR-3 and MDA-MD-231. Subsequently, AuNPs were modified with a galactose-derivative ligand and an amine derivate of the photosensitiser chlorin e6 was incorporated to the nanoparticle surface via amide bond formation using EDC/NHS coupling chemistry. The dual modified nanoparticles were investigated for the targeted cell killing of breast cancer cells, demonstrating the versatility of using glycoAuNPs for selective binding to different cancer cells and their potential use for targeted PDT.
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Affiliation(s)
- Brydie A Thomas-Moore
- Iceni Glycoscience Ltd. Norwich Research Park Norwich NR4 7TJ UK
- School of Chemistry, University of East Anglia Norwich Research Park Norwich NR4 7TJ UK
| | - Simone Dedola
- Iceni Glycoscience Ltd. Norwich Research Park Norwich NR4 7TJ UK
- Department of Chemistry and Manchester Institute of Biotechnology, University of Manchester 131 Princess Street Manchester M1 7DN UK
| | - David A Russell
- School of Chemistry, University of East Anglia Norwich Research Park Norwich NR4 7TJ UK
| | - Robert A Field
- Iceni Glycoscience Ltd. Norwich Research Park Norwich NR4 7TJ UK
- Department of Chemistry and Manchester Institute of Biotechnology, University of Manchester 131 Princess Street Manchester M1 7DN UK
| | - María J Marín
- School of Chemistry, University of East Anglia Norwich Research Park Norwich NR4 7TJ UK
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Parihar A, Dube A. Structural alterations in cell organelles induced by photodynamic treatment with chlorin p 6 -histamine conjugate in human oral carcinoma cells probed by 3D fluorescence microscopy. LUMINESCENCE 2023; 38:1175-1184. [PMID: 35698308 DOI: 10.1002/bio.4307] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/27/2022] [Accepted: 04/18/2022] [Indexed: 11/09/2022]
Abstract
We have explored the intracellular cell organelle's structural alterations after photodynamic treatment with chlorin p6 -histamine conjugate (Cp6 -his) in human oral cancer cells. Herein, the cells were treated with Cp6 -his (10 μm) and counterstained with organelle-specific fluorescence probes to find the site of intracellular localization using confocal microscopy. For photodynamic therapy (PDT), the cells were exposed to ~30 kJ/m2 red light (660 ± 20 nm) to induce ~90% cytotoxicity. We used the three-dimensional (3D) image reconstruction approach to analyze the photodynamic damage to cell organelles. The result showed that Cp6 -his localized mainly in the endoplasmic reticulum (ER) and lysosomes but not in mitochondria and Golgi apparatus (GA). The 3D model revealed that in necrotic cells, PDT led to extensive fragmentation of ER and fragmentation and swelling of GA as well. Results suggest that the indirect damage to GA occurred due to loss of connection between ER and GA. Moreover, in damaged cells with no sign of necrosis, the perinuclear ER appeared condensed and surrounded by several small clumps at the peripheral region of the cell, and the GA was observed to form a single condensed structure. Since these structural changes were associated with apoptotic cell death, it is suggested that the necrotic and apoptotic death induced by PDT with Cp6 -his is determined by the severity of damage to ER and indirect damage to GA. The results suggest that the indirect damage to cell organelle apart from the sites of photosensitizer localization and the severity of damage at the organelle level contribute significantly to the mode of cell death in PDT.
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Affiliation(s)
- Arpana Parihar
- Industrial Waste Utilization, Nano and Biomaterials, CSIR - Advanced Materials and Processes Research Institute (AMPRI), Bhopal, India
| | - Alok Dube
- Laser Biomedical Applications Division, Raja Ramanna Center for Advanced Technology Indore, Madhya Pradesh, India
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Mušković M, Pokrajac R, Malatesti N. Combination of Two Photosensitisers in Anticancer, Antimicrobial and Upconversion Photodynamic Therapy. Pharmaceuticals (Basel) 2023; 16:613. [PMID: 37111370 PMCID: PMC10143496 DOI: 10.3390/ph16040613] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Revised: 04/12/2023] [Accepted: 04/15/2023] [Indexed: 04/29/2023] Open
Abstract
Photodynamic therapy (PDT) is a special form of phototherapy in which oxygen is needed, in addition to light and a drug called a photosensitiser (PS), to create cytotoxic species that can destroy cancer cells and various pathogens. PDT is often used in combination with other antitumor and antimicrobial therapies to sensitise cells to other agents, minimise the risk of resistance and improve overall outcomes. Furthermore, the aim of combining two photosensitising agents in PDT is to overcome the shortcomings of the monotherapeutic approach and the limitations of individual agents, as well as to achieve synergistic or additive effects, which allows the administration of PSs in lower concentrations, consequently reducing dark toxicity and preventing skin photosensitivity. The most common strategies in anticancer PDT use two PSs to combine the targeting of different organelles and cell-death mechanisms and, in addition to cancer cells, simultaneously target tumour vasculature and induce immune responses. The use of PDT with upconversion nanoparticles is a promising approach to the treatment of deep tissues and the goal of using two PSs is to improve drug loading and singlet oxygen production. In antimicrobial PDT, two PSs are often combined to generate various reactive oxygen species through both Type I and Type II processes.
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Affiliation(s)
| | | | - Nela Malatesti
- Department of Biotechnology, University of Rijeka, Radmile Matejčić 2, 51000 Rijeka, Croatia; (M.M.); (R.P.)
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Yang TS, Hsiao YC, Chiang YF, Chang CJ. Imaging and Histopathological Analysis of Microvascular Angiogenesis in Photodynamic Therapy for Oral Cancer. Cancers (Basel) 2023; 15:cancers15041110. [PMID: 36831454 PMCID: PMC9954751 DOI: 10.3390/cancers15041110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Revised: 02/04/2023] [Accepted: 02/06/2023] [Indexed: 02/12/2023] Open
Abstract
The objective of this study is to use imaging and histopathological analysis to characterize and monitor microvascular responses to photodynamic therapy (PDT). In vivo chicken chorioallantoic membranes (CAMs) and a stimulated malignant oral lesions animal model were used to determine the blood flow and the biological activities of Photofrin® (2.5 mg/kg) exposed to different laser power densities at 630 nm. The vascular changes, the velocity of the blood flow, the speckle flow index (SFI) of fluorescence changes, and ultrastructure damage in the microvasculature before and after PDT were recorded. The subcellular localization of Photofrin® revealed satisfactory uptake throughout the cytoplasm of human red blood cells at 10 s and 20 s before PDT. The mean blood-flow velocities of the veins and arteries were 500 ± 40 and 1500 ± 100 μm/s, respectively. A significant decrease in the velocities of the blood flow in the veins and arteries was detected in the CAM model after PDT. The veins and arteries of CAMs, exposed to the power densities of 80, 100, and 120 mW/cm2, had average blood-flow velocities of 100 ± 20, 60 ± 10, and 0 μm/s and 300 ± 50, 150 ± 30, and 0 μm/s, respectively. In the stimulated malignant oral lesions animal model, the treated tumors exhibited hemorrhage and red blood cell extravasation after PDT. The oxyhemoglobin and total hemoglobin levels decreased, which resulted in a decrease in tissue oxygen saturation, while the deoxyhemoglobin levels increased. PDT using Photofrin® has the ability to cause the destruction of the targeted microvasculature under nonthermal mechanisms selectively.
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Affiliation(s)
- Tzu-Sen Yang
- Graduate Institute of Biomedical Optomechatronics, Taipei Medical University, Taipei 110, Taiwan
- International PhD Program in Biomedical Engineering, Taipei Medical University, Taipei 110, Taiwan
- School of Dental Technology, Taipei Medical University, Taipei 110, Taiwan
- Research Center of Biomedical Device, Taipei Medical University, Taipei 110, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan
| | - Yen-Chang Hsiao
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan City 33302, Taiwan
| | - Yu-Fan Chiang
- Medical School, University of Queensland, Saint Lucia, QLD 4072, Australia
| | - Cheng-Jen Chang
- Graduate Institute of Biomedical Optomechatronics, Taipei Medical University, Taipei 110, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan
- Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan City 33302, Taiwan
- Department of Plastic Surgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
- School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
- Correspondence:
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11
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Huis in ‘t Veld RV, Heuts J, Ma S, Cruz LJ, Ossendorp FA, Jager MJ. Current Challenges and Opportunities of Photodynamic Therapy against Cancer. Pharmaceutics 2023; 15:pharmaceutics15020330. [PMID: 36839652 PMCID: PMC9965442 DOI: 10.3390/pharmaceutics15020330] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/06/2023] [Accepted: 01/12/2023] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND Photodynamic therapy (PDT) is an established, minimally invasive treatment for specific types of cancer. During PDT, reactive oxygen species (ROS) are generated that ultimately induce cell death and disruption of the tumor area. Moreover, PDT can result in damage to the tumor vasculature and induce the release and/or exposure of damage-associated molecular patterns (DAMPs) that may initiate an antitumor immune response. However, there are currently several challenges of PDT that limit its widespread application for certain indications in the clinic. METHODS A literature study was conducted to comprehensively discuss these challenges and to identify opportunities for improvement. RESULTS The most notable challenges of PDT and opportunities to improve them have been identified and discussed. CONCLUSIONS The recent efforts to improve the current challenges of PDT are promising, most notably those that focus on enhancing immune responses initiated by the treatment. The application of these improvements has the potential to enhance the antitumor efficacy of PDT, thereby broadening its potential application in the clinic.
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Affiliation(s)
- Ruben V. Huis in ‘t Veld
- Department of Ophthalmology, Leiden University Medical Centre (LUMC), 2333 ZA Leiden, Zuid-Holland, The Netherlands
- Department of Radiology, Leiden University Medical Centre (LUMC), 2333 ZA Leiden, Zuid-Holland, The Netherlands
- Correspondence:
| | - Jeroen Heuts
- Department of Immunology, Leiden University Medical Centre (LUMC), 2333 ZA Leiden, Zuid-Holland, The Netherlands
| | - Sen Ma
- Department of Ophthalmology, Leiden University Medical Centre (LUMC), 2333 ZA Leiden, Zuid-Holland, The Netherlands
| | - Luis J. Cruz
- Department of Radiology, Leiden University Medical Centre (LUMC), 2333 ZA Leiden, Zuid-Holland, The Netherlands
| | - Ferry A. Ossendorp
- Department of Immunology, Leiden University Medical Centre (LUMC), 2333 ZA Leiden, Zuid-Holland, The Netherlands
| | - Martine J. Jager
- Department of Ophthalmology, Leiden University Medical Centre (LUMC), 2333 ZA Leiden, Zuid-Holland, The Netherlands
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12
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Wang X, Chen Y, Yang X, Cheng L, He Z, Xin Y, Huang S, Meng F, Zhang P, Luo L. Activation of ALOX12 by a multi-organelle-orienting photosensitizer drives ACSL4-independent cell ferroptosis. Cell Death Dis 2022; 13:1040. [PMID: 36517470 PMCID: PMC9751149 DOI: 10.1038/s41419-022-05462-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2022] [Revised: 11/20/2022] [Accepted: 11/22/2022] [Indexed: 12/15/2022]
Abstract
Ferroptosis is a recently-defined tumor suppression mechanism, but the sensitivity of many tumorigenic cells to ferroptosis is limited by their deficient expression of acyl-CoA synthetase long-chain family member 4 (ACSL4). Here, we report the discovery of a photosensitizer, namely TPCI, which can evoke ACSL4-independent ferroptosis of cancer cells in photodynamic therapy. Through co-localization with 12-lipoxygenase (ALOX12) in multiple subcellular organelles, TPCI activates ALOX12 to generate lipid reactive oxygen species in large quantity and trigger cell ferroptosis. Intriguingly, confining TPCI exclusively in lysosomes switches the cell death from ferroptosis to apoptosis. More strikingly, the ferroptosis mediated by TPCI-induced ALOX12 activation does not require the participation of ACSL4. Therefore, our study identifies TPCI as the first ALOX12 activator to induce ferroptosis independent of ACSL4, which renders a viable therapeutic approach on the basis of distinct ferroptosis of cancer cells, regardless their ACSL4 expressions.
