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Zhang Y, Zhou J, Wang Y, Wu Y, Li Y, Wang B, Liu G, Gong Q, Luo K, Jing J. Stimuli-responsive polymer-dasatinib prodrug to reprogram cancer-associated fibroblasts for boosted immunotherapy. J Control Release 2025; 381:113606. [PMID: 40054628 DOI: 10.1016/j.jconrel.2025.113606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Revised: 03/02/2025] [Accepted: 03/04/2025] [Indexed: 03/17/2025]
Abstract
The barriers from cancer-associated fibroblasts (CAFs) have diminished the clinical efficacy of immunotherapy for triple-negative breast cancer (TNBC). The obstacles from CAFs often result in poor drug penetration, constrained cytotoxic T lymphocyte infiltration, and an immunosuppressive microenvironment. Herein, chondroitin sulfate (CS) was engineered to conjugate dasatinib (DAS), a tyrosine kinase inhibitor, via the cathepsin B (CTSB)-responsive GFLG linker to produce CS-GFLG-DAS (CGD), which could be employed to reverse the CAF phenotype and regulate the biosynthesis of extracellular matrix (ECM), thus enhancing the efficacy of immune checkpoint blockade (ICB) therapy. Upon reaching the tumor site, DAS released from CGD in response to overexpressed CTSB in the tumor microenvironment could transform CAFs into a quiescent state instead of killing them to prevent CAFs from producing abundant ECM, thereby promoting deep penetration of CGD to effectively kill tumor cells. In addition, ECM remodeling facilitated tumor infiltration of cytotoxic T lymphocytes, synergistically enhancing the anti-PD-1 efficacy in the 4T1 tumor-bearing mice. In summary, this prodrug enhanced deep drug penetration and therapeutic sensitivity of anti-PD-1 by regulating CAFs, providing new insights into optimizing immunotherapy in treating fibrotic tumors via nanomedicine.
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Affiliation(s)
- Yuxin Zhang
- Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Breast Center, Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jie Zhou
- Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Breast Center, Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yiyan Wang
- Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Breast Center, Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yaping Wu
- Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Breast Center, Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Yunkun Li
- Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Breast Center, Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Bing Wang
- Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Breast Center, Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Guohao Liu
- Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Breast Center, Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qiyong Gong
- Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Breast Center, Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Functional and Molecular Imaging Key Laboratory of Sichuan Province, NHC Key Laboratory of Transplant Engineering and Immunology, Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China; Xiamen Key Lab of Psychoradiology and Neuromodulation, Department of Radiology, West China Xiamen Hospital of Sichuan University, Xiamen 361021, China
| | - Kui Luo
- Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Breast Center, Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Functional and Molecular Imaging Key Laboratory of Sichuan Province, NHC Key Laboratory of Transplant Engineering and Immunology, Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China.
| | - Jing Jing
- Department of Radiology, Huaxi MR Research Center (HMRRC), Institution of Radiology and Medical Imaging, Breast Center, Institute of Breast Health Medicine, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
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Delavari B, Bigdeli B, Khazeni S, Varamini P. Nanodiamond-Protein hybrid Nanoparticles: LHRH receptor targeted and co-delivery of doxorubicin and dasatinib for triple negative breast cancer therapy. Int J Pharm 2025; 675:125544. [PMID: 40187703 DOI: 10.1016/j.ijpharm.2025.125544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 03/28/2025] [Accepted: 03/29/2025] [Indexed: 04/07/2025]
Abstract
Triple Negative Breast Cancer (TNBC) is an aggressive type of breast cancer that is difficult to treat with conventional therapies. This study aimed to develop a novel therapeutic approach using a multifunctional protein-nanodiamond nanocomposite to co-deliver doxorubicin (DOX) and dasatinib (DAS) to cancer cells via luteinising hormone-releasing hormone receptors. Nanodiamonds help retain DOX in targeted cells, while α-lactalbumin efficiently encapsulates DAS, reducing side effects. We successfully formulated the nanocomposite with over 80 % drug loading efficiency for both drugs. The imine Schiff-base bond in the nanocomposite hydrolyzes in the acidic pH tumor environment, triggering approximately 65 % drug release after 72 h, compared to less than 20 % in neutral pH. In vitro studies showed enhanced uptake of DOX and DAS in TNBC cell lines, potentially overcoming drug resistance. The combined delivery showed enhanced synergistic cytotoxic effects in drug-resistant TNBC cell models. For example, in the MDA-MB-231 cell line, the IC50 of DOX dropped to 45.63 ng/ml, while in MDA-MB-468, DAS decreased to 35.85 ng/ml with nanoparticle therapy. In vivo experiments utilizing a TNBC mouse model demonstrated the therapeutic effectiveness of the nanocomposite, leading to a 55 % reduction in tumor growth and enhanced survival rates. All mice given the nanocomposite survived after 44 days, but most treated with the DOX/DAS mixture died by day 28. This research showcases multifunctional nanocomposites as targeted drug delivery systems for TNBC, improving drug uptake and cytotoxicity. This strategy presents a promising method for treating drug-resistant breast cancer, with potential clinical applications and synergy with other therapies.
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Affiliation(s)
- Behdad Delavari
- School of Biomedical Science, Faculty of Medicine and Health, University of New South Wales, 2052 NSW, Australia; School of Pharmacy, Faculty of Medicine and Health, University of Sydney, 2006 NSW, Australia.
| | - Bahareh Bigdeli
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, 2006 NSW, Australia.
| | - Sepideh Khazeni
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, 2006 NSW, Australia.
| | - Pegah Varamini
- School of Pharmacy, Faculty of Medicine and Health, University of Sydney, 2006 NSW, Australia; Nano Institute, University of Sydney, 2006 NSW, Australia.
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Madineh H, Mansourinia F, Zarrintaj P, Poostchi M, Gnatowski P, Kucinska-Lipka J, Ghaffari M, Hasanin MS, Chapi S, Yazdi MK, Ashrafizadeh M, Bączek T, Saeb MR, Wang G. Stimuli-responsive delivery systems using carbohydrate polymers: A review. Int J Biol Macromol 2025; 310:142648. [PMID: 40174846 DOI: 10.1016/j.ijbiomac.2025.142648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Revised: 03/08/2025] [Accepted: 03/27/2025] [Indexed: 04/04/2025]
Abstract
Carbohydrate polymers, including Chitosan, Cellulose, Starch, Dextran, Pectin, Alginate, and Hyaluronic Acid, have been considered as stimuli-responsive biopolymers demonstrating significant potential for drug delivery approaches. Relying on the specific design and fabrication, such biopolymers are able to respond to fluctuations in pH, temperature, or enzymatic activity. This review investigates stimuli-responsive biopolymers, known as carbohydrate polymers, mainly chitosan, cellulose, and alginate, utilized as drug delivery approaches, emphasizing that these stimuli-responsive biopolymers accelerate controlled drug release. The pH-responsive delivery systems selectively target acidic tumor microenvironments, while temperature-responsive materials provide precise control for drug release produced by hyperthermia. Light-responsive biopolymers provide spatial and temporal control, providing appropriate for targeted therapy. Redox-responsive structures are especially efficient in responding to elevated glutathione (GSH) in tumor microenvironment, facilitating targeted drug release. Electro- and magnetic-responsive systems provide remote control functionalities, improving the accuracy of drug administration. The incorporation of multi-stimuli-responsive mechanisms implies a remarkable progression in drug delivery, providing a more versatile and adaptable framework for therapeutic applications. Accordingly, the future research on carbohydrate polymer-based stimuli-responsive delivery systems should focus on improving the responsiveness and targeting efficacy through complicated optimization of features and performance of carbohydrate polymers, where the integration of multifunctional moieties facilitates transformation of targeted drugs for broader biological functions.
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Affiliation(s)
- Hossein Madineh
- Polymer Engineering Department, Chemical Engineering Faculty, Tarbiat Modares University, Tehran, Iran
| | - Fatemeh Mansourinia
- Polymer Engineering Department, Chemical Engineering Faculty, Tarbiat Modares University, Tehran, Iran
| | | | - Maryam Poostchi
- Department of Polymer Technology, Faculty of Chemistry, Gdańsk University of Technology, Gabriela Narutowicza 11/12, 80-233 Gdańsk, Poland
| | - Przemysław Gnatowski
- Department of Polymer Technology, Faculty of Chemistry, Gdańsk University of Technology, Gabriela Narutowicza 11/12, 80-233 Gdańsk, Poland; Department of Environmental Toxicology, Faculty of Health Sciences with the Institute of Maritime and Tropical Medicine, Medical University of Gdańsk, Dębowa 23A, Gdańsk 80-204, Poland.
| | - Justyna Kucinska-Lipka
- Department of Polymer Technology, Faculty of Chemistry, Gdańsk University of Technology, Gabriela Narutowicza 11/12, 80-233 Gdańsk, Poland
| | - Mehdi Ghaffari
- Polymer Group, Faculty of Technical and Engineering, Golestan University, P. O. Box 155, Gorgan, Golestan, Iran
| | - Mohamed S Hasanin
- Cellulose and Paper Department, National Research Centre, 33 El Bohouth St., Cairo 12622, Egypt; Department of Polymer and Biomaterials Science, West Pomeranian University of Technology in Szczecin, Al. Piastow 45, 70-311 Szczecin, Poland
| | - Sharanappa Chapi
- Department of Physics, B.M.S. College of Engineering, Basavanagudi - 560019, Bengaluru, Karnataka, India
| | - Mohsen Khodadadi Yazdi
- Division of Electrochemistry and Surface Physical Chemistry, Faculty of Applied Physics and Mathematics, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdańsk, Poland; Advanced Materials Center, Gdańsk University of Technology, Narutowicza 11/12, 80-233 Gdańsk, Poland
| | - Milad Ashrafizadeh
- Department of Radiation Oncology and Shandong Provincial Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China
| | - Tomasz Bączek
- Department of Pharmaceutical Chemistry, Medical University of Gdańsk, J. Hallera 107, 80-416 Gdańsk, Poland
| | - Mohammad Reza Saeb
- Department of Pharmaceutical Chemistry, Medical University of Gdańsk, J. Hallera 107, 80-416 Gdańsk, Poland.
| | - Guizhen Wang
- Department of Emergency, Shanghai Tenth People's Hospital, School of Medicine Tongji University, Shanghai 200072, China.