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Affiliation(s)
- Xiuxia Wang
- grid.207374.50000 0001 2189 3846Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, 450052 China
| | - Yuanhong Chen
- grid.33199.310000 0004 0368 7223National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074 China
| | - Xiang Yang
- grid.33199.310000 0004 0368 7223National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074 China
| | - Lianghui Cheng
- grid.33199.310000 0004 0368 7223National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074 China
| | - Zhenyan He
- grid.33199.310000 0004 0368 7223National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074 China
| | - Yanru Xin
- grid.33199.310000 0004 0368 7223National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074 China
| | - Shan Huang
- grid.33199.310000 0004 0368 7223National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074 China
| | - Fanling Meng
- grid.33199.310000 0004 0368 7223National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074 China
| | - Peijing Zhang
- grid.33199.310000 0004 0368 7223National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074 China ,grid.33199.310000 0004 0368 7223Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074 China
| | - Liang Luo
- grid.33199.310000 0004 0368 7223National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074 China ,grid.33199.310000 0004 0368 7223Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074 China ,grid.33199.310000 0004 0368 7223Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica, School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, 430074 China
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13
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de Almeida DRQ, Dos Santos AF, Wailemann RAM, Terra LF, Gomes VM, Arini GS, Bertoldi ERM, Reis EM, Baptista MS, Labriola L. Necroptosis activation is associated with greater methylene blue-photodynamic therapy-induced cytotoxicity in human pancreatic ductal adenocarcinoma cells. Photochem Photobiol Sci 2022; 22:729-744. [PMID: 36495407 DOI: 10.1007/s43630-022-00347-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 11/23/2022] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinomas (PDAC) are the fourth leading cause of death due to neoplasms. In view of the urgent need of effective treatments for PDAC, photodynamic therapy (PDT) appears as a promising alternative. However, its efficacy against PDAC and the mechanisms involved in cell death induction remain unclear. In this study, we set out to evaluate PDT's cytotoxicity using methylene blue (MB) as a photosensitizer (PS) (MB-PDT) and to evaluate the contribution of necroptosis in its effect in human PDAC cells. Our results demonstrated that MB-PDT induced significant death of different human PDAC models presenting two different susceptibility profiles. This effect was independent of MB uptake or its subcellular localization. We found that the ability of triggering necroptosis was determinant to increase the treatment efficiency. Analysis of single cell RNA-seq data from normal and neoplastic human pancreatic tissues showed that specific necroptosis proteins RIPK1, RIPK3 and MLKL presented significant higher expression levels in cells displaying a transformed phenotype providing further support to the use of approaches that activate necroptosis, like MB-PDT, as useful adjunct to surgery of PDAC to tackle the problem of microscopic residual disease as well as to minimize the chance of local and metastatic recurrence.
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Affiliation(s)
- Daria R Q de Almeida
- Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), Cidade Universitária, Block 09, Room 976, Av. Professor Lineu Prestes 748, São Paulo, 05508-000, Brazil
| | - Ancély F Dos Santos
- Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), Cidade Universitária, Block 09, Room 976, Av. Professor Lineu Prestes 748, São Paulo, 05508-000, Brazil
| | - Rosangela A M Wailemann
- Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), Cidade Universitária, Block 09, Room 976, Av. Professor Lineu Prestes 748, São Paulo, 05508-000, Brazil
| | - Letícia F Terra
- Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), Cidade Universitária, Block 09, Room 976, Av. Professor Lineu Prestes 748, São Paulo, 05508-000, Brazil
| | - Vinícius M Gomes
- Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), Cidade Universitária, Block 09, Room 976, Av. Professor Lineu Prestes 748, São Paulo, 05508-000, Brazil
| | - Gabriel S Arini
- Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), Cidade Universitária, Block 09, Room 976, Av. Professor Lineu Prestes 748, São Paulo, 05508-000, Brazil
| | - Ester R M Bertoldi
- Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), Cidade Universitária, Block 09, Room 976, Av. Professor Lineu Prestes 748, São Paulo, 05508-000, Brazil
| | - Eduardo M Reis
- Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), Cidade Universitária, Block 09, Room 976, Av. Professor Lineu Prestes 748, São Paulo, 05508-000, Brazil
| | - Maurício S Baptista
- Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), Cidade Universitária, Block 09, Room 976, Av. Professor Lineu Prestes 748, São Paulo, 05508-000, Brazil.
| | - Leticia Labriola
- Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), Cidade Universitária, Block 09, Room 976, Av. Professor Lineu Prestes 748, São Paulo, 05508-000, Brazil.
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14
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Carigga Gutierrez NM, Pujol-Solé N, Arifi Q, Coll JL, le Clainche T, Broekgaarden M. Increasing cancer permeability by photodynamic priming: from microenvironment to mechanotransduction signaling. Cancer Metastasis Rev 2022; 41:899-934. [PMID: 36155874 DOI: 10.1007/s10555-022-10064-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 09/06/2022] [Indexed: 01/25/2023]
Abstract
The dense cancer microenvironment is a significant barrier that limits the penetration of anticancer agents, thereby restraining the efficacy of molecular and nanoscale cancer therapeutics. Developing new strategies to enhance the permeability of cancer tissues is of major interest to overcome treatment resistance. Nonetheless, early strategies based on small molecule inhibitors or matrix-degrading enzymes have led to disappointing clinical outcomes by causing increased chemotherapy toxicity and promoting disease progression. In recent years, photodynamic therapy (PDT) has emerged as a novel approach to increase the permeability of cancer tissues. By producing excessive amounts of reactive oxygen species selectively in the cancer microenvironment, PDT increases the accumulation, penetration depth, and efficacy of chemotherapeutics. Importantly, the increased cancer permeability has not been associated to increased metastasis formation. In this review, we provide novel insights into the mechanisms by which this effect, called photodynamic priming, can increase cancer permeability without promoting cell migration and dissemination. This review demonstrates that PDT oxidizes and degrades extracellular matrix proteins, reduces the capacity of cancer cells to adhere to the altered matrix, and interferes with mechanotransduction pathways that promote cancer cell migration and differentiation. Significant knowledge gaps are identified regarding the involvement of critical signaling pathways, and to which extent these events are influenced by the complicated PDT dosimetry. Addressing these knowledge gaps will be vital to further develop PDT as an adjuvant approach to improve cancer permeability, demonstrate the safety and efficacy of this priming approach, and render more cancer patients eligible to receive life-extending treatments.
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Affiliation(s)
| | - Núria Pujol-Solé
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000, Grenoble, France
| | - Qendresa Arifi
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000, Grenoble, France
| | - Jean-Luc Coll
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000, Grenoble, France
| | - Tristan le Clainche
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000, Grenoble, France.
| | - Mans Broekgaarden
- Université Grenoble Alpes, Inserm U 1209, CNRS UMR 5309, Institute for Advanced Biosciences, 38000, Grenoble, France.
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15
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Aung W, Tsuji AB, Hanaoka K, Higashi T. Folate receptor-targeted near-infrared photodynamic therapy for folate receptor-overexpressing tumors. World J Clin Oncol 2022; 13:880-895. [PMID: 36483974 PMCID: PMC9724186 DOI: 10.5306/wjco.v13.i11.880] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 09/12/2022] [Accepted: 10/18/2022] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Photodynamic therapy (PDT) is a minimally invasive form of cancer therapy, and the development of a novel photosensitizer (PS) with optimal properties is important for enhancing PDT efficacy. Folate receptor (FR) membrane protein is frequently overexpressed in 40% of human cancer and a good candidate for tumor-specific targeting. Specific active targeting of PS to FR can be achieved by conjugation with the folate moiety. A folate-linked, near-infrared (NIR)-sensitive probe, folate-Si-rhodamine-1 (FolateSiR-1), was previously developed and is expected to be applicable to NIR-PDT.
AIM To investigate the therapeutic efficacy of NIR-PDT induced by FolateSiR-1, a FR-targeted PS, in preclinical cancer models.
METHODS FolateSiR-1 was developed by conjugating a folate moiety to the Si-rhodamine derivative through a negatively charged tripeptide linker. FR expression in the designated cell lines was examined by western blotting (WB). The selective binding of FolateSiR-1 to FR was confirmed in FR overexpressing KB cells (FR+) and tumors by fluorescence microscopy and in vivo fluorescence imaging. Low FR expressing OVCAR-3 and A4 cell lines were used as negative controls (FR-). The NIR light (635 ± 3 nm)-induced phototoxic effect of FolateSiR-1 was evaluated by cell viability imaging assays. The time-dependent distribution of FolateSiR-1 and its specific accumulation in KB tumors was determined using in vivo longitudinal fluorescence imaging. The PDT effect of FolateSiR-1 was evaluated in KB tumor-bearing mice divided into four experimental groups: (1) FolateSiR-1 (100 μmol/L) alone; (2) FolateSiR-1 (100 μmol/L) followed by NIR irradiation (50 J/cm2); (3) NIR irradiation (50 J/cm2) alone; and (4) no treatment. Tumor volume measurement and immunohistochemical (IHC) and histological examinations of the tumors were performed to analyze the effect of PDT.
RESULTS High FR expression was observed in the KB cells by WB, but not in the OVCAR-3 and A4 cells. Substantial FR-specific binding of FolateSiR-1 was observed by in vitro and in vivo fluorescence imaging. Cell viability imaging assays showed that NIR-PDT induced cell death in KB cells. In vivo longitudinal fluorescence imaging showed rapid peak accumulation of FolateSiR-1 in the KB tumors 2 h after injection. In vivo PDT conducted at this time point caused tumor growth delay. The relative tumor volumes in the PDT group were significantly reduced compared to those in the other groups [5.81 ± 1.74 (NIR-PDT) vs 12.24 ± 2.48 (Folate-SiR-1), vs 11.84 ± 3.67 (IR), vs 12.98 ± 2.78 (Untreated), at Day 16, P < 0.05]. IHC analysis revealed reduced proliferation marker Ki-67-positive cells in the PDT treated tumors, and hematoxylin-eosin staining revealed features of necrotic- and apoptotic cell death.
CONCLUSION FolateSiR-1 has potential for use in PDT, and FR-targeted NIR-PDT may open a new effective strategy for the treatment of FR-overexpressing tumors.
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Affiliation(s)
- Winn Aung
- Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Atsushi B Tsuji
- Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
| | - Kenjiro Hanaoka
- Faculty of Pharmacy and Graduate School of Pharmaceutical Sciences, Keio University, Tokyo 105-8512, Japan
| | - Tatsuya Higashi
- Department of Molecular Imaging and Theranostics, Institute for Quantum Medical Science, National Institutes for Quantum and Radiological Science and Technology, Chiba 263-8555, Japan
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16
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Menilli L, Milani C, Reddi E, Moret F. Overview of Nanoparticle-Based Approaches for the Combination of Photodynamic Therapy (PDT) and Chemotherapy at the Preclinical Stage. Cancers (Basel) 2022; 14:cancers14184462. [PMID: 36139623 PMCID: PMC9496990 DOI: 10.3390/cancers14184462] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2022] [Revised: 09/06/2022] [Accepted: 09/09/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary The present review represents the outstanding and promising recent literature reports (2017–2022) on nanoparticle-based formulations developed for anticancer therapy with photodynamic therapy (PDT), photosensitizers, and chemotherapeutics. Besides brief descriptions of chemotherapeutics’ classification and of PDT mechanisms and limitations, several examples of nanosystems endowed with different responsiveness (e.g., acidic pH and reactive oxygen species) and peculiarity (e.g., tumor oxygenation capacity, active tumor targeting, and biomimetic features) are described, and for each drug combination, in vitro and in vivo results on preclinical cancer models are reported. Abstract The widespread diffusion of photodynamic therapy (PDT) as a clinical treatment for solid tumors is mainly limited by the patient’s adverse reaction (skin photosensivity), insufficient light penetration in deeply seated neoplastic lesions, unfavorable photosensitizers (PSs) biodistribution, and photokilling efficiency due to PS aggregation in biological environments. Despite this, recent preclinical studies reported on successful combinatorial regimes of PSs with chemotherapeutics obtained through the drugs encapsulation in multifunctional nanometric delivery systems. The aim of the present review deals with the punctual description of several nanosystems designed not only with the objective of co-transporting a PS and a chemodrug for combination therapy, but also with the goal of improving the therapeutic efficacy by facing the main critical issues of both therapies (side effects, scarce tumor oxygenation and light penetration, premature drug clearance, unspecific biodistribution, etc.). Therefore, particular attention is paid to the description of bio-responsive drugs and nanoparticles (NPs), targeted nanosystems, biomimetic approaches, and upconverting NPs, including analyzing the therapeutic efficacy of the proposed photo-chemotherapeutic regimens in in vitro and in vivo cancer models.
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Affiliation(s)
- Luca Menilli
- Department of Biology, University of Padova, 35100 Padova, Italy
| | - Celeste Milani
- Department of Biology, University of Padova, 35100 Padova, Italy
- Institute of Organic Synthesis and Photoreactivity, ISOF-CNR, 40129 Bologna, Italy
| | - Elena Reddi
- Department of Biology, University of Padova, 35100 Padova, Italy
- Correspondence: (E.R.); (F.M.)
| | - Francesca Moret
- Department of Biology, University of Padova, 35100 Padova, Italy
- Correspondence: (E.R.); (F.M.)
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17
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Huang CH, Wang FT, Chan WH. Low-dose silver nanoparticles plus methyl mercury exert embryotoxic effects on mouse blastocysts via endoplasmic reticulum stress and mitochondrial apoptosis. Toxicol Res (Camb) 2022; 11:460-474. [PMID: 35782646 PMCID: PMC9244727 DOI: 10.1093/toxres/tfac028] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Revised: 04/29/2022] [Accepted: 05/02/2022] [Indexed: 07/30/2023] Open
Abstract
The health and environmental impacts of the increasing commercial use of silver nanoparticles (AgNPs) are a growing concern. Methyl mercury (MeHg) is a potent toxin that biotransforms from mercury or inorganic mercury compounds in waterways and causes dangerous environmental contamination. However, the potential interactions and combined effects of AgNPs and MeHg are yet to be established. In the current study, we showed that low/non-embryotoxic doses of AgNPs and MeHg interact synergistically to induce embryotoxicity and further explored the underlying mechanisms affecting mouse embryo development. Notably, co-treatment with noncytotoxic concentrations of AgNPs (10 μM) and MeHg (0.1 μM) triggered apoptotic processes and embryotoxicity in mouse blastocysts and evoked intracellular reactive oxygen species (ROS) generation, which was effectively blocked by preincubation with 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox), a classic antioxidant. Further experiments demonstrated that ROS serve as a key upstream inducer of endoplasmic reticulum (ER) stress and mitochondria-dependent apoptotic processes in AgNP/MeHg-induced injury of mouse embryo implantation and pre- and postimplantation development. Our results collectively indicate that AgNP and MeHg at non-embryotoxic concentrations can synergistically evoke ROS, ultimately causing embryotoxicity through promotion of ER stress and mitochondria-dependent apoptotic signaling cascades.
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Affiliation(s)
- Chien-Hsun Huang
- Department of Obstetrics and Gynecology, Taoyuan General Hospital, Ministry of Health & Welfare, Zhongshan Road, Taoyuan District, Taoyuan City 33004, Taiwan
| | - Fu-Ting Wang
- Rehabilitation and Technical Aid Center, Taipei Veterans General Hospital, Section 2, Shipai Road, Beitou District, Taipei City 11217, Taiwan
| | - Wen-Hsiung Chan
- Corresponding author: Department of Bioscience Technology and Center for Nanotechnology, Chung Yuan Christian University, Zhongbei Road, Zhongli District, Taoyuan City 32023, Taiwan.
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18
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Peng Z, Lv X, Huang S. Photoimmunotherapy: A New Paradigm in Solid Tumor Immunotherapy. Cancer Control 2022. [PMCID: PMC9016614 DOI: 10.1177/10732748221088825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
In recent years, the incidence of cancer has been increasing worldwide. Conventional cancer treatments include surgery, chemotherapy, and radiation, which mostly kill tumor cells at the expense of normal and immune cells. Although immunotherapy is an accurate, rapid, efficient tumor immune treatment, it causes serious adverse reactions, such as cytokine release syndrome (CRS) and neurotoxicity. Therefore, there is an urgent need to develop an effective and nontoxic procedure for immunotherapy. The clinical combination of phototherapy and immunoadjuvant therapy can induce immunogenic cell death and enhance antigen presentation synergy. It also causes a systemic antitumor immune response to manage residual tumors and distant metastases. Photoimmunotherapy (PIT) is a tumor treatment combining phototherapy with immunotherapy based on injecting a conjugate photosensitizer (IR700) and a monoclonal antibody (mAb) to target an expressed antigen on the tumor surface. This combination can enhance the immune response ability, thus having a good effect on the treatment of residual tumor and metastatic cancer. In this review, we summarize the recent progress in photoimmunotherapy, including photoimmunoconjugate (PIC), the activation mechanism of immunogenic cell death (ICD), the combination therapy model, opportunities and prospects. Specifically, we aim to provide a promising clinical therapy for solid tumor clinical transformation.
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Affiliation(s)
- Zheng Peng
- Faculty of Health Sciences, University of Macau, Taipa, China
| | - Xiaolan Lv
- Department of Laboratory Medicine, Liuzhou Maternity and Child Healthcare Hospital, Liu Zhou, China
| | - Shigao Huang
- Department of Radiation Oncology, Xijing Hospital, Air Force Medical University, Xi’an, China
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19
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The Immunogenetic Aspects of Photodynamic Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1367:433-448. [DOI: 10.1007/978-3-030-92616-8_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
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20
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Lin MHC, Chang LC, Chung CY, Huang WC, Lee MH, Chen KT, Lai PS, Yang JT. Photochemical Internalization of Etoposide Using Dendrimer Nanospheres Loaded with Etoposide and Protoporphyrin IX on a Glioblastoma Cell Line. Pharmaceutics 2021; 13:pharmaceutics13111877. [PMID: 34834292 PMCID: PMC8621426 DOI: 10.3390/pharmaceutics13111877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Revised: 10/27/2021] [Accepted: 11/02/2021] [Indexed: 11/16/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most common malignant primary neoplasm of the adult central nervous system originating from glial cells. The prognosis of those affected by GBM has remained poor despite advances in surgery, chemotherapy, and radiotherapy. Photochemical internalization (PCI) is a release mechanism of endocytosed therapeutics into the cytoplasm, which relies on the membrane disruptive effect of light-activated photosensitizers. In this study, phototherapy by PCI was performed on a human GBM cell-line using the topoisomerase II inhibitor etoposide (Etop) and the photosensitizer protoporphyrin IX (PpIX) loaded in nanospheres (Ns) made from generation-5 polyamidoamine dendrimers (PAMAM(G5)). The resultant formulation, Etop/PpIX-PAMAM(G5) Ns, measured 217.4 ± 2.9 nm in diameter and 40.5 ± 1.3 mV in charge. Confocal microscopy demonstrated PpIX fluorescence within the endo-lysosomal compartment, and an almost twofold increase in cellular uptake compared to free PpIX by flow cytometry. Phototherapy with 3 min and 5 min light illumination resulted in a greater extent of synergism than with co-administered Etop and PpIX; notably, antagonism was observed without light illumination. Mechanistically, significant increases in oxidative stress and apoptosis were observed with Etop/PpIX-PAMAM(G5) Ns upon 5 min of light illumination in comparison to treatment with either of the agents alone. In conclusion, simultaneous delivery and endo-lysosomal co-localization of Etop and PpIX by PAMAM(G5) Ns leads to a synergistic effect by phototherapy; in addition, the finding of antagonism without light illumination can be advantageous in lowering the dark toxicity and improving photo-selectivity.
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Affiliation(s)
- Martin Hsiu-Chu Lin
- Department of Neurosurgery, Chang Gung Memorial Hospital, Chia-Yi Branch, Chia-Yi 61363, Taiwan; (M.H.-C.L.); (C.-Y.C.); (W.-C.H.); (M.-H.L.); (K.-T.C.)
- Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan;
- Ph.D. Program in Tissue Engineering and Regenerative Medicine, Biotechnology Center, National Chung Hsing University, Taichung 402, Taiwan
| | - Li-Ching Chang
- Department of Dentistry, Chang Gung Memorial Hospital, Chia-Yi Branch, Chia-Yi 61363, Taiwan;
- Department of Nursing, Chang Gung University of Science and Technology, Chia-Yi 61363, Taiwan
| | - Chiu-Yen Chung
- Department of Neurosurgery, Chang Gung Memorial Hospital, Chia-Yi Branch, Chia-Yi 61363, Taiwan; (M.H.-C.L.); (C.-Y.C.); (W.-C.H.); (M.-H.L.); (K.-T.C.)
| | - Wei-Chao Huang
- Department of Neurosurgery, Chang Gung Memorial Hospital, Chia-Yi Branch, Chia-Yi 61363, Taiwan; (M.H.-C.L.); (C.-Y.C.); (W.-C.H.); (M.-H.L.); (K.-T.C.)
| | - Ming-Hsueh Lee
- Department of Neurosurgery, Chang Gung Memorial Hospital, Chia-Yi Branch, Chia-Yi 61363, Taiwan; (M.H.-C.L.); (C.-Y.C.); (W.-C.H.); (M.-H.L.); (K.-T.C.)
| | - Kuo-Tai Chen
- Department of Neurosurgery, Chang Gung Memorial Hospital, Chia-Yi Branch, Chia-Yi 61363, Taiwan; (M.H.-C.L.); (C.-Y.C.); (W.-C.H.); (M.-H.L.); (K.-T.C.)
| | - Ping-Shan Lai
- Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan;
| | - Jen-Tsung Yang
- Department of Neurosurgery, Chang Gung Memorial Hospital, Chia-Yi Branch, Chia-Yi 61363, Taiwan; (M.H.-C.L.); (C.-Y.C.); (W.-C.H.); (M.-H.L.); (K.-T.C.)
- College of Medicine, Chang Gung University, Tao-Yuan 33302, Taiwan
- Correspondence: ; Tel.: +886-5-3621000 (ext. 3412); Fax: +886-5-3621000 (ext. 3002)
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21
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From Basic Mechanisms to Clinical Research: Photodynamic Therapy Applications in Head and Neck Malignancies and Vascular Anomalies. J Clin Med 2021; 10:jcm10194404. [PMID: 34640423 PMCID: PMC8509369 DOI: 10.3390/jcm10194404] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 09/13/2021] [Accepted: 09/17/2021] [Indexed: 01/10/2023] Open
Abstract
Head and neck cancers are largely squamous cell carcinomas derived from the epithelial lining of the structures in the region, and are often classified anatomically into oral, oropharyngeal, nasopharyngeal and laryngeal carcinomas. The region’s component structures serve complex and intricate functions, such as speaking, swallowing and breathing, which are often compromised by these neoplasms. Such lesions may also cause disfigurement, leading to distressing social and psychological issues. Conventional treatments of these neoplasms usually involve surgical intervention with or without chemoradiotherapy. These have shown to be efficacious; however, they can also cause damage to healthy as well as diseased tissue, exacerbating the aforementioned problems. Access to a given region to deliver the treatments is also often a problem, due to the complex anatomical structures involved. The use of photodynamic therapy in the head and neck region has been established for about two decades. In this review, we looked at the basic mechanisms of this intervention, examined its use in common head and neck malignancies and vascular anomalies, and reported on the most recent clinical studies. We further included a clinical guide which can help replicate the use of this technology by any unit. Based on this review, photodynamic therapy has been shown to be efficacious in the treatment of head and neck malignancies and vascular tumours. This therapy can be targeted to the diseased tissue and causes no damage to underlying structures. Recent studies have shown this therapy to be as effective as conventional therapies, without causing major adverse effects.
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Broadwater D, Medeiros HCD, Lunt RR, Lunt SY. Current Advances in Photoactive Agents for Cancer Imaging and Therapy. Annu Rev Biomed Eng 2021; 23:29-60. [PMID: 34255992 DOI: 10.1146/annurev-bioeng-122019-115833] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Photoactive agents are promising complements for both early diagnosis and targeted treatment of cancer. The dual combination of diagnostics and therapeutics is known as theranostics. Photoactive theranostic agents are activated by a specific wavelength of light and emit another wavelength, which can be detected for imaging tumors, used to generate reactive oxygen species for ablating tumors, or both. Photodynamic therapy (PDT) combines photosensitizer (PS) accumulation and site-directed light irradiation for simultaneous imaging diagnostics and spatially targeted therapy. Although utilized since the early 1900s, advances in the fields of cancer biology, materials science, and nanomedicine have expanded photoactive agents to modern medical treatments. In this review we summarize the origins of PDT and the subsequent generations of PSs and analyze seminal research contributions that have provided insight into rational PS design, such as photophysics, modes of cell death, tumor-targeting mechanisms, and light dosing regimens. We highlight optimizable parameters that, with further exploration, can expand clinical applications of photoactive agents to revolutionize cancer diagnostics and treatment.
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Affiliation(s)
- Deanna Broadwater
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA
| | - Hyllana C D Medeiros
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA
| | - Richard R Lunt
- Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan 48824, USA; , .,Department of Physics and Astronomy, Michigan State University, East Lansing, Michigan 48824, USA
| | - Sophia Y Lunt
- Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA.,Department of Chemical Engineering and Materials Science, Michigan State University, East Lansing, Michigan 48824, USA; ,
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Xie J, Wang Y, Choi W, Jangili P, Ge Y, Xu Y, Kang J, Liu L, Zhang B, Xie Z, He J, Xie N, Nie G, Zhang H, Kim JS. Overcoming barriers in photodynamic therapy harnessing nano-formulation strategies. Chem Soc Rev 2021; 50:9152-9201. [PMID: 34223847 DOI: 10.1039/d0cs01370f] [Citation(s) in RCA: 268] [Impact Index Per Article: 67.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Photodynamic therapy (PDT) has been extensively investigated for decades for tumor treatment because of its non-invasiveness, spatiotemporal selectivity, lower side-effects, and immune activation ability. It can be a promising treatment modality in several medical fields, including oncology, immunology, urology, dermatology, ophthalmology, cardiology, pneumology, and dentistry. Nevertheless, the clinical application of PDT is largely restricted by the drawbacks of traditional photosensitizers, limited tissue penetrability of light, inefficient induction of tumor cell death, tumor resistance to the therapy, and the severe pain induced by the therapy. Recently, various photosensitizer formulations and therapy strategies have been developed to overcome these barriers. Significantly, the introduction of nanomaterials in PDT, as carriers or photosensitizers, may overcome the drawbacks of traditional photosensitizers. Based on this, nanocomposites excited by various light sources are applied in the PDT of deep-seated tumors. Modulation of cell death pathways with co-delivered reagents promotes PDT induced tumor cell death. Relief of tumor resistance to PDT with combined therapy strategies further promotes tumor inhibition. Also, the optimization of photosensitizer formulations and therapy procedures reduces pain in PDT. Here, a systematic summary of recent advances in the fabrication of photosensitizers and the design of therapy strategies to overcome barriers in PDT is presented. Several aspects important for the clinical application of PDT in cancer treatment are also discussed.