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Yang C, Liu P. Structural aspects of dimeric prodrug-based carrier-free nanomedicines for tumor chemotherapy. J Mater Chem B 2025; 13:3292-3294. [PMID: 39980397 DOI: 10.1039/d4tb02850c] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
The effect of flexible linker length in dimeric prodrugs was explained through their aggregation structures, as revealed by molecular dynamics simulations. The results indicated that the aggregation structure of the dimeric prodrug was controlled by the molecular structure (mainly flexible linkers) as an internal factor and the fabrication methods as an external factor.
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Affiliation(s)
- Chen Yang
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
| | - Peng Liu
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
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Vakilzadeh H, Varshosaz J, Dinari M, Mirian M, Soghrati S. Co-delivery of Interferon Regulatory Factor 5 (IRF5) siRNA and dasatinib by a disulfide bond bearing polymeric carrier for enhanced anti-inflammatory effects. Int J Biol Macromol 2024; 282:137094. [PMID: 39486736 DOI: 10.1016/j.ijbiomac.2024.137094] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Revised: 10/23/2024] [Accepted: 10/29/2024] [Indexed: 11/04/2024]
Abstract
Co-delivery of chemical drugs and nucleic acids has attracted a great interest recently for treatment of inflammatory diseases. Dasatinib (DB), a tyrosine kinase inhibitor with anti-cancer effects, and Interferon Regulatory Factor 5 (IRF5) siRNA have shown anti-inflammatory effects. In the present study, a novel redox-responsive polymeric micelle was designed for co-delivery of DB and IRF5 siRNA-expressing plasmid (psiRF5) to enhance anti-inflammatory effects on macrophages. psiRF5 was condensed efficiently to redox-responsive micelles of DB-conjugated chitosan (CN) composed of disulfide bond, from different molecular weights of CN to form CN-SS-DB/psiRF5 micelles. The micelles with optimum N/P ratios had particle sizes of 287.8 and 245.4 nm and positive zeta potentials. The disulfide bond bearing micelles showed a redox-responsive drug release, protected the plasmid from being dissociated or degraded in exposure with heparin, serum and DNase I, and significantly enhanced the transfection efficiency and IRF5-gene silencing compared to naked psiRF5. The optimum micelles exhibited a dramatic reduction in IRF5 expression and revealed a notably higher anti-inflammatory effect than either DB or psiRF5, as indicated by more IL-10 and less IL-6 and TNF-α production by LPS-stimulated RAW264.7 macrophages incubated with the co-delivery system. The resultant nanocarriers might be promising for more effective treatment of inflammatory diseases.
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Affiliation(s)
- Hamed Vakilzadeh
- Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Jaleh Varshosaz
- Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Mohammad Dinari
- Department of Chemistry, Isfahan University of Technology, Isfahan, Iran.
| | - Mina Mirian
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Science, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Sahel Soghrati
- Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
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Albulaihed Y, Mishra P, Saeed M, Alabdallah NM, Ginawi T, Ansari IA. Biogenically synthesized gold nanocarrier ameliorated antiproliferative and apoptotic efficacy of doxorubicin against lung cancer. Front Pharmacol 2024; 15:1438237. [PMID: 39534088 PMCID: PMC11555439 DOI: 10.3389/fphar.2024.1438237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 10/02/2024] [Indexed: 11/16/2024] Open
Abstract
Introduction Conventional chemotherapy treatment is commonly linked to significant side effects due to high therapeutic doses. In this regard, nanoformulations with chemotherapeutic medications hold promise in enhancing drug effectiveness through the reduction of therapeutic dosages, thereby mitigating the potential for adverse side effects. Because of numerous applications in the biomedical arena, there has been a rising interest in developing an environmentally acceptable, long-lasting, and affordable technique for the production of gold nanoparticles. In this particular context, the incorporation of plant extracts in the production of metallic nanoparticles has garnered the interest of numerous scholars. Here, we report the synthesis of gold particles by the green method using Cannabis sativa L. leaf extract and their conjugation with doxorubicin. Methods The gold nanoparticles were synthesized by using Cannabis sativa extract and were characterized with various biophysical techniques. Subsequently, gold nanoparticles were conjugated with doxorubicin and their efficacy was tested on A549 cells. Results and Discussion The biogenic synthesis of gold nanoparticles was ascertained through an absorption peak at a wavelength of 524 nm, and it was shifted to 527 nm when conjugated with doxorubicin. Nanoparticles were found to be stable exhibiting a zeta potential value of -20.1 mV, and it changed to -12.7 mV when loaded with doxorubicin. The hydrodynamic diameter of nanoparticles was determined to be 45.64 nm and it was increased to 58.95 nm when conjugated with the drug. The average size of nanoparticles analyzed by TEM was found to be approximately 17.2 nm, while it was 23.5 nm in the case of drug-nanoconjugate. Moreover, there was a significant amelioration in the antiproliferative potential of doxorubicin against lung cancer A549 cells when delivered with gold nanocarrier, which was evident by the lower IC50 and IC75 values of drug-nanoconjugates in comparison to drug alone. Furthermore, the inhibitory effect of drug-nanoconjugates and drug alone was characterized by alteration in the cell morphology, nuclear condensation, increased production of reactive oxygen species, abrogation of mitochondrial membrane potential, and enhanced caspase activities in A549 cells. In sum, our results suggested enhanced efficacy of doxorubicin-gold nanoconjugates, indicating effective delivery of doxorubicin inside the cell by gold nanoparticles.
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Affiliation(s)
- Yazeed Albulaihed
- Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia
| | - Prakriti Mishra
- Department of Biosciences, Integral University, Lucknow, India
| | - Mohd Saeed
- Department of Biology, College of Science, University of Hail, Hail, Saudi Arabia
| | - Nadiyah M. Alabdallah
- Department of Biology, College of Science, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
- Basic and Applied Scientific Research Centre, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Tarig Ginawi
- Department of Biochemistry, College of Medicine, University of Hail, Hail, Saudi Arabia
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Wang H, Gong F, Liu J, Xiang L, Hu Y, Che W, Li R, Yang S, Zhuang Q, Teng X. Engineering Docetaxel Micelles for Enhanced Cancer Therapy Through Intermolecular Forces. Bioengineering (Basel) 2024; 11:1078. [PMID: 39593738 PMCID: PMC11591415 DOI: 10.3390/bioengineering11111078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Revised: 10/17/2024] [Accepted: 10/24/2024] [Indexed: 11/28/2024] Open
Abstract
Docetaxel has exhibited excellent therapeutic effects in cancer treatment; however, its hydrophobicity, short blood circulation time, and high blood toxicity restrict its clinical application. The use of mPEG-PLA micelles to deliver docetaxel into the body has been verified as an effective approach to enhance its therapeutic efficacy. However, mPEG-PLA micelles are easily disassembled in the bloodstream, which can easily lead to premature drug release. To broaden the application scenarios of mPEG PLA micelles, we utilized the π-π stacking effect as an intermolecular force to design a novel mPEG-PLA-Lys(Fmoc) micelle to enhance the blood stability and permeability of drug-loaded micelles. The result showed that drug-loaded micelles for injection did not alter the tissue selectivity of docetaxel. Intravenous injection of the micelles in nude mice showed better antitumor efficacy than docetaxel injection and tumor recurrence rate is 0%, which is significantly lower than that of docetaxel injection (100%). The micelles designed by this research institute are anticipated to improve the clinical therapeutic effect of docetaxel.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Xin Teng
- National Material Experimental Teaching Demonstration Center, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China (Q.Z.)
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Yang C, Liu P. Regulating Drug Release Performance of Acid-Triggered Dimeric Prodrug-Based Drug Self-Delivery System by Altering Its Aggregation Structure. Molecules 2024; 29:3619. [PMID: 39125024 PMCID: PMC11313937 DOI: 10.3390/molecules29153619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 07/24/2024] [Accepted: 07/26/2024] [Indexed: 08/12/2024] Open
Abstract
Dimeric prodrugs have been investigated intensely as carrier-free drug self-delivery systems (DSDSs) in recent decades, and their stimuli-responsive drug release has usually been controlled by the conjugations between the drug molecules, including the stimuli (pH or redox) and responsive sensitivity. Here, an acid-triggered dimeric prodrug of doxorubicin (DOX) was synthesized by conjugating two DOX molecules with an acid-labile ketal linker. It possessed high drug content near the pure drug, while the premature drug leakage in blood circulation was efficiently suppressed. Furthermore, its aggregation structures were controlled by fabricating nanomedicines via different approaches, such as fast precipitation and slow self-assembly, to regulate the drug release performance. Such findings are expected to enable better anti-tumor efficacy with the desired drug release rate, beyond the molecular structure of the dimeric prodrug.