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Affiliation(s)
- Jianlei Xie
- Key Laboratory of Optoelectronic Devices and Systems of Ministry of Education and Guangdong Province, Institute of Microscale Optoelectronics, and Otolaryngology Department and Biobank of the First Affiliated Hospital, Shenzhen Second People's Hospital, Health Science Center, Shenzhen University, Shenzhen 518060, P. R. China.
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In vivo photobleaching kinetics and epithelial biodistribution of hexylaminolevulinate-induced protoporphyrin IX in rat bladder cancer. Curr Urol 2021; 15:2-10. [PMID: 34084115 PMCID: PMC8137026 DOI: 10.1097/cu9.0000000000000004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 09/16/2019] [Indexed: 12/18/2022] Open
Abstract
In a previous paper, we showed that rat bladder instillations with 8 or 16 mM of hexyl aminolevulinate (hALA) result in diametrically opposed photodynamic therapy efficiency. Although the same fluorescent intensities were detected spectroscopically and by fluorescent microscopy in both conditions, while a given light dose resulted in tumor necrosis with an intact bladder wall after 8 mM hALA, bladders instilled with 16 mM showed total wall necrosis without impact on the tumor. The current study investigated the photobleaching and localization pattern of protoporphyrin IX (PpIX) after both hALA intravesical instillations in tumor-bearing rat bladders. The total PpIX content was evaluated by the extraction of postmortem whole bladders. Photobleaching was evaluated in vivo by fluorescent spectroscopy. Cryosections of bladders were subjected to fluorescent microscopy for cellular localization of the photosensitizer. PpIX extraction showed identical amounts of photosensitizer in tumor-bearing bladders at both concentrations. Photobleaching experiments revealed mono-exponential decay curves in both situations but with a two times faster decay constant in 16 mM bladders. Fluorescent microscopy showed an identical fluorescent pattern for normal bladders at both concentrations and tumor bladders at 8 mM with bright spots. Tumor bladders at 16 mM exhibited a more diffuse cytoplasmatic fluorescent distribution. The different response to photodynamic therapy with regard to the initial pro-drug concentration can thus be attributed to the different cellular localizations.
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Maitra D, Pinsky BM, Soherawardy A, Zheng H, Banerjee R, Omary MB. Protein-aggregating ability of different protoporphyrin-IX nanostructures is dependent on their oxidation and protein-binding capacity. J Biol Chem 2021; 297:100778. [PMID: 34023387 PMCID: PMC8253973 DOI: 10.1016/j.jbc.2021.100778] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 05/08/2021] [Accepted: 05/12/2021] [Indexed: 02/08/2023] Open
Abstract
Porphyrias are rare blood disorders caused by genetic defects in the heme biosynthetic pathway and are associated with the accumulation of high levels of porphyrins that become cytotoxic. Porphyrins, due to their amphipathic nature, spontaneously associate into different nanostructures, but very little is known about the cytotoxic effects of these porphyrin nanostructures. Previously, we demonstrated the unique ability of fluorescent biological porphyrins, including protoporphyrin-IX (PP-IX), to cause organelle-selective protein aggregation, which we posited to be a major mechanism by which fluorescent porphyrins exerts their cytotoxic effect. Herein, we tested the hypothesis that PP-IX-mediated protein aggregation is modulated by different PP-IX nanostructures via a mechanism that depends on their oxidizing potential and protein-binding ability. UV–visible spectrophotometry showed pH-mediated reversible transformations of PP-IX nanostructures. Biochemical analysis showed that PP-IX nanostructure size modulated PP-IX-induced protein oxidation and protein aggregation. Furthermore, albumin, the most abundant serum protein, preferentially binds PP-IX dimers and enhances their oxidizing ability. PP-IX binding quenched albumin intrinsic fluorescence and oxidized His-91 residue to Asn/Asp, likely via a previously described photo-oxidation mechanism for other proteins. Extracellular albumin protected from intracellular porphyrinogenic stress and protein aggregation by acting as a PP-IX sponge. This work highlights the importance of PP-IX nanostructures in the context of porphyrias and offers insights into potential novel therapeutic approaches.
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Affiliation(s)
- Dhiman Maitra
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, USA.
| | | | - Amenah Soherawardy
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, USA
| | - Haiyan Zheng
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, USA
| | - Ruma Banerjee
- University of Michigan Medical School, Ann Arbor, Michigan, USA; Department of Biological Chemistry, Ann Arbor, Michigan, USA
| | - M Bishr Omary
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, New Jersey, USA; University of Michigan Medical School, Ann Arbor, Michigan, USA
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Induced photo-cytotoxicity on prostate cancer cells with the photodynamic action of toluidine Blue ortho. Photodiagnosis Photodyn Ther 2021; 34:102306. [PMID: 33901692 DOI: 10.1016/j.pdpdt.2021.102306] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 03/19/2021] [Accepted: 04/19/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Photodynamic therapy (PDT) has become an advantageous therapeutic approach for the treatment of select cancers and microbial infections. PDT generates toxic reactive oxygen species as an end product of the interaction between the photosensitizer and light with an appropriate wavelength. Toluidine blue ortho is a photosensitizer that is commonly used in the photodynamic treatment of bacterial infection and a promising photosensitizer for cancer treatment. This study aims to evaluate the potential photo-cytotoxicity of toluidine blue ortho-mediated photodynamic therapy on PC-3 prostate cancer cells. METHODS In this study toluidine blue ortho-mediated photodynamic therapy was assessed on PC-3 cancer cells with various photosensitizer concentrations and light energy densities of the 655-nm diode laser. MTT analysis was used for the determination of the cytotoxicity on the cells and viability/cytotoxicity assay was used for live/dead cell staining after the applications. The mechanism of this application was further analyzed with the determination of intracellular reactive oxygen species and nitric oxide release. RESULTS The light applications and the photosensitizer alone did not inhibit the cell viability of PC-3 cells. 20 J/cm2 laser energy density together with 100 μM photosensitizer concentration resulted in maximum cancer cell death with a rate of approximately 89 %. The level of intracellular reactive oxygen species increased with the increasing parameters of the applications that resulted in more cell death. CONCLUSION This study showed the successful anticancer activity of toluidine blue ortho upon irradiation with 655 nm of laser light against PC-3 cancer cells and it was mediated with the production of reactive oxygen species.
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Wang X, Gong Q, Song C, Fang J, Yang Y, Liang X, Huang X, Liu J. Berberine-photodynamic therapy sensitizes melanoma cells to cisplatin-induced apoptosis through ROS-mediated P38 MAPK pathways. Toxicol Appl Pharmacol 2021; 418:115484. [PMID: 33716044 DOI: 10.1016/j.taap.2021.115484] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 03/05/2021] [Accepted: 03/06/2021] [Indexed: 12/17/2022]
Abstract
The clinical use of cisplatin are limited due to its drug resistance. Thus, it is urgent to find effective combination therapy that sensitizes tumor cells to this drug. The combined chemo-photodynamic therapy could increase anti-tumor efficacy while also reduce the side effects of cisplatin. Berberine is an isoquinoline alkaloid, which has been reported to show high photosensitizing activity. In this study, we have examined the effect of a combination of cisplatin and berberine-PDT in cisplatin-resistant melanoma cells. The cytotoxic effects of berberine-PDT alone or in combination with cisplatin were tested by MTT assays. We then examined the subcellular localization of berberine with confocal fluorescence microscopy. The percentage of apoptotic cells, the mitochondrial membrane potential (Δψm) and reactive oxygen species (ROS) generation assessed using flow cytometry analysis. Western blotting used in this study to determine the expression levels of MAPK signaling pathways and apoptosis-related proteins. Experimental data revealed that the mode of cell death is the caspase-dependent mitochondrial apoptotic pathways. Excessive accumulation of ROS played a key role in this process, which is confirmed by alleviation of cytotoxicity upon pretreatment with NAC. Furthermore, we found that the combined treatment activated MAPK signaling pathway. The inhibition of p38 MAPK by pretreating with SB203580 block the combined treatment-induced apoptotic cell death. In conclusion, berberine-PDT could be used as a chemo-sensitizer by promoting cell death through activation of a ROS/p38/caspase cascade.
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Affiliation(s)
- Xiaotong Wang
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China
| | - Qianyi Gong
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China
| | - Changfeng Song
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China
| | - Jiaping Fang
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China
| | - Yun Yang
- Department of Pharmacy, School of Medicine, Jiaxing University, Jiaxing, Zhejiang 314001, China
| | - Xin Liang
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China.
| | - Xuan Huang
- Department of Pharmacy, School of Medicine, Jiaxing University, Jiaxing, Zhejiang 314001, China; Natural Medicine and Health Food Research & Technology Innovation Team of Jiaxing, Jiaxing, Zhejiang 314001, China; Jiaxing Key Laboratory of Oncological Photodynamic Therapy and Targeted Drug Research, China.
| | - Jianwen Liu
- State Key Laboratory of Bioreactor Engineering and Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, PR China.
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Dias LM, Sharifi F, de Keijzer MJ, Mesquita B, Desclos E, Kochan JA, de Klerk DJ, Ernst D, de Haan LR, Franchi LP, van Wijk AC, Scutigliani EM, Cavaco JEB, Tedesco AC, Huang X, Pan W, Ding B, Krawczyk PM, Heger M. Attritional evaluation of lipophilic and hydrophilic metallated phthalocyanines for oncological photodynamic therapy. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2021; 216:112146. [PMID: 33601256 DOI: 10.1016/j.jphotobiol.2021.112146] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 01/22/2021] [Accepted: 01/26/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Oncological photodynamic therapy (PDT) relies on photosensitizers (PSs) to photo-oxidatively destroy tumor cells. Currently approved PSs yield satisfactory results in superficial and easy-to-access tumors but are less suited for solid cancers in internal organs such as the biliary system and the pancreas. For these malignancies, second-generation PSs such as metallated phthalocyanines are more appropriate. Presently it is not known which of the commonly employed metallated phtahlocyanines, namely aluminum phthalocyanine (AlPC) and zinc phthalocyanine (ZnPC) as well as their tetrasulfonated derivatives AlPCS4 and ZnPCS4, is most cytotoxic to tumor cells. This study therefore employed an attritional approach to ascertain the best metallated phthalocyanine for oncological PDT in a head-to-head comparative analysis and standardized experimental design. METHODS ZnPC and AlPC were encapsulated in PEGylated liposomes. Analyses were performed in cultured A431 cells as a template for tumor cells with a dysfunctional P53 tumor suppressor gene and EGFR overexpression. First, dark toxicity was assessed as a function of PS concentration using the WST-1 and sulforhodamine B assay. Second, time-dependent uptake and intracellular distribution were determined by flow cytometry and confocal microscopy, respectively, using the intrinsic fluorescence of the PSs. Third, the LC50 values were established for each PS at 671 nm and a radiant exposure of 15 J/cm2 following 1-h PS exposure. Finally, the mode of cell death as a function of post-PDT time and cell cycle arrest at 24 h after PDT were analyzed. RESULTS In the absence of illumination, AlPC and ZnPC were not toxic to cells up to a 1.5-μM PS concentration and exposure for up to 72 h. Dark toxicity was noted for AlPCS4 at 5 μM and ZnPCS4 at 2.5 μM. Uptake of all PSs was observed as early as 1 min after PS addition to cells and increased in amplitude during a 2-h incubation period. After 60 min, the entire non-nuclear space of the cell was photosensitized, with PS accumulation in multiple subcellular structures, especially in case of AlPC and AlPCS4. PDT of cells photosensitized with ZnPC, AlPC, and AlPCS4 yielded LC50 values of 0.13 μM, 0.04 μM, and 0.81 μM, respectively, 24 h post-PDT (based on sulforhodamine B assay). ZnPCS4 did not induce notable phototoxicity, which was echoed in the mode of cell death and cell cycle arrest data. At 4 h post-PDT, the mode of cell death comprised mainly apoptosis for ZnPC and AlPC, the extent of which was gradually exacerbated in AlPC-photosensitized cells during 8 h. ZnPC-treated cells seemed to recover at 8 h post-PDT compared to 4 h post-PDT, which had been observed before in another cell line. AlPCS4 induced considerable necrosis in addition to apoptosis, whereby most of the cell death had already manifested at 2 h after PDT. During the course of 8 h, necrotic cell death transitioned into mainly late apoptotic cell death. Cell death signaling coincided with a reduction in cells in the G0/G1 phase (ZnPC, AlPC, AlPCS4) and cell cycle arrest in the S-phase (ZnPC, AlPC, AlPCS4) and G2 phase (ZnPC and AlPC). Cell cycle arrest was most profound in cells that had been photosensitized with AlPC and subjected to PDT. CONCLUSIONS Liposomal AlPC is the most potent PS for oncological PDT, whereas ZnPCS4 was photodynamically inert in A431 cells. AlPC did not induce dark toxicity at PS concentrations of up to 1.5 μM, i.e., > 37 times the LC50 value, which is favorable in terms of clinical phototoxicity issues. AlPC photosensitized multiple intracellular loci, which was associated with extensive, irreversible cell death signaling that is expected to benefit treatment efficacy and possibly immunological long-term tumor control, granted that sufficient AlPC will reach the tumor in vivo. Given the differential pharmacokinetics, intracellular distribution, and cell death dynamics, liposomal AlPC may be combined with AlPCS4 in a PS cocktail to further improve PDT efficacy.
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Affiliation(s)
- Lionel Mendes Dias
- Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China; CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal; Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
| | - Farangis Sharifi
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands; Laboratory of Experimental Oncology and Radiobiology (LEXOR), Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
| | - Mark J de Keijzer
- Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Barbara Mesquita
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
| | - Emilie Desclos
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands; Laboratory of Experimental Oncology and Radiobiology (LEXOR), Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
| | - Jakub A Kochan
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands; Laboratory of Experimental Oncology and Radiobiology (LEXOR), Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
| | - Daniel J de Klerk
- Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
| | - Daniël Ernst
- Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
| | - Lianne R de Haan
- Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
| | - Leonardo P Franchi
- Departamento de Bioquímica e Biologia Molecular, Instituto de Ciências Biológicas (ICB) 2, Campus Samambaia, Universidade Federal de Goiás (UFG), Goiânia, GO, Brazil; Department of Chemistry, Center of Nanotechnology and Tissue Engineering - Photobiology and Photomedicine Research Group, Faculty of Philosophy, Sciences, and Letters of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Albert C van Wijk
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands
| | - Enzo M Scutigliani
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands; Laboratory of Experimental Oncology and Radiobiology (LEXOR), Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
| | - José E B Cavaco
- CICS-UBI, Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal
| | - Antonio C Tedesco
- Department of Chemistry, Center of Nanotechnology and Tissue Engineering - Photobiology and Photomedicine Research Group, Faculty of Philosophy, Sciences, and Letters of Ribeirão Preto, University of São Paulo, São Paulo, Brazil
| | - Xuan Huang
- Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
| | - Weiwei Pan
- Department of Cell Biology, College of Medicine, Jiaxing University, Jiaxing, PR China
| | - Baoyue Ding
- Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China
| | - Przemek M Krawczyk
- Department of Medical Biology, Cancer Center Amsterdam, Amsterdam UMC, Amsterdam, The Netherlands; Laboratory of Experimental Oncology and Radiobiology (LEXOR), Cancer Center Amsterdam, Academic Medical Center, Amsterdam, The Netherlands
| | - Michal Heger
- Department of Pharmaceutics, Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing, Zhejiang, PR China; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
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Liang P, Kolodieznyi D, Creeger Y, Ballou B, Bruchez MP. Subcellular Singlet Oxygen and Cell Death: Location Matters. Front Chem 2020; 8:592941. [PMID: 33282833 PMCID: PMC7705227 DOI: 10.3389/fchem.2020.592941] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 10/12/2020] [Indexed: 12/16/2022] Open
Abstract
We developed a tool for targeted generation of singlet oxygen using light activation of a genetically encoded fluorogen-activating protein complexed with a unique dye molecule that becomes a potent photosensitizer upon interaction with the protein. By targeting the protein receptor to activate this dye in distinct subcellular locations at consistent per-cell concentrations, we investigated the impact of localized production of singlet oxygen on induction of cell death. We analyzed light dose-dependent cytotoxic response and characterized the apoptotic vs. necrotic cell death as a function of subcellular location, including the nucleus, the cytosol, the endoplasmic reticulum, the mitochondria, and the membrane. We find that different subcellular origins of singlet oxygen have different potencies in cytotoxic response and the pathways of cell death, and we observed that CT26 and HEK293 cell lines are differentially sensitive to mitochondrially localized singlet oxygen stresses. This work provides new insight into the function of type II reactive oxygen generating photosensitizing processes in inducing targeted cell death and raises interesting mechanistic questions about tolerance and survival mechanisms in studies of oxidative stress in clonal cell populations.
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Affiliation(s)
- Pingping Liang
- Molecular Biosensor and Imaging Center, Carnegie Mellon University, Pittsburgh, PA, United States.,Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, United States.,Key Laboratory of Flexible Electronics (KLOFE), Institute of Advanced Materials (IAM), Nanjing Tech University, Nanjing, China
| | - Dmytro Kolodieznyi
- Molecular Biosensor and Imaging Center, Carnegie Mellon University, Pittsburgh, PA, United States.,Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, United States
| | - Yehuda Creeger
- Molecular Biosensor and Imaging Center, Carnegie Mellon University, Pittsburgh, PA, United States
| | - Byron Ballou
- Molecular Biosensor and Imaging Center, Carnegie Mellon University, Pittsburgh, PA, United States
| | - Marcel P Bruchez
- Molecular Biosensor and Imaging Center, Carnegie Mellon University, Pittsburgh, PA, United States.,Department of Chemistry, Carnegie Mellon University, Pittsburgh, PA, United States.,Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
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Photodynamic inactivation of circulating tumor cells: An innovative approach against metastatic cancer. Eur J Pharm Biopharm 2020; 157:38-46. [PMID: 33059005 DOI: 10.1016/j.ejpb.2020.10.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 08/11/2020] [Accepted: 10/08/2020] [Indexed: 12/15/2022]
Abstract
The spread of a primary malignant tumor is the major reason for most of the cancer-associated deaths. To this day, treatment regimen and available drugs are still insufficient to manage these conditions. In this work, a new therapeutic concept based on photodynamic therapy (PDT) of metastasis-initiating cells is introduced. To address this issue, an experimental model was developed to simulate the movement and photodynamic inactivation of circulating tumor cells (CTCs) in vitro. Using curcumin loaded poly(lactic-co-glycolic acid) nanoparticles, a significant reduction in the cell viability of human breast cancer cells (MDA-MB-231) could be achieved after 30 min laser irradiation (λ = 447 nm, P = 100mW) under flow conditions (5 cm s-1). Confocal laser scanning microscopy images confirmed the immediate accumulation of curcumin on the cell membrane and an increased fluorescence signal after irradiation. PDT caused time-dependent morphological cell alterations (i.e. membrane evaginations and disruption) indicating apoptosis and early necrosis. During the photoactivation of curcumin, a blue shift in the absorption spectra and a decrease in the curcumin content could be determined. This study confirms that the presented experimental model is suitable for in vitro investigations of CTCs under in vivo-like conditions, at the same time encouraging the clinical implementation of PDT as an innovative strategy against metastasis.
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Gao H, Shi X, Chen Q, Che B, Yin H, Li Y. Deep proteome profiling of SW837 cells treated by photodynamic therapy (PDT) reveals the underlying mechanisms of metronomic and acute PDTs. Photodiagnosis Photodyn Ther 2020; 31:101809. [PMID: 32437970 DOI: 10.1016/j.pdpdt.2020.101809] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 04/30/2020] [Accepted: 04/30/2020] [Indexed: 11/17/2022]
Abstract
AIM Metronomic photodynamic therapy (mPDT) with a longer irradiation time and lower energy compared with acute (or classic) photodynamic therapy (aPDT) is a more effective treatment than aPDT for tumor cells, especially colorectal cancer. However, the underlying mechanisms of the superior effects of mPDT are unknown. METHODS we used SWATH-MS (sequential window acquisition of all theoretical mass spectra) to identify differentially expressed proteins (DEPs) specific to aPDT (conventional fluence rate, 20 mW/cm2, 4 min 10 s), mPDT (metronomic fluence rate, 0.4 mW/cm2, 3.5 h), and control groups of SW837 cells. The photosensitizer used in both PDT methods was aminolevulinic acid which were incubated with the cells before irradiation. RESULTS A total of 6805 proteins were identified in the three groups of SW837 cells. aPDT induced 333 DEPs and mPDT induced 1716 DEPs compared with the control. We identified 185 common DEPs in the two PDT groups, 148 different DEPs in the aPDT group, and 1531 different DEPs in the mPDT group. Most of the 185 common DEPs were involved in the extracellular component, participated in the processes of vesicle transport and secretion, binding, and hydrolase/catalytic activity. They were also involved in PI3K-Akt, cGMP-PKG, RAS, and aAMP signaling pathways. In addition, the 1531 different DEPs in the mPDT group participated in similar processes and molecular functions, but in a more complex manner than those in the aPDT group. CONCLUSION our proteome data suggest that mPDT has a complex tumor destruction mechanism with more involved proteins compared with aPDT, which may explain the better tumor killing effect of mPDT.
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Affiliation(s)
- Hao Gao
- Department of Colorectal Surgery, Tianjin People's Hospital Tianjin Union Medical Center, 190 Jieyuan Road, Hongqiao District, Tianjin 300121, China
| | - Xiafei Shi
- Laboratory of Laser Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Biomedical Engineering, 236 Baidi Road, Nankai District, Tianjin 300192, China
| | - Qianqian Chen
- Laboratory of Laser Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Biomedical Engineering, 236 Baidi Road, Nankai District, Tianjin 300192, China
| | - Bochen Che
- Laboratory of Laser Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Biomedical Engineering, 236 Baidi Road, Nankai District, Tianjin 300192, China
| | - Huijuan Yin
- Laboratory of Laser Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Biomedical Engineering, 236 Baidi Road, Nankai District, Tianjin 300192, China.
| | - Yingxin Li
- Laboratory of Laser Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College Institute of Biomedical Engineering, 236 Baidi Road, Nankai District, Tianjin 300192, China
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Alberdi E, Gómez C. Methylene blue vs methyl aminolevulinate photodynamic therapy in combination with oral terbinafine in the treatment of severe dermatophytic toenail onychomycosis: Short- and long-term effects. Mycoses 2020; 63:859-868. [PMID: 32506733 DOI: 10.1111/myc.13125] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 05/27/2020] [Accepted: 05/31/2020] [Indexed: 01/10/2023]
Abstract
BACKGROUND Photodynamic therapy (PDT) kills target microorganisms via reactive oxygen species (ROS) production. PDT seems to be a good alternative treatment option for onychomycosis. OBJECTIVE To compare the efficacy of combined therapies based on oral terbinafine (TN) plus adjunctive PDT mediated by methylene blue (MB) (TN + MB/PDT) or methyl aminolevulinate (MAL) (TN + MAL/PDT) in the treatment of onychomycosis. METHODS Twenty patients affected by severe dermatophyte onychomycosis in the nails of the big toe (>60% disease involvement of target nail) received oral TN for 12 weeks and concomitantly were randomly allocated to receive nine sessions, separated by 2-week intervals, of urea (40%) plus a PDT protocol mediated by MB (TN + MB/PDT: group I) or mediated by MAL (TN + MAL/PDT: group II). Clinical and mycological efficacy was evaluated at 16-, 40- and 52-week follow-up. RESULTS Both protocols showed a significant decrease in Onychomycosis Severity Index (OSI) scores (P < .05), from 24.2 ± 4.6 to 0.7 ± 0.6 (group I)) and from 18.5 ± 10.1 to 2.1 ± 2.0 (group II). No side effects or complications were reported in any of the combinations used. Mycological cure rates were significantly higher during the last third of the evaluated period of time, reaching 100% and 90% in group I and group II, respectively, at the 52-week follow-up. In both modalities, complete cure was achieved in 70% of the patients at the 52-week follow-up. CONCLUSIONS TN + MB/PDT and TN + MAL/PDT show similar outcomes in the treatment of toenails with severe onychomycosis. PDT is an effective method to accelerate the TN-mediated healing process.