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Affiliation(s)
| | - Peng Liu
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China;
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Li Y, Xie J, Du X, Chen Y, Wang C, Liu T, Yi Z, Wang Y, Zhao M, Li X, Shi S. Oridonin, a small molecule inhibitor of cancer stem cell with potent cytotoxicity and differentiation potential. Eur J Pharmacol 2024; 975:176656. [PMID: 38754536 DOI: 10.1016/j.ejphar.2024.176656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 05/10/2024] [Accepted: 05/14/2024] [Indexed: 05/18/2024]
Abstract
Cancer stem cells (CSCs) drive malignant tumor progression, recurrence, and metastasis with unique characteristics, including self-renewal and resistance to conventional treatments. Conventional differentiation inducers, although promising, have limited cytotoxicity and may inadvertently enhance CSC stemness. To address these challenges, ongoing efforts are dedicated to developing strategies that can effectively combine both cytotoxicity and differentiation-inducing effects. In this study, we introduce oridonin (Ori), a small molecule with dual differentiation-inducing and cytotoxicity properties capable of eliminating tumor CSCs. We isolated CSCs in B16F10 cells using the Hoechst side population method and assessed the differentiation effect of Ori. Ori's differentiation-inducing effect was further evaluated using human acute promyelocytic leukemia. The cytotoxic potential of Ori against MCF-7 and B16F10 cell lines was assessed through various methods. In vivo anti-tumor and anti-CSC efficacy of Ori was investigated using mouse melanoma and CSCs melanoma models. Safety evaluation included zebrafish embryotoxicity and mouse acute toxicity experiments. As a result, Ori effectively dismantles tumorspheres, inhibits proliferation, and reduces the expression of CSC-specific markers. It induces significant differentiation, especially in the case of NB4. Additionally, Ori upregulates TP53 expression, mitigates the hypoxic tumor microenvironment, suppresses stemness, and inhibits PD-L1 expression, prompting a robust anti-cancer immune response. Ori demonstrates pronounced cytotoxicity, inducing notable pro-apoptotic effects on B16F10 and MCF-7 cells, with specific triggering of mitochondrial apoptosis. Importantly, Ori maintains a commendable biosafety record. The dual-action prowess of Ori not only induces the differentiation of CSCs but also dispatches differentiated and residual tumor cells, effectively thwarting the relentless march of tumor progression.
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Affiliation(s)
- Yuke Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinjin Xie
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xin Du
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Chuan Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tiantian Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhiwen Yi
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yue Wang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Mengnan Zhao
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaofang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
| | - Sanjun Shi
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
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Yang C, Liu P. Disulfide/α-Amide-Bridged Doxorubicin Dimeric Prodrug: Effect of Aggregation Structures on pH/GSH Dual-Triggered Drug Release. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2024; 40:11098-11105. [PMID: 38739904 DOI: 10.1021/acs.langmuir.4c00663] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Disulfide bonding has attracted intense interest in the tumor intracellular microenvironment-activated drug delivery systems (DDSs) in the last decades. Although various molecular structures of redox-responsive disulfide-containing DDSs have been developed, no investigation was reported on the effect of aggregation structures. Here, the effect of aggregation structures on pH/GSH dual-triggered drug release was investigated with the simplest pH/GSH dual-triggered doxorubicin-based drug self-delivery system (DSDS), the disulfide/α-amide-bridged doxorubicin dimeric prodrug (DDOX), as a model. By fast precipitation or slow self-assembly, DDOX nanoparticles were obtained. With similar diameters, they exhibited different pH/GSH dual-triggered drug releases, demonstrating the effect of aggregation structures. The π-π stacking in different degrees was revealed by the UV-vis, fluorescence, and BET analysis of the DDOX nanoparticles. The effect of the π-π stacking between the dimeric prodrug and its activated products on drug release was also explored with the molecular simulation approach. The finding opens new ideas in the design of high-performance DDSs for future precise tumor treatment.
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Affiliation(s)
- Chen Yang
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| | - Peng Liu
- State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
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Bakand A, Moghaddam SV, Naseroleslami M, André H, Mousavi-Niri N, Alizadeh E. Efficient targeting of HIF-1α mediated by YC-1 and PX-12 encapsulated niosomes: potential application in colon cancer therapy. J Biol Eng 2023; 17:58. [PMID: 37749603 PMCID: PMC10521571 DOI: 10.1186/s13036-023-00375-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 08/30/2023] [Indexed: 09/27/2023] Open
Abstract
A number of molecular biofactors have been documented in pathogenesis and poor prognosis of colorectal cancer (CRC). Among them, the Hypoxia-Inducible Factor (HIF-1a) is frequently reported to become over-expressed, and its targeting could restrict and control a variety of essential hallmarks of CRC. Niosomes are innovative drug delivery vehicles with the encapsulating capacity for co-loading both hydrophilic and hydrophobic drugs at the same time. Also, they can enhance the local accumulation while minimizing the dose and side effects of drugs. YC-1 and PX-12 are two inhibitors of HIF-1a. The purpose of this work was to synthesize dual-loaded YC-1 and PX-12 niosomes to efficiently target HIF-1α in CRC, HT-29 cells. The niosomes were prepared by the thin-film hydration method, then the niosomal formulation of YC-1 and PX-12 (NIO/PX-YC) was developed and optimized by the central composition method (CCD) using the Box-Behnken design in terms of size, polydispersity index (PDI), entrapment efficiency (EE). Also, they are characterized by DLS, FESEM, and TEM microscopy, as well as FTIR spectroscopy. Additionally, entrapment efficiency, in vitro drug release kinetics, and stability were assessed. Cytotoxicity, apoptosis, and cell cycle studies were performed after the treatment of HT-29 cells with NIO/PX-YC. The expression of HIF-1αat both mRNA and protein levels were studied after NIO/PX-YC treatment. The prepared NIO/PX-YC showed a mean particle size of 185 nm with a zeta potential of about-7.10 mv and a spherical morphology. Also, PX-12 and YC-1 represented the entrapment efficiency of about %78 and %91, respectively, with a sustainable and controllable release. The greater effect of NIO/PX-YC than the free state of PX-YC on the cell survival rate, cell apoptosis, and HIF-1α gene/protein expression were detected (p < 0.05). In conclusion, dual loading of niosomes with YC-1 and PX-12 enhanced the effect of drugs on HIF-1α inhibition, thus boosting their anticancer effects.
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Affiliation(s)
- Azar Bakand
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sevil Vaghefi Moghaddam
- Clinical Research Development, Unit of Tabriz Valiasr Hospital, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Naseroleslami
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Helder André
- Department of Clinical Neuroscience, St. Erik Eye Hospital, Karolinska Institute, 11282, Stockholm, Sweden
| | - Neda Mousavi-Niri
- Department of Biotechnology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Effat Alizadeh
- Department of Medical Biotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran.
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12
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Liu C, Liu W, Liu Y, Duan H, Chen L, Zhang X, Jin M, Cui M, Quan X, Pan L, Hu J, Gao Z, Wang Y, Huang W. Versatile flexible micelles integrating mucosal penetration and intestinal targeting for effectively oral delivery of paclitaxel. Acta Pharm Sin B 2023; 13:3425-3443. [PMID: 37655335 PMCID: PMC10466001 DOI: 10.1016/j.apsb.2023.05.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 05/24/2023] [Accepted: 05/25/2023] [Indexed: 09/02/2023] Open
Abstract
The extremely low bioavailability of oral paclitaxel (PTX) mainly due to the complicated gastrointestinal environment, the obstruction of intestinal mucus layer and epithelium barrier. Thus, it is of great significance to construct a coordinative delivery system which can overcome multiple intestinal physicochemical obstacles simultaneously. In this work, a high-density PEGylation-based glycocholic acid-decorated micelles (PTX@GNPs) was constructed by a novel polymer, 9-Fluorenylmethoxycarbonyl-polyethylene glycocholic acid (Fmoc-PEG-GCA). The Fmoc motif in this polymer could encapsulate PTX via π‒π stacking to form the core of micelles, and the low molecular weight and non-long hydrophobic chain of Fmoc ensures the high-density of PEG. Based on this versatile and flexible carriers, PTX@GNPs possess mucus trapping escape ability due to the flexible PEG, and excellent intestine epithelium targeting attributed to the high affinity of GCA with apical sodium-dependent bile acid transporter. The in vitro and in vivo results showed that this oral micelle could enhance oral bioavailability of PTX, and exhibited similar antitumor efficacy to Taxol injection via intravenous route. In addition, oral PTX@GNPs administered with lower dosage within shorter interval could increase in vivo retention time of PTX, which supposed to remodel immune microenvironment and enhance oral chemotherapy efficacy by synergistic effect.
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Affiliation(s)
- Chao Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Wei Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Department of Histology and Embryology, Chongqing Key Laboratory of Neurobiology, Brain and Intelligence Research Key Laboratory of Chongqing Education Commission, Third Military Medical University, Chongqing 400038, China
| | - Yanhong Liu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Hongxia Duan
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Liqing Chen
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Xintong Zhang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Mingji Jin
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Minhu Cui
- Department of Gastroenterology, Yanbian University Hospital, Yanji 133000, China
| | - Xiuquan Quan
- Department of Gastroenterology, Yanbian University Hospital, Yanji 133000, China
| | - Libin Pan
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Jiachun Hu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Zhonggao Gao
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Yan Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
| | - Wei Huang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
- Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
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13
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Zhang Q, Wu P, Wu J, Shou H, Ming X, Wang S, Wang B. Chemoimmunological Cascade Cancer Therapy Using Fluorine Assembly Nanomedicine. ACS NANO 2023; 17:7498-7510. [PMID: 37011376 DOI: 10.1021/acsnano.2c12600] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/09/2023]
Abstract
Classical chemotherapeutic drugs may cause immunogenic cell death (ICD), followed by activating CD8+ T cells to promote cell-mediated antitumor immune responses. However, CD8+ T cells become exhausted due to tumor antigens' continuous stimulation, creating a major obstacle to effectively suppressing tumor growth and metastasis. Here, we develop an approach of chemo-gene combinational nanomedicine to bridge and reprogram chemotherapy and immunotherapy. The dually loaded nanomedicine induces ICD in tumor cells through doxorubicin and reverses the antitumor effects of exhausted CD8+ T cells through the small interfering RNA. The synergistic chemo-gene and fluorine assembly nanomedicine enriched in reactive oxygen species and acid-sensitive bonds results in enhanced cancer immunotherapy to inhibit tumor growth and the lung metastasis of breast cancer in a mouse model of breast cancer and melanoma. This study provides an efficient strategy and insights into chemoimmunological cascade therapy for combating malignant metastatic tumors.