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Affiliation(s)
| | - Clara Gómez
- Institute of Physical Chemistry Rocasolano, CSIC, Madrid, Spain
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Damke GMZF, Damke E, de Souza Bonfim-Mendonça P, Ratti BA, de Freitas Meirelles LE, da Silva VRS, Gonçalves RS, César GB, de Oliveira Silva S, Caetano W, Hioka N, Souza RP, Consolaro MEL. Selective photodynamic effects on cervical cancer cells provided by P123 Pluronic®-based nanoparticles modulating hypericin delivery. Life Sci 2020; 255:117858. [PMID: 32497635 DOI: 10.1016/j.lfs.2020.117858] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/22/2020] [Accepted: 05/25/2020] [Indexed: 12/24/2022]
Abstract
At present, cervical cancer is the fourth leading cause of cancer among women worldwide with no effective treatment options. In this study we aimed to evaluate the efficacy of hypericin (HYP) encapsulated on Pluronic® P123 (HYP/P123) photodynamic therapy (PDT) in a comprehensive panel of human cervical cancer-derived cell lines, including HeLa (HPV 18-positive), SiHa (HPV 16-positive), CaSki (HPV 16 and 18-positive), and C33A (HPV-negative), compared to a nontumorigenic human epithelial cell line (HaCaT). Were investigated: (i) cell cytotoxicity and phototoxicity, cellular uptake and subcellular distribution; (ii) cell death pathway and cellular oxidative stress; (iii) migration and invasion. Our results showed that HYP/P123 micelles had effective and selective time- and dose-dependent phototoxic effects on cervical cancer cells but not in HaCaT. Moreover, HYP/P123 micelles accumulated in endoplasmic reticulum, mitochondria and lysosomes, resulting in photodynamic cell death mainly by necrosis. HYP/P123 induced cellular oxidative stress mainly via type II mechanism of PDT and inhibited cancer cell migration and invasion mainly via MMP-2 inhibition. Taken together, our results indicate a potentially useful role of HYP/P123 micelles as a platform for HYP delivery to more specifically and effectively treat cervical cancers through PDT, suggesting they are worthy for in vivo preclinical evaluations.
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Affiliation(s)
| | - Edilson Damke
- Department of Clinical Analysis and Biomedicine, Universidade Estadual de Maringá, Av. Colombo, 5790, 87025-210 Maringá, Paraná, Brazil
| | - Patrícia de Souza Bonfim-Mendonça
- Department of Clinical Analysis and Biomedicine, Universidade Estadual de Maringá, Av. Colombo, 5790, 87025-210 Maringá, Paraná, Brazil
| | - Bianca Altrão Ratti
- Department of Basic Health Sciences, Universidade Estadual de Maringá, Av. Colombo, 5790, 87025-210 Maringá, Paraná, Brazil
| | - Lyvia Eloiza de Freitas Meirelles
- Department of Clinical Analysis and Biomedicine, Universidade Estadual de Maringá, Av. Colombo, 5790, 87025-210 Maringá, Paraná, Brazil
| | - Vânia Ramos Sela da Silva
- Department of Clinical Analysis and Biomedicine, Universidade Estadual de Maringá, Av. Colombo, 5790, 87025-210 Maringá, Paraná, Brazil
| | - Renato Sonchini Gonçalves
- Department of Chemistry, Universidade Estadual de Maringá, Av. Colombo, 5790, 87025-210 Maringá, Paraná, Brazil
| | - Gabriel Batista César
- Department of Chemistry, Universidade Estadual de Maringá, Av. Colombo, 5790, 87025-210 Maringá, Paraná, Brazil
| | - Sueli de Oliveira Silva
- Department of Basic Health Sciences, Universidade Estadual de Maringá, Av. Colombo, 5790, 87025-210 Maringá, Paraná, Brazil
| | - Wilker Caetano
- Department of Chemistry, Universidade Estadual de Maringá, Av. Colombo, 5790, 87025-210 Maringá, Paraná, Brazil
| | - Noboru Hioka
- Department of Chemistry, Universidade Estadual de Maringá, Av. Colombo, 5790, 87025-210 Maringá, Paraná, Brazil
| | - Raquel Pantarotto Souza
- Department of Clinical Analysis and Biomedicine, Universidade Estadual de Maringá, Av. Colombo, 5790, 87025-210 Maringá, Paraná, Brazil
| | - Marcia Edilaine Lopes Consolaro
- Department of Clinical Analysis and Biomedicine, Universidade Estadual de Maringá, Av. Colombo, 5790, 87025-210 Maringá, Paraná, Brazil.
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Sorrin AJ, Ruhi MK, Ferlic NA, Karimnia V, Polacheck WJ, Celli JP, Huang HC, Rizvi I. Photodynamic Therapy and the Biophysics of the Tumor Microenvironment. Photochem Photobiol 2020; 96:232-259. [PMID: 31895481 PMCID: PMC7138751 DOI: 10.1111/php.13209] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Accepted: 11/27/2019] [Indexed: 02/07/2023]
Abstract
Targeting the tumor microenvironment (TME) provides opportunities to modulate tumor physiology, enhance the delivery of therapeutic agents, impact immune response and overcome resistance. Photodynamic therapy (PDT) is a photochemistry-based, nonthermal modality that produces reactive molecular species at the site of light activation and is in the clinic for nononcologic and oncologic applications. The unique mechanisms and exquisite spatiotemporal control inherent to PDT enable selective modulation or destruction of the TME and cancer cells. Mechanical stress plays an important role in tumor growth and survival, with increasing implications for therapy design and drug delivery, but remains understudied in the context of PDT and PDT-based combinations. This review describes pharmacoengineering and bioengineering approaches in PDT to target cellular and noncellular components of the TME, as well as molecular targets on tumor and tumor-associated cells. Particular emphasis is placed on the role of mechanical stress in the context of targeted PDT regimens, and combinations, for primary and metastatic tumors.
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Affiliation(s)
- Aaron J. Sorrin
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA
| | - Mustafa Kemal Ruhi
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC and North Carolina State University, Raleigh, NC, 27599, USA
| | - Nathaniel A. Ferlic
- Department of Electrical and Computer Engineering, University of Maryland, College Park, MD, 20742, USA
| | - Vida Karimnia
- Department of Physics, College of Science and Mathematics, University of Massachusetts at Boston, Boston, MA, 02125, USA
| | - William J. Polacheck
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC and North Carolina State University, Raleigh, NC, 27599, USA
- Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA
| | - Jonathan P. Celli
- Department of Physics, College of Science and Mathematics, University of Massachusetts at Boston, Boston, MA, 02125, USA
| | - Huang-Chiao Huang
- Fischell Department of Bioengineering, University of Maryland, College Park, MD, 20742, USA
- Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA
| | - Imran Rizvi
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC and North Carolina State University, Raleigh, NC, 27599, USA
- Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA
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Chen Y, Gao P, Wu T, Pan W, Li N, Tang B. Organelle-localized radiosensitizers. Chem Commun (Camb) 2020; 56:10621-10630. [DOI: 10.1039/d0cc03245j] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
This feature article highlights the recent advances of organelle-localized radiosensitizers and discusses the current challenges and future directions.
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Affiliation(s)
- Yuanyuan Chen
- College of Chemistry
- Chemical Engineering and Materials Science
- Key Laboratory of Molecular and Nano Probes
- Ministry of Education
- Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong
| | - Peng Gao
- College of Chemistry
- Chemical Engineering and Materials Science
- Key Laboratory of Molecular and Nano Probes
- Ministry of Education
- Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong
| | - Tong Wu
- College of Chemistry
- Chemical Engineering and Materials Science
- Key Laboratory of Molecular and Nano Probes
- Ministry of Education
- Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong
| | - Wei Pan
- College of Chemistry
- Chemical Engineering and Materials Science
- Key Laboratory of Molecular and Nano Probes
- Ministry of Education
- Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong
| | - Na Li
- College of Chemistry
- Chemical Engineering and Materials Science
- Key Laboratory of Molecular and Nano Probes
- Ministry of Education
- Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong
| | - Bo Tang
- College of Chemistry
- Chemical Engineering and Materials Science
- Key Laboratory of Molecular and Nano Probes
- Ministry of Education
- Collaborative Innovation Center of Functionalized Probes for Chemical Imaging in Universities of Shandong
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Tsubone TM, Baptista MS, Itri R. Understanding membrane remodelling initiated by photosensitized lipid oxidation. Biophys Chem 2019; 254:106263. [DOI: 10.1016/j.bpc.2019.106263] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 08/13/2019] [Accepted: 09/03/2019] [Indexed: 12/19/2022]
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Ursolic Acid Derivatives as Potential Agents Against Acanthamoeba Spp. Pathogens 2019; 8:pathogens8030130. [PMID: 31443577 PMCID: PMC6789456 DOI: 10.3390/pathogens8030130] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 08/20/2019] [Accepted: 08/21/2019] [Indexed: 11/17/2022] Open
Abstract
The current chemotherapy of Acanthamoeba keratitis relies on few drugs with low potential and limited efficacy, for all this there is an urgent need to identify new classes of anti-Acanthamoeba agents. In this regard, natural products play an important role in overcoming the current need and medicinal chemistry of natural products represents an attractive approach for the discovery and development of new agents. Ursolic acid, a natural pentacyclic triterpenoid compound, possesses a broad spectrum of activities including anti-Acanthamoeba. Herein, we report on the development by chemical transformation of an ursolic acid-based series of seven compounds (2-8), one of them reported for the first time. The structure-activity relationship (SAR) analysis of their anti-Acanthamoeba activity revealed that acylation/ether formation or oxidation enhances their biological profile, suggesting that the hydrophobic moiety contributes to activity, presumably by increasing the affinity and/or cell membrane permeability. These ursolic acid derivatives highlight the potential of this source as a good base for the development of novel therapeutic agents against Acanthamoeba infections.
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Donohoe C, Senge MO, Arnaut LG, Gomes-da-Silva LC. Cell death in photodynamic therapy: From oxidative stress to anti-tumor immunity. Biochim Biophys Acta Rev Cancer 2019; 1872:188308. [PMID: 31401103 DOI: 10.1016/j.bbcan.2019.07.003] [Citation(s) in RCA: 237] [Impact Index Per Article: 39.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 07/25/2019] [Accepted: 07/25/2019] [Indexed: 01/11/2023]
Abstract
Photodynamic therapy is a promising approach for cancer treatment that relies on the administration of a photosensitizer followed by tumor illumination. The generated oxidative stress may activate multiple mechanisms of cell death which are counteracted by cells through adaptive stress responses that target homeostasis rescue. The present renaissance of PDT was leveraged by the acknowledgment that this therapy has an immediate impact locally, in the illumination volume, but that subsequently it may also elicit immune responses with systemic impact. The investigation of the mechanisms of cell death under the oxidative stress of PDT is of paramount importance to understand how the immune system is activated and, ultimately, to make PDT a more appealing/relevant therapeutic option.
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Affiliation(s)
- Claire Donohoe
- CQC, Coimbra Chemistry Center, University of Coimbra, Portugal; Medicinal Chemistry, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, Trinity College Dublin, The University of Dublin, St. James's Hospital, Dublin 8, Ireland
| | - Mathias O Senge
- Medicinal Chemistry, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, Trinity College Dublin, The University of Dublin, St. James's Hospital, Dublin 8, Ireland
| | - Luís G Arnaut
- CQC, Coimbra Chemistry Center, University of Coimbra, Portugal
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Maitra D, Bragazzi Cunha J, Elenbaas JS, Bonkovsky HL, Shavit JA, Omary MB. Porphyrin-Induced Protein Oxidation and Aggregation as a Mechanism of Porphyria-Associated Cell Injury. Cell Mol Gastroenterol Hepatol 2019; 8:535-548. [PMID: 31233899 PMCID: PMC6820234 DOI: 10.1016/j.jcmgh.2019.06.006] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 06/14/2019] [Accepted: 06/14/2019] [Indexed: 12/12/2022]
Abstract
Genetic porphyrias comprise eight diseases caused by defects in the heme biosynthetic pathway that lead to accumulation of heme precursors. Consequences of porphyria include photosensitivity, liver damage and increased risk of hepatocellular carcinoma, and neurovisceral involvement, including seizures. Fluorescent porphyrins that include protoporphyrin-IX, uroporphyrin and coproporphyrin, are photo-reactive; they absorb light energy and are excited to high-energy singlet and triplet states. Decay of the porphyrin excited to ground state releases energy and generates singlet oxygen. Porphyrin-induced oxidative stress is thought to be the major mechanism of porphyrin-mediated tissue damage. Although this explains the acute photosensitivity in most porphyrias, light-induced porphyrin-mediated oxidative stress does not account for the effect of porphyrins on internal organs. Recent findings demonstrate the unique role of fluorescent porphyrins in causing subcellular compartment-selective protein aggregation. Porphyrin-mediated protein aggregation associates with nuclear deformation, cytoplasmic vacuole formation and endoplasmic reticulum dilation. Porphyrin-triggered proteotoxicity is compounded by inhibition of the proteasome due to aggregation of some of its subunits. The ensuing disruption in proteostasis also manifests in cell cycle arrest coupled with aggregation of cell proliferation-related proteins, including PCNA, cdk4 and cyclin B1. Porphyrins bind to native proteins and, in presence of light and oxygen, oxidize several amino acids, particularly methionine. Noncovalent interaction of oxidized proteins with porphyrins leads to formation of protein aggregates. In internal organs, particularly the liver, light-independent porphyrin-mediated protein aggregation occurs after secondary triggers of oxidative stress. Thus, porphyrin-induced protein aggregation provides a novel mechanism for external and internal tissue damage in porphyrias that involve fluorescent porphyrin accumulation.
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Affiliation(s)
- Dhiman Maitra
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan.
| | - Juliana Bragazzi Cunha
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Jared S Elenbaas
- Medical Scientist Training Program, Washington University in St. Louis, St. Louis, Missouri
| | - Herbert L Bonkovsky
- Gastroenterology & Hepatology, and Molecular Medicine & Translational Science, Wake Forest University School of Medicine/NC Baptist Hospital, Winston-Salem, North Carolina
| | - Jordan A Shavit
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, University of Michigan Medical School, Ann Arbor, Michigan
| | - M Bishr Omary
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan; Cell Biology, Faculty of Science and Technology, Åbo Akademi University, Turku, Finland
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Baldea I, Giurgiu L, Teacoe ID, Olteanu DE, Olteanu FC, Clichici S, Filip GA. Photodynamic Therapy in Melanoma - Where do we Stand? Curr Med Chem 2019; 25:5540-5563. [PMID: 29278205 DOI: 10.2174/0929867325666171226115626] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 11/21/2017] [Accepted: 11/29/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Malignant melanoma is one of the most aggressive malignant tumors, with unpredictable evolution. Despite numerous therapeutic options, like chemotherapy, BRAF inhibitors and immunotherapy, advanced melanoma prognosis remains severe. Photodynamic therapy (PDT) has been successfully used as the first line or palliative therapy for the treatment of lung, esophageal, bladder, non melanoma skin and head and neck cancers. However, classical PDT has shown some drawbacks that limit its clinical application in melanoma. OBJECTIVE The most important challenge is to overcome melanoma resistance, due to melanosomal trapping, presence of melanin, enhanced oxidative stress defense, defects in the apoptotic pathways, immune evasion, neoangiogenesis stimulation. METHOD In this review we considered: (1) main signaling molecular pathways deregulated in melanoma as potential targets for personalized therapy, including PDT, (2) results of the clinical studies regarding PDT of melanoma, especially advanced metastatic stage, (3) progresses made in the design of anti-melanoma photosensitizers (4) inhibition of tumor neoangiogenesis, as well as (5) advantages of the derived therapies like photothermal therapy, sonodynamic therapy. RESULTS PDT represents a promising alternative palliative treatment for advanced melanoma patients, mainly due to its minimal invasive character and low side effects. Efficient melanoma PDT requires: (1) improved, tumor targeted, NIR absorbing photosensitizers, capable of inducing high amounts of different ROS inside tumor and vasculature cells, possibly allowing a theranostic approach; (2) an efficient adjuvant immune therapy. CONCLUSION Combination of PDT with immune stimulation might be the key to overcome the melanoma resistance and to obtain better, sustainable clinical results.
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Affiliation(s)
- Ioana Baldea
- Physiology Department, University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania
| | - Lorin Giurgiu
- Physiology Department, University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania
| | - Ioana Diana Teacoe
- Physiology Department, University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania
| | - Diana Elena Olteanu
- Physiology Department, University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania
| | - Florin Catalin Olteanu
- Industrial Engineering and Management Department, Transylvania University, Brasov, Romania
| | - Simona Clichici
- Physiology Department, University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania
| | - Gabriela Adriana Filip
- Physiology Department, University of Medicine and Pharmacy, Iuliu Hatieganu, Cluj-Napoca, Romania
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Fernando W, Rupasinghe HPV, Hoskin DW. Dietary phytochemicals with anti-oxidant and pro-oxidant activities: A double-edged sword in relation to adjuvant chemotherapy and radiotherapy? Cancer Lett 2019; 452:168-177. [PMID: 30910593 DOI: 10.1016/j.canlet.2019.03.022] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Revised: 02/25/2019] [Accepted: 03/08/2019] [Indexed: 12/21/2022]
Abstract
Many advances have been made in the development and introduction of new anti-cancer drugs to the clinic. However, limited attention has been paid to improving the efficacy of currently available treatments through complementary phytochemical interventions that affect cellular reactive oxygen species (ROS) levels, which are important for the etiology of certain cancers and the effectiveness of radiotherapy and some chemotherapy. In this regard, the maintenance of redox homeostasis may be influenced by the intake of anti-oxidant and pro-oxidant compounds from dietary sources. Interestingly, certain dietary phytochemicals exhibit both anti-oxidant and pro-oxidant activities, depending on their concentration and cellular microenvironment. There is evidence that concurrent administration of some dietary phytochemicals enhances the efficacy of certain cancer treatments by increasing intracellular ROS accumulation. Paradoxically, consumption of the same dietary phytochemicals under conditions that result in the scavenging of ROS might also negatively affect the outcome of ROS-dependent cancer treatments. This review discusses the potential impact of consuming dietary phytochemicals with anti-oxidant and/or pro-oxidant activities on the effectiveness of concurrent chemotherapy and/or radiotherapy in cancer patients.
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Affiliation(s)
- Wasundara Fernando
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - H P Vasantha Rupasinghe
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada; Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS, Canada.
| | - David W Hoskin
- Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada; Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada; Department of Surgery, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
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Zhang W, Huang Y, Chen Y, Zhao E, Hong Y, Chen S, Lam JWY, Chen Y, Hou J, Tang BZ. Amphiphilic Tetraphenylethene-Based Pyridinium Salt for Selective Cell-Membrane Imaging and Room-Light-Induced Special Reactive Oxygen Species Generation. ACS APPLIED MATERIALS & INTERFACES 2019; 11:10567-10577. [PMID: 30801178 DOI: 10.1021/acsami.9b00643] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
The cell membrane is the protecting frontier of cells, which is crucial for maintaining cell integrity, and has a close relationship with cell growth and death. There is a growing need for cell membrane imaging and monitoring in both living and dying cells. Herein, we report a new amphiphilic tetraphenylethene-based pyridinium salt (TPE-MEM) with aggregation-induced emission features for discriminatory cell membrane imaging. The fluorogenic probe with high yield was synthesized following asymmetric McMurry reaction, Williamson ether synthesis reaction, Suzuki coupling, and aldol condensation between a double-charged pyridinium salt and hexyloxytetraphenylethene benzaldehyde. TPE-MEM shows good water solubility, biocompatibility, and cell membrane specificity. Interestingly, a reactive oxygen species (ROS) is produced by the molecule (TPE-MEM) under room-light irradiation, which could destroy the integrity of the plasma membrane and cause cell necrosis. This enables a visible observation of cell necrosis and the phototherapeutic effect under a mild condition. Preliminary animal investigations also demonstrated the photodynamic therapy (PDT) effectiveness of TPE-MEM in tumor growth inhibition. We conclude that TPE-MEM is potentially a cell membrane-selective photosensitizer for PDT and it is worthy of further exploration of the phototherapeutic effect on animals systematically.
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Affiliation(s)
- Weijie Zhang
- Department of Urology , The First Affiliated Hospital of Soochow University , 188 Shizi RD , Suzhou 215006 , China
| | - Yuhua Huang
- Department of Urology , The First Affiliated Hospital of Soochow University , 188 Shizi RD , Suzhou 215006 , China
| | - Yilong Chen
- HKUST Shenzhen Research Institute , No. 9 Yuexing 1st RD, South Area, Hi-tech Park Nanshan , Shenzhen 518057 , China
- Department of Chemistry, The Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction and Institute for Advanced Study , The Hong Kong University of Science & Technology , Clear Water Bay, Kowloon, Hong Kong , China
| | - Engui Zhao
- School of Chemical Engineering and Energy Technology , Dongguan University of Technology , 1st University Road, Songshan Lake District , Dongguan 523808 , China
| | - Yuning Hong
- Department of Chemistry and Physics, La Trobe Institute of Molecular Science , La Trobe University , Melbourne , Victoria , Australia 2086
| | - Sijie Chen
- Department of Chemistry, The Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction and Institute for Advanced Study , The Hong Kong University of Science & Technology , Clear Water Bay, Kowloon, Hong Kong , China
| | - Jacky W Y Lam
- Department of Chemistry, The Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction and Institute for Advanced Study , The Hong Kong University of Science & Technology , Clear Water Bay, Kowloon, Hong Kong , China
| | - Yuncong Chen
- Department of Chemistry, The Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction and Institute for Advanced Study , The Hong Kong University of Science & Technology , Clear Water Bay, Kowloon, Hong Kong , China
| | - Jianquan Hou
- Department of Urology , The First Affiliated Hospital of Soochow University , 188 Shizi RD , Suzhou 215006 , China
| | - Ben Zhong Tang
- HKUST Shenzhen Research Institute , No. 9 Yuexing 1st RD, South Area, Hi-tech Park Nanshan , Shenzhen 518057 , China
- Department of Chemistry, The Hong Kong Branch of Chinese National Engineering Research Center for Tissue Restoration and Reconstruction and Institute for Advanced Study , The Hong Kong University of Science & Technology , Clear Water Bay, Kowloon, Hong Kong , China
- Center for Aggregation-Induced Emission, SCUT-HKUST Joint Research Laboratory, State Key Laboratory of Luminescent Materials and Devices , South China University of Technology , Guangzhou 510640 , China
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Ni K, Lan G, Veroneau SS, Duan X, Song Y, Lin W. Nanoscale metal-organic frameworks for mitochondria-targeted radiotherapy-radiodynamic therapy. Nat Commun 2018; 9:4321. [PMID: 30333489 PMCID: PMC6193046 DOI: 10.1038/s41467-018-06655-7] [Citation(s) in RCA: 224] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2018] [Accepted: 09/12/2018] [Indexed: 11/29/2022] Open
Abstract
Selective delivery of photosensitizers to mitochondria of cancer cells can enhance the efficacy of photodynamic therapy (PDT). Though cationic Ru-based photosensitizers accumulate in mitochondria, they require excitation with less penetrating short-wavelength photons, limiting their application in PDT. We recently discovered X-ray based cancer therapy by nanoscale metal-organic frameworks (nMOFs) via enhancing radiotherapy (RT) and enabling radiodynamic therapy (RDT). Herein we report Hf-DBB-Ru as a mitochondria-targeted nMOF for RT-RDT. Constructed from Ru-based photosensitizers, the cationic framework exhibits strong mitochondria-targeting property. Upon X-ray irradiation, Hf-DBB-Ru efficiently generates hydroxyl radicals from the Hf6 SBUs and singlet oxygen from the DBB-Ru photosensitizers to lead to RT-RDT effects. Mitochondria-targeted RT-RDT depolarizes the mitochondrial membrane to initiate apoptosis of cancer cells, leading to significant regression of colorectal tumors in mouse models. Our work establishes an effective strategy to selectively target mitochondria with cationic nMOFs for enhanced cancer therapy via RT-RDT with low doses of deeply penetrating X-rays.
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Affiliation(s)
- Kaiyuan Ni
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA
| | - Guangxu Lan
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA
| | - Samuel S Veroneau
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA
| | - Xiaopin Duan
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA
| | - Yang Song
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA
| | - Wenbin Lin
- Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA.
- Department of Radiation and Cellular Oncology, Ludwig Center for Metastasis Research, The University of Chicago, Chicago, IL, 60637, USA.
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Thompson SA, Aggarwal A, Singh S, Adam AP, Tome JP, Drain CM. Compromising the plasma membrane as a secondary target in photodynamic therapy-induced necrosis. Bioorg Med Chem 2018; 26:5224-5228. [DOI: 10.1016/j.bmc.2018.09.026] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 09/04/2018] [Accepted: 09/21/2018] [Indexed: 01/11/2023]
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Houang J, Perrone G, Mawad D, Boughton PC, Ruys AJ, Lauto A. Light treatments of nail fungal infections. JOURNAL OF BIOPHOTONICS 2018; 11:e201700350. [PMID: 29227574 DOI: 10.1002/jbio.201700350] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 12/07/2017] [Indexed: 06/07/2023]
Abstract
Nail fungal infections are notoriously persistent and difficult to treat which can lead to severe health impacts, particularly in the immunocompromized. Current antifungal treatments, including systemic and topical drugs, are prolonged and do not effectively provide a complete cure. Severe side effects are also associated with systemic antifungals, such as hepatotoxicity. Light treatments of onychomycosis are an emerging therapy that has localized photodynamic, photothermal or photoablative action. These treatments have shown to be an effective alternative to traditional antifungal remedies with comparable or better cure rates achieved in shorter times and without systemic side effects. This report reviews significant clinical and experimental studies in the field, highlighting mechanisms of action and major effects related to light therapy; in particular, the impact of light on fungal genetics.