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Affiliation(s)
- Qingyan Zhang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China
| | - Pengkai Wu
- Department of Hepatobiliary Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Jicheng Wu
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China
| | - Hao Shou
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China
| | - Xinliang Ming
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China
| | - Shuqi Wang
- Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China
- Department of Respiratory and Critical Care Medicine, Provincial Clinical Research Center for Respiratory Diseases, West China Hospital, Sichuan University, Chengdu 610041, China
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610065, China
| | - Ben Wang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China
- Institute of Translational Medicine, Zhejiang University, Hangzhou 310029, China
- Cancer Center, Zhejiang University, Hangzhou 310029, China
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14
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Zhang P, Rashidi A, Zhao J, Silvers C, Wang H, Castro B, Ellingwood A, Han Y, Lopez-Rosas A, Zannikou M, Dmello C, Levine R, Xiao T, Cordero A, Sonabend AM, Balyasnikova IV, Lee-Chang C, Miska J, Lesniak MS. STING agonist-loaded, CD47/PD-L1-targeting nanoparticles potentiate antitumor immunity and radiotherapy for glioblastoma. Nat Commun 2023; 14:1610. [PMID: 36959214 PMCID: PMC10036562 DOI: 10.1038/s41467-023-37328-9] [Citation(s) in RCA: 102] [Impact Index Per Article: 51.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 03/08/2023] [Indexed: 03/25/2023] Open
Abstract
As a key component of the standard of care for glioblastoma, radiotherapy induces several immune resistance mechanisms, such as upregulation of CD47 and PD-L1. Here, leveraging these radiotherapy-elicited processes, we generate a bridging-lipid nanoparticle (B-LNP) that engages tumor-associated myeloid cells (TAMCs) to glioblastoma cells via anti-CD47/PD-L1 dual ligation. We show that the engager B-LNPs block CD47 and PD-L1 and promote TAMC phagocytic activity. To enhance subsequent T cell recruitment and antitumor responses after tumor engulfment, the B-LNP was encapsulated with diABZI, a non-nucleotidyl agonist for stimulator of interferon genes. In vivo treatment with diABZI-loaded B-LNPs induced a transcriptomic and metabolic switch in TAMCs, turning these immunosuppressive cells into antitumor effectors, which induced T cell infiltration and activation in brain tumors. In preclinical murine models, B-LNP/diABZI administration synergized with radiotherapy to promote brain tumor regression and induce immunological memory against glioma. In summary, our study describes a nanotechnology-based approach that hijacks irradiation-triggered immune checkpoint molecules to boost potent and long-lasting antitumor immunity against glioblastoma.
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Affiliation(s)
- Peng Zhang
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| | - Aida Rashidi
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Junfei Zhao
- Program for Mathematical Genomics, Department of Systems Biology, Columbia University, New York, NY, USA
- Department of Biomedical Informatics, Columbia University, New York, NY, USA
| | - Caylee Silvers
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Hanxiang Wang
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Brandyn Castro
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Abby Ellingwood
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Yu Han
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Aurora Lopez-Rosas
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Markella Zannikou
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Crismita Dmello
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Rebecca Levine
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ting Xiao
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Alex Cordero
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Adam M Sonabend
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Irina V Balyasnikova
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Catalina Lee-Chang
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jason Miska
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| | - Maciej S Lesniak
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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15
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Zhang Y, Zhou J, Chen X, Li Z, Gu L, Pan D, Zheng X, Zhang Q, Chen R, Zhang H, Gong Q, Gu Z, Luo K. Modulating tumor-stromal crosstalk via a redox-responsive nanomedicine for combination tumor therapy. J Control Release 2023; 356:525-541. [PMID: 36918084 DOI: 10.1016/j.jconrel.2023.03.015] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 02/12/2023] [Accepted: 03/08/2023] [Indexed: 03/16/2023]
Abstract
Interaction between carcinoma-associated fibroblasts (CAFs) and tumor cells leads to the invasion and metastasis of breast cancer. Herein, we prepared a redox-responsive chondroitin sulfate (CS)-based nanomedicine, in which hydrophobic cabazitaxel (CTX) was conjugated to the backbone of CS via glutathione (GSH)-sensitive dithiomaleimide (DTM) to form an amphipathic CS-DTM-CTX (CDC) conjugate, and dasatinib (DAS) co-assembled with the CDC conjugate to obtain DAS@CDC. After CD44 receptor-mediated internalization by CAFs, the nanomedicine could reverse CAFs to normal fibroblasts, blocking their crosstalk with tumor cells and reducing synthesis of major tumor extracellular matrix proteins, including collagen and fibronectin. Meanwhile, the nanomedicine internalized by tumor cells could effectively inhibit tumor proliferation and metastasis, leading to shrinkage of the tumor volume and inhibition of lung metastasis in a subcutaneous 4T1 tumor model with low side effects. Collectively, the nanomedicine showed a remarkably synergistic therapy effect against breast cancer by modulating tumor-stromal crosstalk.
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Affiliation(s)
- Yuxin Zhang
- Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jie Zhou
- Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xiaoting Chen
- Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Zhiqian Li
- Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lei Gu
- Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Dayi Pan
- Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Functional and molecular imaging Key Laboratory of Sichuan Province, Key Laboratory of Transplant Engineering and Immunology, NHC, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China
| | - Xiuli Zheng
- Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Qianfeng Zhang
- Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Rongjun Chen
- Department of Chemical Engineering, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom
| | - Hu Zhang
- Amgen Bioprocessing Centre, Keck Graduate Institute, Claremont, CA 91711, USA
| | - Qiyong Gong
- Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Functional and molecular imaging Key Laboratory of Sichuan Province, Key Laboratory of Transplant Engineering and Immunology, NHC, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China; Department of Radiology, West China Xiamen Hospital of Sichuan University, Xiamen, Fujian, China
| | - Zhongwei Gu
- Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Kui Luo
- Huaxi MR Research Center (HMRRC), Department of Radiology, Animal Experimental Center, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Functional and molecular imaging Key Laboratory of Sichuan Province, Key Laboratory of Transplant Engineering and Immunology, NHC, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China.
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16
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Vakilzadeh H, Varshosaz J, Dinari M, Mirian M, Hajhashemi V, Shamaeizadeh N, Sadeghi HMM. Smart redox-sensitive micelles based on chitosan for dasatinib delivery in suppressing inflammatory diseases. Int J Biol Macromol 2023; 229:696-712. [PMID: 36529222 DOI: 10.1016/j.ijbiomac.2022.12.111] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/03/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022]
Abstract
Dasatinib (DAS) exhibits anti-inflammatory effects by retrieving the balance between inflammatory and anti-inflammatory cytokines secreted by macrophages. The aim of this study was the development of redox-responsive micelles with the potential of passive targeting and on-demand drug release for DAS delivery to macrophages. For this purpose, two molecular weights of chitosan (CHIT) were conjugated to DAS at different molar ratios using 3,3'-dithiodipropionic anhydride (DTDPA) as disulfide bond containing linker to synthesize a series of CHIT-S-S-DAS amphiphilic conjugates. Micelles obtained by the sonication method had particle sizes of 129.3-172.2 nm, zeta potentials of +17.5 to +20.9 mV, drug contents of 0.90-7.20 %, CMC values of 35.3-96.6 μg/ml, and exhibited redox-responsive in vitro drug release. Optimized micelles were non-toxic and dramatically more efficient than non-redox responsive micelles in reducing TNF-α and IL-6 and increasing IL-10 secretion from LPS-stimulated RAW264.7 cells. Furthermore, the redox-responsive micelles were able to reduce the mice paw edema, reduce the plasma levels of pro-inflammatory cytokines and increase plasma level of IL-10, considerably more than free DAS and non-redox responsive micelles in carrageenan-induced mice paw edema model of inflammation.
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Affiliation(s)
- Hamed Vakilzadeh
- Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Jaleh Varshosaz
- Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Mohammad Dinari
- Department of Chemistry, Isfahan University of Technology, Isfahan, Iran.
| | - Mina Mirian
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Science, Isfahan University of Medical Sciences, Isfahan, Iran.
| | - Valiollah Hajhashemi
- Department of Pharmacology, School of Pharmacy and Pharmaceutical Science, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nahal Shamaeizadeh
- Department of Pharmaceutics, Faculty of Pharmacy and Novel Drug Delivery Systems Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hamid Mir-Mohammad Sadeghi
- Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Science, Isfahan University of Medical Sciences, Isfahan, Iran.
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17
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Zhang M, Ge Y, Xu S, Fang X, Meng J, Yu L, Wang C, Liu J, Wen T, Yang Y, Wang C, Xu H. Nanomicelles co-loading CXCR4 antagonist and doxorubicin combat the refractory acute myeloid leukemia. Pharmacol Res 2022; 185:106503. [DOI: 10.1016/j.phrs.2022.106503] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 09/27/2022] [Accepted: 10/09/2022] [Indexed: 10/31/2022]
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18
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Torrik A, Zaerin S, Zarif M. Doxorubicin and Imatinib co-drug delivery using non-covalently functionalized carbon nanotube: Molecular dynamics study. J Mol Liq 2022. [DOI: 10.1016/j.molliq.2022.119789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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19
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Wang SY, Chen G, Chen JF, Wang J, Deng SH, Cheng D. Glutathione-depleting polymer delivering chlorin e6 for enhancing photodynamic therapy. RSC Adv 2022; 12:21609-21620. [PMID: 35975058 PMCID: PMC9346557 DOI: 10.1039/d2ra01877b] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Accepted: 07/16/2022] [Indexed: 11/21/2022] Open
Abstract
The therapeutic effect of photodynamic therapy (PDT) is highly dependent on the intracellular production of reactive oxygen species (ROS). However, the ROS generated by photosensitizers can be consumed by the highly concentrated glutathione (GSH) in tumor cells, severely impairing the therapeutic effect of PDT. Herein, we synthesized a GSH-scavenging copolymer to deliver photosensitizer chlorin e6 (Ce6). The pyridyl disulfide groups, which have faster reactivity with the thiol groups of GSH than other disulfide groups, were grafted onto a hydrophobic block to encapsulate the Ce6. Under NIR irradiation, the Ce6 generated ROS to kill tumor cells, and the pyridyl disulfide groups depleted the GSH to prevent ROS consumption, which synergistically enhanced the therapeutic effect of PDT. In vitro and in vivo experiments confirmed the combinatory antitumor effect of Ce6-induced ROS generation and the pyridyl disulfide group-induced GSH depletion. Therefore, the pyridyl disulfide group-grafted amphiphilic copolymer provides a more efficient strategy for enhancing PDT and has promising potential for clinical application.
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Affiliation(s)
- Shi-Yin Wang
- PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University Guangzhou 510275 P. R. China
| | - Guo Chen
- PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University Guangzhou 510275 P. R. China
| | - Ji-Feng Chen
- PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University Guangzhou 510275 P. R. China
| | - Jin Wang
- Department of Radiology, The Third Affiliated Hospital of Sun Yat-sen University Guangzhou 510630 P. R. China
| | - Shao-Hui Deng
- PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University Guangzhou 510275 P. R. China
| | - Du Cheng
- PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University Guangzhou 510275 P. R. China
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Fatfat Z, Fatfat M, Gali-Muhtasib H. Micelles as potential drug delivery systems for colorectal cancer treatment. World J Gastroenterol 2022; 28:2867-2880. [PMID: 35978871 PMCID: PMC9280727 DOI: 10.3748/wjg.v28.i25.2867] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 03/22/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Despite the significant progress in cancer therapy, colorectal cancer (CRC) remains one of the most fatal malignancies worldwide. Chemotherapy is currently the mainstay therapeutic modality adopted for CRC treatment. However, the long-term effectiveness of chemotherapeutic drugs has been hampered by their low bioavailability, non-selective tumor targeting mechanisms, non-specific biodistribution associated with low drug concentrations at the tumor site and undesirable side effects. Over the last decade, there has been increasing interest in using nanotechnology-based drug delivery systems to circumvent these limitations. Various nanoparticles have been developed for delivering chemotherapeutic drugs among which polymeric micelles are attractive candidates. Polymeric micelles are biocompatible nanocarriers that can bypass the biological barriers and preferentially accumulate in tumors via the enhanced permeability and retention effect. They can be easily engineered with stimuli-responsive and tumor targeting moieties to further ensure their selective uptake by cancer cells and controlled drug release at the desirable tumor site. They have been shown to effectively improve the pharmacokinetic properties of chemotherapeutic drugs and enhance their safety profile and anticancer efficacy in different types of cancer. Given that combination therapy is the new strategy implemented in cancer therapy, polymeric micelles are suitable for multidrug delivery and allow drugs to act concurrently at the action site to achieve synergistic therapeutic outcomes. They also allow the delivery of anticancer genetic material along with chemotherapy drugs offering a novel approach for CRC therapy. Here, we highlight the properties of polymeric micelles that make them promising drug delivery systems for CRC treatment. We also review their application in CRC chemotherapy and gene therapy as well as in combination cancer chemotherapy.
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Affiliation(s)
- Zaynab Fatfat
- Department of Biology, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Maamoun Fatfat
- Department of Biology, American University of Beirut, Beirut 1107 2020, Lebanon
| | - Hala Gali-Muhtasib
- Department of Biology, American University of Beirut, Beirut 1107 2020, Lebanon
- Center for Drug Discovery, American University of Beirut, Beirut 1107 2020, Lebanon
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21
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Tajik S, Afshar AA, Shamsaddini S, Askari MB, Dourandish Z, Garkani Nejad F, Beitollahi H, Di Bartolomeo A. Fe 3O 4@MoS 2/rGO Nanocomposite/Ionic Liquid Modified Carbon Paste Electrode for Electrochemical Sensing of Dasatinib in the Presence of Doxorubicin. Ind Eng Chem Res 2022. [DOI: 10.1021/acs.iecr.2c00370] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Somayeh Tajik
- Research Center of Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman 76169-13555, Iran
| | - Abbas Aghaei Afshar
- Research Center of Tropical and Infectious Diseases, Kerman University of Medical Sciences, Kerman 76169-13555, Iran
| | - Saeedeh Shamsaddini
- Research Center for Hydatid Disease in Iran, Kerman University of Medical Sciences, Kerman 76169-13555, Iran
| | - Mohammad Bagher Askari
- Environment Department, Institute of Science and High Technology and Environmental Sciences, Graduate University of Advanced Technology, Kerman 76318-85356, Iran
| | - Zahra Dourandish
- Department of Chemistry, Faculty of Science, Shahid Bahonar University of Kerman, Kerman 76169-14111, Iran
| | - Fariba Garkani Nejad
- Department of Chemistry, Faculty of Science, Shahid Bahonar University of Kerman, Kerman 76169-14111, Iran
| | - Hadi Beitollahi
- Environment Department, Institute of Science and High Technology and Environmental Sciences, Graduate University of Advanced Technology, Kerman 76318-85356, Iran
| | - Antonio Di Bartolomeo
- Physics Department “E.R. Caianiello”, University of Salerno, via Giovanni Paolo II 132, 84084 Fisciano, Salerno, Italy
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22
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Wen Y, Song Z, Xu H, Feng S, Zhu L, Teng F, Feng R. Azithromycin-loaded linolenic acid-modified methoxy poly(ethylene glycol) micelles for bacterial infection treatment. Drug Deliv Transl Res 2022; 12:550-561. [PMID: 33718980 DOI: 10.1007/s13346-021-00953-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2021] [Indexed: 01/10/2023]
Abstract
In the study, new polymeric micelles loaded with azithromycin were prepared to enhance azithromycin's solubility and evaluate its in vitro/in vivo antibacterial activity against Staphylococcus aureus. Amphiphilic α-Linolenic acid-methoxy poly (ethylene glycol) polymer (MPEG-LNA) was synthesized through DCC-DMAP esterification procedure. Through thin-film hydration method, optimized azithromycin-loaded micelles (AZI-M) were prepared with 87.15% of encapsulation efficiency and 11.07% of drug loading capacity when the ratio of LNA to MPEG was 4. Azithromycin's water-solubility was obviously enhanced due to its loading into the polymeric micelles. The azithromycin-loaded micelles were characterized in terms of x-ray diffraction, Fourier transform infrared spectroscopy, in vitro release, and in vitro/in vivo antibacterial experiments. Although the drug-loaded micelles provided a slow and continuous azithromycin's release in comparison with free azithromycin, in vitro antibacterial activity results confirmed that its effect on the inhibition of bacterial growth and biofilm formation was similar to free azithromycin. It is more interesting that the azithromycin-loaded micelles achieved good in vivo antibacterial therapeutic effect like QiXian® (azithromycin lactobionate injection) in mouse model of intraperitoneal infection. AZI-M can be considered as a potential candidate for in vivo antibiotic therapy of Staphylococcus aureus infections.
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Affiliation(s)
- Yi Wen
- School of Biological Science and Technology, University of Jinan, No. 336 West Road of Nanxinzhuang, Jinan, 250022, Shandong Province, People's Republic of China
| | - Zhimei Song
- School of Biological Science and Technology, University of Jinan, No. 336 West Road of Nanxinzhuang, Jinan, 250022, Shandong Province, People's Republic of China
| | - Hongmei Xu
- School of Biological Science and Technology, University of Jinan, No. 336 West Road of Nanxinzhuang, Jinan, 250022, Shandong Province, People's Republic of China
| | - Sijia Feng
- School of Basic Medical Sciences, Dali University, Dali, 671000, Yunnan, People's Republic of China
| | - Li Zhu
- School of Biological Science and Technology, University of Jinan, No. 336 West Road of Nanxinzhuang, Jinan, 250022, Shandong Province, People's Republic of China
| | - Fangfang Teng
- The People's Hospital of Guangrao, Guangrao, 257300, Shandong Province, People's Republic of China
| | - Runliang Feng
- School of Biological Science and Technology, University of Jinan, No. 336 West Road of Nanxinzhuang, Jinan, 250022, Shandong Province, People's Republic of China.
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23
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Folic acid-conjugated pH-responsive poly(methacrylic acid) nanospheres for targeted delivery of anticancer drugs to breast cancer cells. J Mol Liq 2022. [DOI: 10.1016/j.molliq.2021.118028] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
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24
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Lin YK, Wang SW, Lee RS. Redox-responsive dasatinib-containing hyaluronic acid prodrug and co-delivery of doxorubicin for cancer therapy. INT J POLYM MATER PO 2021. [DOI: 10.1080/00914037.2020.1798434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Affiliation(s)
- Yin-Ku Lin
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan
| | - Shiu-Wei Wang
- Division of Natural Science, Center of General Education, Chang Gung University, Tao-Yuan, Taiwan
| | - Ren-Shen Lee
- Division of Natural Science, Center of General Education, Chang Gung University, Tao-Yuan, Taiwan
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25
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Aziz A, Sefidbakht Y, Rezaei S, Kouchakzadeh H, Uskoković V. Doxorubicin-loaded, pH-sensitive Albumin Nanoparticles for Lung Cancer Cell Targeting. J Pharm Sci 2021; 111:1187-1196. [PMID: 34896345 DOI: 10.1016/j.xphs.2021.12.006] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 11/21/2021] [Accepted: 12/06/2021] [Indexed: 12/13/2022]
Abstract
In recent decades, scientific and medical communities have continuously sought new methods and chemistries to improve the treatment of cancer. Among many types of nanoparticles considered as carriers for drug delivery, the protein ones count among the safest. The present study aimed to investigate the physicochemical and biological effects of the supplementation of albumin nanoparticles with doxorubicin (DOX). DOX was co-precipitated with albumin in a desolvation process and entrapped inside the cross-linked albumin nanoparticles, where it disrupted the protein structure at various levels: (a) it reduced the particle size distribution homogeneity; (b) it extended the peptide bond length; (c) it lowered the thermal stability of albumin; (d) it lowered the crystallinity of the protein. Physicochemical mechanisms underlying these changes are discussed. The drug release was incomplete under the physiological conditions, but the nanoparticles fully released their chemotherapeutic payload when pH was decreased by a single unit from the physiological value. Because the extracellular pH of tumors is usually by a single pH unit lower than that of healthy tissues, this environmentally responsive drug delivery system composed of albumin nanoparticles may be applicable in the targeting of cancer cells. In vitro assays against human lung cancer cells demonstrated that DOX released from albumin nanoparticles had a four times higher apoptotic activity than the equivalent concentration of free DOX. The ability of albumin to prevent the agglomeration of partially hydrophobic DOX and release it at a sustained, zero-order rate over the first 12 h of incubation, with no burst effect, explains this ability to augment the activity of DOX against the lung cancer cells.