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Affiliation(s)
- Jessica Houang
- Biomedical Engineering, School of Aerospace, Mechanical and Mechatronic Engineering, University of Sydney, Sydney, NSW, Australia
| | - Gabriel Perrone
- School of Science and Health, Western Sydney University, Penrith, NSW, Australia
| | - Damia Mawad
- School of Materials Science and Engineering, University of New South Wales, Kensington, NSW, Australia
- Australian Centre for NanoMedicine and ARC Centre of Excellence in Convergent BioNano Science and Technology, University of New South Wales, Sydney, NSW, Australia
- Centre for Advanced Macromolecular Design, University of New South Wales, Sydney, NSW, Australia
| | - Philip C Boughton
- Biomedical Engineering, School of Aerospace, Mechanical and Mechatronic Engineering, University of Sydney, Sydney, NSW, Australia
| | - Andrew J Ruys
- Biomedical Engineering, School of Aerospace, Mechanical and Mechatronic Engineering, University of Sydney, Sydney, NSW, Australia
| | - Antonio Lauto
- School of Science and Health, Western Sydney University, Penrith, NSW, Australia
- School of Medicine, Western Sydney University, Penrith, NSW, Australia
- Biomedical Engineering & Neuroscience Research Group, The MARCS Institute, Western Sydney University, Penrith, NSW, Australia
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van Lith SA, van den Brand D, Wallbrecher R, Wübbeke L, van Duijnhoven SM, Mäkinen PI, Hoogstad-van Evert JS, Massuger L, Ylä-Herttuala S, Brock R, Leenders WP. The effect of subcellular localization on the efficiency of EGFR-targeted VHH photosensitizer conjugates. Eur J Pharm Biopharm 2018; 124:63-72. [DOI: 10.1016/j.ejpb.2017.12.009] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2017] [Revised: 12/11/2017] [Accepted: 12/19/2017] [Indexed: 12/19/2022]
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Domagala A, Stachura J, Gabrysiak M, Muchowicz A, Zagozdzon R, Golab J, Firczuk M. Inhibition of autophagy sensitizes cancer cells to Photofrin-based photodynamic therapy. BMC Cancer 2018; 18:210. [PMID: 29463237 PMCID: PMC5819678 DOI: 10.1186/s12885-018-4126-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Accepted: 02/12/2018] [Indexed: 12/16/2022] Open
Abstract
Background Accumulating evidence suggest that autophagy plays a pivotal role in various anticancer therapies, including photodynamic therapy (PDT), acting as a pro-death or pro-survival mechanism in a context-dependent manner. Therefore, we aimed to determine the role of autophagy in Photofrin-based PDT. Methods In vitro cytotoxic/cytostatic effects of PDT were evaluated with crystal violet cell viability assay. Autophagy induction was analyzed by immunoblotting and immunofluorescence using anti-LC3 antibody. Autophagy was inhibited by shRNA-mediated ATG5 knockdown or CRISPR/Cas9-mediated ATG5 knockout. Apoptosis was assessed by flow cytometry analysis of propidium iodide and anexin V-positive cells as well as by detection of cleaved PARP and caspase 3 proteins using immunoblotting. Protein carbonylation was evaluated by the 2,4-dinitrophenylhydrazine (DNPH) method. Results Photofrin-PDT leads to robust autophagy induction in two cancer cell lines, Hela and MCF-7. shRNA-mediated knockdown of ATG5 only partially blocks autophagic response and only marginally affects the sensitivity of Hela and MCF-7 cells to PDT. ATG5 knockout in HeLa cell line utilizing CRISPR/Cas9 genome editing results in increased PDT-mediated cytotoxicity, which is accompanied by an enhanced apoptotic response and increased accumulation of carbonylated proteins. Conclusions Altogether, these observations imply that autophagy contributes to Photofrin-PDT resistance by enabling clearance of carbonylated and other damaged proteins. Therefore, autophagy inhibition may serve as a strategy to improve PDT efficacy.
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Affiliation(s)
- Antoni Domagala
- Department of Immunology, Medical University of Warsaw, 1A Banacha Str., F building, 02-097, Warsaw, Poland
| | - Joanna Stachura
- Department of Immunology, Medical University of Warsaw, 1A Banacha Str., F building, 02-097, Warsaw, Poland.,Postgraduate School of Molecular Medicine, Warsaw, Poland
| | - Magdalena Gabrysiak
- Department of Immunology, Medical University of Warsaw, 1A Banacha Str., F building, 02-097, Warsaw, Poland.,Immunity&Cancer Laboratory, The Francis Crick Institute, London, UK
| | - Angelika Muchowicz
- Department of Immunology, Medical University of Warsaw, 1A Banacha Str., F building, 02-097, Warsaw, Poland
| | - Radoslaw Zagozdzon
- Department of Immunology, Medical University of Warsaw, 1A Banacha Str., F building, 02-097, Warsaw, Poland.,Department of Clinical Immunology, Transplantation Institute, Medical University of Warsaw, Warsaw, Poland.,Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Jakub Golab
- Department of Immunology, Medical University of Warsaw, 1A Banacha Str., F building, 02-097, Warsaw, Poland.,Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland
| | - Malgorzata Firczuk
- Department of Immunology, Medical University of Warsaw, 1A Banacha Str., F building, 02-097, Warsaw, Poland.
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Inai M, Honda N, Hazama H, Akter S, Fuse S, Nakamura H, Nishikawa T, Kaneda Y, Awazu K. Photodynamic therapy using a cytotoxic photosensitizer porphyrus envelope that targets the cell membrane. Photodiagnosis Photodyn Ther 2017; 20:238-245. [DOI: 10.1016/j.pdpdt.2017.10.017] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 10/17/2017] [Accepted: 10/20/2017] [Indexed: 01/10/2023]
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Raza MH, Siraj S, Arshad A, Waheed U, Aldakheel F, Alduraywish S, Arshad M. ROS-modulated therapeutic approaches in cancer treatment. J Cancer Res Clin Oncol 2017; 143:1789-1809. [PMID: 28647857 DOI: 10.1007/s00432-017-2464-9] [Citation(s) in RCA: 201] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2017] [Accepted: 06/16/2017] [Indexed: 02/08/2023]
Abstract
PURPOSE Reactive oxygen species (ROS) are produced in cancer cells as a result of increased metabolic rate, dysfunction of mitochondria, elevated cell signaling, expression of oncogenes and increased peroxisome activities. Certain level of ROS is required by cancer cells, above or below which lead to cytotoxicity in cancer cells. This biochemical aspect can be exploited to develop novel therapeutic agents to preferentially and selectively target cancer cells. METHODS We searched various electronic databases including PubMed, Web of Science, and Google Scholar for peer-reviewed english-language articles. Selected articles ranging from research papers, clinical studies, and review articles on the ROS production in living systems, its role in cancer development and cancer treatment, and the role of microbiota in ROS-dependent cancer therapy were analyzed. RESULTS This review highlights oxidative stress in tumors, underlying mechanisms of different relationships of ROS and cancer cells, different ROS-mediated therapeutic strategies and the emerging role of microbiota in cancer therapy. CONCLUSION Cancer cells exhibit increased ROS stress and disturbed redox homeostasis which lead to ROS adaptations. ROS-dependent anticancer therapies including ROS scavenging anticancer therapy and ROS boosting anticancer therapy have shown promising results in vitro as well as in vivo. In addition, response to cancer therapy is modulated by the human microbiota which plays a critical role in systemic body functions.
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Affiliation(s)
- Muhammad Hassan Raza
- Department of Bioinformatics and Biotechnology, International Islamic University, Sector H-10, Islamabad, 44000, Pakistan.
| | - Sami Siraj
- Institute of Basic Medical Sciences, Khyber Medical University (KMU), Peshawar, 25000, Pakistan
| | - Abida Arshad
- Department of Biology, PMAS-Arid Agriculture University, Rawalpindi, 46000, Pakistan
| | - Usman Waheed
- Department of Pathology and Blood Bank, Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad, 44000, Pakistan
| | - Fahad Aldakheel
- Department of Clinical Laboratory Medicine, College of Applied Medical Sciences, King Saud University, Riyadh, 11564, Saudi Arabia
| | - Shatha Alduraywish
- Department of Family and Community Medicine, College of Medicine, King Saud University, Riyadh, 11564, Saudi Arabia
| | - Muhammad Arshad
- Department of Bioinformatics and Biotechnology, International Islamic University, Sector H-10, Islamabad, 44000, Pakistan
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50
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Sifaoui I, Reyes-Batlle M, López-Arencibia A, Wagner C, Chiboub O, De Agustino Rodríguez J, Rocha-Cabrera P, Valladares B, Piñero JE, Lorenzo-Morales J. Evaluation of the anti-Acanthamoeba activity of two commercial eye drops commonly used to lower eye pressure. Exp Parasitol 2017; 183:117-123. [PMID: 28778743 DOI: 10.1016/j.exppara.2017.07.012] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 06/28/2017] [Accepted: 07/30/2017] [Indexed: 11/25/2022]
Abstract
Efficient treatments against Acanthamoeba Keratitis (AK), remains until the moment, as an issue to be solved due to the existence of a cyst stage which is highly resistant to most chemical and physical agents. In this study, two antiglaucoma eye drops were tested for their activity against Acanthamoeba. Moreover, this study was based on previous data which gave us evidence of a possible link between the absences of Acanthamoeba at the ocular surface in patients treated with beta blockers for high eye pressure both containing timolol as active principle. The amoebicidal activity of the tested eye drops was evaluated against four strains of Acanthamoeba using Alamar blue method. For the most active drug the cysticidal activity against A. castellanii Neff cysts and further experiments studying changes in chromatin condensation levels, in the permeability of the plasmatic membrane, the mitochondrial membrane potential and the ATP levels in the treated amoebic strains were done. Even though both eye drops were active against the different tested strains of Acanthamoeba, statistical analysis revealed that one of them (Timolol Sandoz) was the most effective one against all the tested strains presenting IC50s ranging from 0.529% ± 0.206 for the CLC 16 strain to 3.962% ± 0.150 for the type strain Acanthamoeba castellanii Neff. Timolol Sandoz 0.50% seems to induce amoebic cell death by damaging the amoebae at the mitochondrial level. Considering its effect, Timolol Sandoz 0.50% could be used in the case of contact lens wearers and patients with glaucoma.
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Affiliation(s)
- Ines Sifaoui
- University Institute of Tropical Diseases and Public Health, University of La Laguna, Avda Francisco Sanchez s/n, Campus de Anchieta, 38271 la Laguna Tenerife, Canary Islands, Spain; Laboratoire Matériaux-Molécules et Applications, IPEST, B.P 51 2070, LA Marsa, University of Carthage, Tunisia.
| | - María Reyes-Batlle
- University Institute of Tropical Diseases and Public Health, University of La Laguna, Avda Francisco Sanchez s/n, Campus de Anchieta, 38271 la Laguna Tenerife, Canary Islands, Spain
| | - Atteneri López-Arencibia
- University Institute of Tropical Diseases and Public Health, University of La Laguna, Avda Francisco Sanchez s/n, Campus de Anchieta, 38271 la Laguna Tenerife, Canary Islands, Spain
| | - Carolina Wagner
- University Institute of Tropical Diseases and Public Health, University of La Laguna, Avda Francisco Sanchez s/n, Campus de Anchieta, 38271 la Laguna Tenerife, Canary Islands, Spain; Catédra de Parasitologia, Facultad de Medicina, Escuela de Bioanalisis, Universidad Central de Venezuela, Caracas, Venezuela
| | - Olfa Chiboub
- University Institute of Tropical Diseases and Public Health, University of La Laguna, Avda Francisco Sanchez s/n, Campus de Anchieta, 38271 la Laguna Tenerife, Canary Islands, Spain; Catédra de Parasitologia, Facultad de Medicina, Escuela de Bioanalisis, Universidad Central de Venezuela, Caracas, Venezuela
| | - Jacqueline De Agustino Rodríguez
- University Institute of Tropical Diseases and Public Health, University of La Laguna, Avda Francisco Sanchez s/n, Campus de Anchieta, 38271 la Laguna Tenerife, Canary Islands, Spain; Department of Ophthalmology, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain
| | - Pedro Rocha-Cabrera
- University Institute of Tropical Diseases and Public Health, University of La Laguna, Avda Francisco Sanchez s/n, Campus de Anchieta, 38271 la Laguna Tenerife, Canary Islands, Spain; Department of Ophthalmology, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain
| | - Basilio Valladares
- University Institute of Tropical Diseases and Public Health, University of La Laguna, Avda Francisco Sanchez s/n, Campus de Anchieta, 38271 la Laguna Tenerife, Canary Islands, Spain
| | - José E Piñero
- University Institute of Tropical Diseases and Public Health, University of La Laguna, Avda Francisco Sanchez s/n, Campus de Anchieta, 38271 la Laguna Tenerife, Canary Islands, Spain
| | - Jacob Lorenzo-Morales
- University Institute of Tropical Diseases and Public Health, University of La Laguna, Avda Francisco Sanchez s/n, Campus de Anchieta, 38271 la Laguna Tenerife, Canary Islands, Spain
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