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Affiliation(s)
- Ahmed Aziz
- Protein Research Center, Shahid Beheshti University, G.C. Tehran, Iran
| | - Yahya Sefidbakht
- Protein Research Center, Shahid Beheshti University, G.C. Tehran, Iran.
| | - Shokouh Rezaei
- Protein Research Center, Shahid Beheshti University, G.C. Tehran, Iran
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26
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Zhang Y, Li T, Hu Y, Chen J, He Y, Gao X, Zhang Y. Co-delivery of doxorubicin and curcumin via cRGD-peptide modified PEG-PLA self-assembly nanomicelles for lung cancer therapy. CHINESE CHEM LETT 2021. [DOI: 10.1016/j.cclet.2021.11.076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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27
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Li Z, Wang F, Li Y, Wang X, Lu Q, Wang D, Qi C, Li C, Li Z, Lian B, Tian G, Gao Z, Zhang B, Wu J. Combined anti-hepatocellular carcinoma therapy inhibit drug-resistance and metastasis via targeting "substance P-hepatic stellate cells-hepatocellular carcinoma" axis. Biomaterials 2021; 276:121003. [PMID: 34273686 DOI: 10.1016/j.biomaterials.2021.121003] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 06/21/2021] [Accepted: 07/01/2021] [Indexed: 12/13/2022]
Abstract
Peripheral nerves have emerged as the important components in tumor microenvironment (TME), which could activate hepatic stellate cells (HSCs) by secreting substance P (SP), leading to hepatocellular carcinoma (HCC) invasion and metastasis. Herein, we proposed a novel anti-HCC concept of blocking "SP-HSCs-HCC" axis for omnidirectional inhibition of HCC development. To pursue this aim, the novel CAP/GA-sHA-DOX NPs were developed for targeted co-delivery of capsaicin (CAP) and doxorubicin (DOX) using glycyrrhetinic acid (GA) modified sulfated-HA (sHA) as nanocarriers. Among that, CAP could inhibit the activation of HSCs as an inhibitor of SP. Notably, to real mimic "SP-HSCs-HCC" axis for in vitro and in vivo evaluation, both "SP + LX-2+BEL-7402" co-cultured cell model and "SP + m-HSC + H22" co-implantation mice model were attempted for the first time. Furthermore, in vivo anti-HCC effects were performed in three different tumor-bearing models: subcutaneous implantation of H22 or "SP + m-HSC + H22", intravenous injection of H22 for lung metastasis, and orthotopic implantation of H22 for primary HCC. Our results showed that CAP/GA-sHA-DOX NPs could be efficiently taken up by tumor cells and activated HSCs (aHSCs) simultaneously, and effectively inhibit tumor drug-resistance and migration by blocking SP-induced HSCs activation. In addition, CAP/GA-sHA-DOX NPs exhibited low ECM deposition, less tumor angiogenesis, and superior in vivo anti-HCC effects. The anti-HCC mechanisms revealed that CAP/GA-sHA-DOX NPs could down-regulate the expression level of Vimentin and P-gp, reverse epithelial-mesenchymal transition (EMT) of tumor cells. In brief, the nano-sized combination therapy based on GA-sHA-DOX polymers could effectively inhibit drug-resistance and metastasis of HCC by blocking "SP-HSCs-HCC" axis, which provides a promising approach for cancer therapy.
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Affiliation(s)
- Zhipeng Li
- School of Bioscience and Technology, Weifang Medical University, PR China
| | - Fangqing Wang
- School of Bioscience and Technology, Weifang Medical University, PR China
| | - Yanying Li
- School of Bioscience and Technology, Weifang Medical University, PR China
| | - Xiaoxue Wang
- School of Bioscience and Technology, Weifang Medical University, PR China
| | - Qiao Lu
- School of Bioscience and Technology, Weifang Medical University, PR China
| | - Di Wang
- School of Nursing, Weifang Medical University, PR China
| | - Cuiping Qi
- School of Nursing, Weifang Medical University, PR China
| | - Chenglei Li
- School of Pharmacy, Weifang Medical University, Weifang, 261053, PR China
| | - Zhaohuan Li
- School of Pharmacy, Weifang Medical University, Weifang, 261053, PR China
| | - Bo Lian
- School of Bioscience and Technology, Weifang Medical University, PR China
| | - Guixiang Tian
- School of Bioscience and Technology, Weifang Medical University, PR China
| | - Zhiqin Gao
- School of Bioscience and Technology, Weifang Medical University, PR China.
| | - Bo Zhang
- School of Pharmacy, Weifang Medical University, Weifang, 261053, PR China.
| | - Jingliang Wu
- School of Bioscience and Technology, Weifang Medical University, PR China.
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28
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Sun Y, Yang J, Yang T, Li Y, Zhu R, Hou Y, Liu Y. Co-delivery of IL-12 cytokine gene and cisplatin prodrug by a polymetformin-conjugated nanosystem for lung cancer chemo-gene treatment through chemotherapy sensitization and tumor microenvironment modulation. Acta Biomater 2021; 128:447-461. [PMID: 33894351 DOI: 10.1016/j.actbio.2021.04.034] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/14/2021] [Accepted: 04/15/2021] [Indexed: 12/27/2022]
Abstract
The combination of chemotherapy and gene therapy has been indicated as a promising approach for cancer therapy. However, this combination strategy is still faced a challenge by the lack of suitable carriers to co-loaded chemotherapeutic drug and gene into one single nanoplatform. In this study, a tumor-targeted HC/pIL-12/polyMET micelleplexes were developed for the co-loading and co-delivery of cisplatin (CDDP) and plasmid encoding interleukin-12 gene (pIL-12), which would be utilized to generate synergistic actions through chemotherapy sensitization and microenvironment modulation. The HC/pIL-12/polyMET exhibited desirable particle size, superior serum stability, effective intracellular CDDP release and pIL-12 transfection efficiency. More important, the HC/pIL-12/polyMET generated the enhanced LLC cell proliferation inhibition and apoptosis induction efficiency. The long-circulating HC/pIL-12/polyMET micelleplexes promoted the accumulation of CDDP and pIL-12 in tumor site, which resulted in significantly inhibiting the growth of lung cancer, and prolonging the overall survival of tumor-bearing mice. The underlying immune mechanism demonstrated the combination of CDDP and pIL-12 activated immune effector cells to release IFN-γ and induced M1-type differentiation of tumor-related macrophages, thereby generating synergistic chemoimmunotherapy effect. Taken together, this study may provide an effective strategy for drug/gene co-delivery and cancer chemoimmunotherapy. STATEMENT OF SIGNIFICANCE: Chemoimmunotherapy has been indicated as an approach to improve efficacy of cancer therapy. Herein, a tumor-targeted micelleplexes (HC/pIL-12/polyMET) were developed for the co-delivery of cisplatin (CDDP) and plasmid encoding IL-12 gene (pIL-12), which can employ the synergistic effects through chemotherapy sensitization and microenvironment modulation. The HC/pIL-12/polyMET exhibited desirable particle size, superior serum stability, high gene transfection efficiency and antitumor activity on tumor cell proliferation inhibition and apoptosis induction. More importantly, the long-circulating HC/pIL-12/polyMET micelleplexes could effectively accumulate in tumor sites and then rapidly release the CDDP and pIL-12, significantly inhibit the growth of lung cancer. This strategy provides a new concept for chemo-gene combination with a strengthened overall therapeutic efficacy of chemoimmunotherapy.
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Affiliation(s)
- Yue Sun
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China
| | - Jiayu Yang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China
| | - Tong Yang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China
| | - Yifan Li
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China
| | - Rongyue Zhu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China
| | - Yanhui Hou
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China
| | - Yanhua Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan, 750004, China; Key Laboratory of Hui Ethnic Medicine Modernization, Ningxia Medical University, Yinchuan, 750004, China.
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29
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Russo E, Spallarossa A, Tasso B, Villa C, Brullo C. Nanotechnology of Tyrosine Kinase Inhibitors in Cancer Therapy: A Perspective. Int J Mol Sci 2021; 22:6538. [PMID: 34207175 PMCID: PMC8235113 DOI: 10.3390/ijms22126538] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 12/23/2022] Open
Abstract
Nanotechnology is an important application in modern cancer therapy. In comparison with conventional drug formulations, nanoparticles ensure better penetration into the tumor mass by exploiting the enhanced permeability and retention effect, longer blood circulation times by a reduced renal excretion and a decrease in side effects and drug accumulation in healthy tissues. The most significant classes of nanoparticles (i.e., liposomes, inorganic and organic nanoparticles) are here discussed with a particular focus on their use as delivery systems for small molecule tyrosine kinase inhibitors (TKIs). A number of these new compounds (e.g., Imatinib, Dasatinib, Ponatinib) have been approved as first-line therapy in different cancer types but their clinical use is limited by poor solubility and oral bioavailability. Consequently, new nanoparticle systems are necessary to ameliorate formulations and reduce toxicity. In this review, some of the most important TKIs are reported, focusing on ongoing clinical studies, and the recent drug delivery systems for these molecules are investigated.
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Affiliation(s)
- Eleonora Russo
- Section of Medicinal and Cosmetic Chemistry, Department of Pharmacy, University of Genova, Viale Benedetto XV, 3-16132 Genova, Italy; (A.S.); (B.T.); (C.V.)
| | | | | | | | - Chiara Brullo
- Section of Medicinal and Cosmetic Chemistry, Department of Pharmacy, University of Genova, Viale Benedetto XV, 3-16132 Genova, Italy; (A.S.); (B.T.); (C.V.)
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30
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Gao J, Qiao Z, Liu S, Xu J, Wang S, Yang X, Wang X, Tang R. A small molecule nanodrug consisting of pH-sensitive ortho ester-dasatinib conjugate for cancer therapy. Eur J Pharm Biopharm 2021; 163:188-197. [PMID: 33864903 DOI: 10.1016/j.ejpb.2021.04.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/20/2021] [Accepted: 04/09/2021] [Indexed: 12/17/2022]
Abstract
The main objective of this paper is to develop a self-delivered prodrug system with nanoscale characteristics to enhance the efficacy of tumor therapy. The pH-sensitive prodrug was composed of ortho ester-linked dasatinib (DAS-OE), which was further self-assembled with or without doxorubicin (DOX) to obtain two carrier-free nanoparticles (DOX/DAS-OE NPs or DAS-OE NPs). The prodrug-based nanoparticles united the superiorities of small molecules and nano-assemblies together and displayed well-defined structure, uniform spherical shape, high drug loading ratio and on-demand drug release behavior. The drug loading content of DAS and DOX was 61.6% and 21.9%, respectively, and more than 80.2% of DAS and 60.2% DOX were released from DOX/DAS-OE NPs within 20 h at pH 5.0. Both in vitro and in vivo studies demonstrated that the pH-sensitive ortho ester bonds in the prodrug underwent hydrolysis to release DAS and DOX simultaneously after cellular internalization, resulting in remarkable antitumor effect. Tumor growth inhibition rate was 19.9% (free DAS), 35.5% (free DOX), 66.3% (DAS-OE NPs) and 82.8% (DOX/DAS-OE NPs), respectively. Thus, the ortho ester-linked prodrug system shows great potentials in cancer therapy.
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Affiliation(s)
- Jialu Gao
- Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China
| | - Zhen Qiao
- Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China
| | - Shuo Liu
- Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China
| | - Jiaxi Xu
- Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China
| | - Shi Wang
- Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China
| | - Xia Yang
- Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China
| | - Xin Wang
- Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China
| | - Rupei Tang
- Engineering Research Center for Biomedical Materials, School of Life Science, Anhui University, 111 Jiulong Road, Hefei, Anhui Province 230601, PR China.
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31
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Huang H, Huang Y, Chen Y, Luo Z, Zhang Z, Sun R, Wan Z, Sun J, Lu B, Zhang L, Hu J, Li S. A novel immunochemotherapy based on targeting of cyclooxygenase and induction of immunogenic cell death. Biomaterials 2021; 270:120708. [PMID: 33578254 PMCID: PMC7910750 DOI: 10.1016/j.biomaterials.2021.120708] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/26/2021] [Accepted: 02/01/2021] [Indexed: 02/08/2023]
Abstract
Cyclooxygenase (COX) plays a crucial role in the "inflammogenesis of cancer", which leads to tumor progression, metastasis, and immunotherapy resistance. Therefore, reducing "inflammogenesis" by COX inhibition may be a key perspective for cancer therapy. However, the role of tumor-derived COX in the actions of COX inhibitors remains incompletely understood. In this study, applying "old drug new tricks" to repurpose 5-aminosalicylic acid (5-ASA), a COX inhibitor, we examined the effect of 5-ASA, alone or in combination with doxorubicin (DOX), in several cancer cell lines with different levels of COX expression. To facilitate the evaluation of the combination effect on tumors in vivo, a new micellar carrier based on PEG-b-PNHS polymer-conjugated 5-ASA (PASA) was developed to enhance codelivery of 5-ASA and DOX. Folate was also introduced to the polymer (folate-PEG-NH2-conjugated PASA (FASA)) to further improve delivery to tumors via targeting both tumor cells and tumor macrophages. An unprecedented high DOX loading capacity of 42.28% was achieved through various mechanisms of carrier/drug interactions. FASA was highly effective in targeting to and in inhibiting the growth of both 4T1.2 and CT26 tumors in BALB/c mice. However, FASA was more effective in CT26 tumor that has a high level of COX expression. Codelivery of DOX via PASA and FASA led to a further improvement in antitumor activity. Mechanistic studies suggest that inhibition of COX in vivo led to a more active tumor immune microenvironment. Interestingly, treatment with FASA led to upregulation of PD-1 on T cells, likely due to repressing the inhibitory effect of prostaglandin E2 (PGE2) on PD-1 expression on T cells. Combination of FASA/DOX with anti-PD-1 antibody led to a drastic improvement in the overall antitumor activity including regression of some established tumors at a suboptimal dose of FASA/DOX. Our data suggest that FASA/DOX may represent a new and effective immunochemotherapy for various types of cancers, particularly those cancers with high levels of COX expression.
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Affiliation(s)
- Haozhe Huang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Yixian Huang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Yuang Chen
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Zhangyi Luo
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Ziqian Zhang
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Runzi Sun
- Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Zhuoya Wan
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Jingjing Sun
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Binfeng Lu
- Department of Immunology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Lin Zhang
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Jing Hu
- UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, 15261, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Song Li
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA; University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
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Ye H, Chu X, Cao Z, Hu X, Wang Z, Li M, Wan L, Li Y, Cao Y, Diao Z, Peng F, Liu J, Xu L. A Novel Targeted Therapy System for Cervical Cancer: Co-Delivery System of Antisense LncRNA of MDC1 and Oxaliplatin Magnetic Thermosensitive Cationic Liposome Drug Carrier. Int J Nanomedicine 2021; 16:1051-1066. [PMID: 33603368 PMCID: PMC7886386 DOI: 10.2147/ijn.s258316] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Accepted: 01/05/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND This study was aimed to prepare a novel magnetic thermosensitive cationic liposome drug carrier for the codelivery of Oxaliplatin (OXA) and antisense lncRNA of MDC1 (MDC1-AS) to Cervical cancer cells and evaluate the efficiency of this drug carrier and its antitumor effects on Cervical cancer. METHODS Thermosensitive magnetic cationic liposomes were prepared using thin-film hydration method. The OXA and MDC1-AS vectors were loaded into the codelivery system, and the in vitro OXA thermosensitive release activity, efficiency of MDC1-AS regulating MDC1, in vitro cytotoxicity, and in vivo antitumor activity were determined. RESULTS The codelivery system had desirable targeted delivery efficacy, OXA thermosensitive release, and MDC1-AS regulating MDC1. Codelivery of OXA and MDC1-AS enhanced the inhibition of cervical cancer cell growth in vitro and in vivo, compared with single drug delivery. CONCLUSION The novel codelivery of OXA and MDC1-AS magnetic thermosensitive cationic liposome drug carrier can be applied in the combined chemotherapy and gene therapy for cervical cancer.
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Affiliation(s)
- Hui Ye
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China
| | - Xiaoying Chu
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China
| | - Zhensheng Cao
- School of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China
| | - Xuanxuan Hu
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China
| | - Zihan Wang
- School of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China
| | - Meiqi Li
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China
| | - Leyu Wan
- School of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China
| | - Yongping Li
- Department of Surgery, Chengdu Shuangliu District Maternal and Child Health Hospital, ChengDu, Sichuan, 610200, People’s Republic of China
| | - Yongge Cao
- Department of Stomatology, Haiyuan College, Kunming, Yunnan, 650106, People’s Republic of China
| | - Zhanqiu Diao
- School of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China
| | - Fengting Peng
- School of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China
| | - Jinsong Liu
- School of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, People’s Republic of China
| | - Lihua Xu
- Department of General Medicine, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, 325000, People’s Republic of China
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Yan T, Hui W, Zhu S, He J, Liu Z, Cheng J. Carboxymethyl chitosan based redox-responsive micelle for near-infrared fluorescence image-guided photo-chemotherapy of liver cancer. Carbohydr Polym 2021; 253:117284. [DOI: 10.1016/j.carbpol.2020.117284] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 10/04/2020] [Accepted: 10/17/2020] [Indexed: 01/29/2023]
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Abstract
The anticancer drug dasatinib (Sprycel) is a BCR-ABL1-targeted tyrosine kinase inhibitor used in treating chronic myelogenous leukemia that has been shown in clinical trials to display cardiovascular toxicities. While dasatinib potently inhibits BCR-ABL1, it is not a highly selective kinase inhibitor and may have off-target effects. A neonatal rat cardiac myocyte model was used to investigate potential mechanisms by which dasatinib damaged myocytes. The anthracycline cardioprotective drug dexrazoxane was shown to be ineffective in preventing dasatinib-induced myocyte damage. Dasatinib treatment increased doxorubicin accumulation in myocytes and doxorubicin-induced myocyte damage, likely through its ability to bind to one or more ABC-type efflux transporters. Dasatinib induced myocyte damage either after a brief treatment that mimicked the clinical situation, or more potently after continuous treatment. Dasatinib slightly induced apoptosis in myocytes as evidenced by increases in caspase-3/7 activity. Dasatinib treatment reduced pERK levels in myocytes most likely through inhibition of RAF, which dasatinib strongly inhibits. Thus, inhibition of the RAF/MEK/ERK pro-survival pathway in the heart may be, in part, a mechanism by which dasatinib induces cardiovascular toxicity.
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35
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Xiong Y, Shi C, Li L, Tang Y, Zhang X, Liao S, Zhang B, Sun C, Ren C. A review on recent advances in amino acid and peptide-based fluorescence and its potential applications. NEW J CHEM 2021. [DOI: 10.1039/d1nj02230j] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Fluorescence is widely used to detect functional groups and ions, and peptides are used in various fields due to their excellent biological activity.
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Affiliation(s)
- Yingshuo Xiong
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Changxin Shi
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Lingyi Li
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Yuanhan Tang
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Xin Zhang
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Sisi Liao
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Beibei Zhang
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Changmei Sun
- School of Chemistry and Materials Science, Ludong University, Yantai 264025, China
| | - Chunguang Ren
- Yantai Institute of Materia Medica, Yantai 264000, China
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36
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Zhou Y, Sun X, Zhou L, Zhang X. pH-Sensitive and Long-Circulation Nanoparticles for Near-Infrared Fluorescence Imaging-Monitored and Chemo-Photothermal Synergistic Treatment Against Gastric Cancer. Front Pharmacol 2020; 11:610883. [PMID: 33381047 PMCID: PMC7768901 DOI: 10.3389/fphar.2020.610883] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2020] [Accepted: 10/23/2020] [Indexed: 12/22/2022] Open
Abstract
Gastrectomy is the primary therapeutic option for gastric cancer. Postoperative treatment also plays a crucial role. The strategy to improve the postoperative prognosis of gastric cancer requires a combined system that includes a more efficient synergistic treatment and real-time monitoring after surgery. In this study, photothermal-chemotherapy combined nanoparticles (PCC NPs) were prepared via π-π stacking to perform chemo-photothermal synergistic therapy and continuous imaging of gastric cancer. PCC NPs had a spherical morphology and good monodispersity under aqueous conditions. The hydrodynamic diameter of PCC NPs was 59.4 ± 3.6 nm. PCC NPs possessed strong encapsulation ability, and the maximum drug loading rate was approximately 37%. The NPs exhibited extraordinary stability and pH-response release profiles. The NPs were rapidly heated under irradiation. The maximum temperature was close to 58°C. PCC NPs showed good biocompatibility both in vitro and in vivo. Moreover, the NPs could effectively be used for in vivo continuous monitoring of gastric cancer. After one injection, the fluorescent signal remained in tumor tissues for nearly a week. The inhibitory effect of PCC NPs was evaluated in a gastric cancer cell line and xenograft mouse model. Both in vitro and in vivo evaluations demonstrated that PCC NPs could be used for chemo-photothermal synergistic therapy. The suppression effect of PCC NPs was significantly better than that of single chemotherapy or photothermal treatment. This study lays the foundation for the development of novel postoperative treatments for gastric cancer.
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Affiliation(s)
- Yun Zhou
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, China.,College of Clinical Medicine, Xi'an Medical University, Xi'an, China
| | - Xuanzi Sun
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, China
| | - Liansuo Zhou
- College of Clinical Medicine, Xi'an Medical University, Xi'an, China
| | - Xiaozhi Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an Jiaotong University, Xi'an, China
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Liu Y, Wang J, Zhang J, Marbach S, Xu W, Zhu L. Targeting Tumor-Associated Macrophages by MMP2-Sensitive Apoptotic Body-Mimicking Nanoparticles. ACS APPLIED MATERIALS & INTERFACES 2020; 12:52402-52414. [PMID: 33169982 PMCID: PMC8229024 DOI: 10.1021/acsami.0c15983] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Tumor-associated macrophages (TAMs), a major player in the tumor microenvironment, were recently recognized as a potential therapeutic target. To date, very few anticancer drugs or drug-delivery systems were designed to target the TAMs. Inspired by the "eat me" signal, phosphatidylserine (PS), mediated phagocytic clearance of apoptotic bodies, in this study, the matrix metalloproteinase 2 (MMP2)-sensitive PS-modified nanoparticles were developed. In the design, the PS is externalized to the nanoparticles' surface only when the nanoparticles reach the MMP2-overexpressing tumor site, allowing for the TAM-specific phagocytosis. The nanoparticles' excellent macrophage/TAM selectivity was observed in various biological models, including various cell lines, coculture cells, coculture cell spheroids, zebrafish, and tumor-bearing mice. The nanoparticles' TAM specificity remarkably enhanced the TAM depletion capability of the loaded model drug, dasatinib, resulting in the improved anticancer activity. The MMP2-sensitive apoptotic body-mimicking nanoparticles might be a promising delivery tool for TAM-centered cancer diagnoses and treatments.
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Affiliation(s)
- Yin Liu
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University College Station, Kingsville 78363, Texas, United States
| | - Jiao Wang
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University College Station, Kingsville 78363, Texas, United States
| | - Jian Zhang
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University College Station, Kingsville 78363, Texas, United States
| | - Sandra Marbach
- Department of Life Sciences, College of Science and Engineering, Texas A&M University, Corpus Christi 78412, Texas, United States
| | - Wei Xu
- Department of Life Sciences, College of Science and Engineering, Texas A&M University, Corpus Christi 78412, Texas, United States
| | - Lin Zhu
- Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University College Station, Kingsville 78363, Texas, United States
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Ho DK, LeGuyader C, Srinivasan S, Roy D, Vlaskin V, Chavas TEJ, Lopez CL, Snyder JM, Postma A, Chiefari J, Stayton PS. Fully synthetic injectable depots with high drug content and tunable pharmacokinetics for long-acting drug delivery. J Control Release 2020; 329:257-269. [PMID: 33217474 DOI: 10.1016/j.jconrel.2020.11.030] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 11/06/2020] [Accepted: 11/15/2020] [Indexed: 12/27/2022]
Abstract
Clinical studies have validated that antiretroviral (ARV) drugs can serve as an HIV pre-exposure prophylactic (PrEP) strategy. Dosing adherence remains a crucial factor determining the final efficacy outcomes, and both long-acting implants and injectable depot systems are being developed to improve patient adherence. Here, we describe an injectable depot platform that exploits a new mechanism for both formation and controlled release. The depot is a polymeric prodrug synthesized from monomers that incorporate an ARV drug tenofovir alafenamide (TAF) with degradable linkers that can be designed to control release rates. The prodrug monomers are synthetically incorporated into homopolymer or block designs that exhibit high drug weight percent (wt%) and also are hydrophobized in these prodrug segments to drive depot formation upon injection. Drug release converts those monomers to more hydrophilic pendant groups via linker cleavage, and as this drug release proceeds, the polymer chains losing hydrophobicity are then disassociated from the depot and released over time to provide a depot dissolution mechanism. We show that long-acting TAF depots can be designed as block copolymers or as homopolymers. They can also be designed with different linkers, for example with faster or slower degrading p-hydroxybenzyloxycarbonyl (Benzyl) and ethyloxycarbonyl (Alkyl) linkers, respectively. Diblock designs of p(glycerol monomethacrylate)-b-p(Alkyl-TAF-methacrylate) and p(glycerol monomethacrylate)-b-p(Benzyl-TAF-methacrylate) were first characterized in a mouse subcutaneous injection model. The alkylcarbamate linker design (TAF 51 wt%) showed excellent sustained release profiles of the key metabolite tenofovir (TFV) in skin and plasma over a 50-day period. Next, the homopolymer design with a high TAF drug wt% of 73% was characterized in the same model. The homopolymer depots with p(Alkyl-TAFMA) exhibited sustained TFV and TAF release profiles in skin and blood over 60 days, and TFV-DP concentrations in peripheral blood mononuclear cells (PBMC) were found to be at least 10-fold higher than the clinically suggested minimally EC90 protective concentration of 24 fmol/106 cells. These are the first reports of sustained parent TAF dosing observed in mouse and TFV-DP in mouse PBMC. IVIS imaging of rhodamine labeled homopolymer depots showed that degradation and release of the depot coincided with the sustained TAF release. Finally, these polymers showed excellent stability in accelerated stability studies over a six-month time period, and exceptional solubility of over 700 mg/mL in the DMSO formulation solvent. The homopolymer designs have a drug reservoir potential of well over a year at mg/day dosing and may not require cold chain storage for global health and developed world long-acting drug delivery applications.
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Affiliation(s)
- Duy-Khiet Ho
- Department of Bioengineering, University of Washington, Seattle, WA 98195, United States
| | - Clare LeGuyader
- Department of Bioengineering, University of Washington, Seattle, WA 98195, United States
| | - Selvi Srinivasan
- Department of Bioengineering, University of Washington, Seattle, WA 98195, United States
| | - Debashish Roy
- Department of Bioengineering, University of Washington, Seattle, WA 98195, United States
| | - Vladimir Vlaskin
- Department of Bioengineering, University of Washington, Seattle, WA 98195, United States
| | - Thomas E J Chavas
- Department of Bioengineering, University of Washington, Seattle, WA 98195, United States
| | - Ciana L Lopez
- Department of Bioengineering, University of Washington, Seattle, WA 98195, United States
| | - Jessica M Snyder
- Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA 98195, United States
| | - Almar Postma
- CSIRO Manufacturing, Bag 10, Clayton South MDC, Victoria 3169, Australia
| | - John Chiefari
- CSIRO Manufacturing, Bag 10, Clayton South MDC, Victoria 3169, Australia
| | - Patrick S Stayton
- Department of Bioengineering, University of Washington, Seattle, WA 98195, United States.
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Liu Y, Li L, Liu J, Yang M, Wang H, Chu X, Zhou J, Huo M, Yin T. Biomineralization-inspired dasatinib nanodrug with sequential infiltration for effective solid tumor treatment. Biomaterials 2020; 267:120481. [PMID: 33189053 DOI: 10.1016/j.biomaterials.2020.120481] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 10/16/2020] [Accepted: 10/18/2020] [Indexed: 12/11/2022]
Abstract
The complex blood environment, heterogenic enhanced permeability and retention (EPR) effect, and dense matrix comprise the primary "leakage obstacles" impeding specific accumulation and penetration of nanodrugs against solid tumors, thus forming a key bottleneck for their clinical application. Herein, we present a biomineralization-inspired dasatinib (DAS) nanodrug (CIPHD/DAS) that sequentially permeates all of the abovementioned hindrances for efficient treatment of solid tumors. CIPHD/DAS exhibited a robust hybrid structure constructed from an iRGD-modified hyaluronic acid-deoxycholic acid organic core and a calcium phosphate mineral shell. In vitro and in vivo data demonstrated the mechanism of sequential tumoral infiltration was based on mineral-stiffened blood circulation with decreased premature drug leakage, iRGD-endowed tumor-specific transendothelial transport for "first-order promotion of accumulation" and DAS-mediated restoration of fibrotic stromal homeostasis for "second-order promotion of penetration". Resultantly, CIPHD/DAS showed remarkable distal drug availability in desmoplastic 4T1/CAFs orthotropic mouse models and significantly suppressed tumor growth and metastasis. This optimized strategy with sequential permeabilization of the capital "leakage obstacles" validates a promising paradigm to conquer the "impaired delivery and penetration" associated bottleneck of nanodrugs in the clinical treatment of solid tumors.
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Affiliation(s)
- Yanhong Liu
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China
| | - Lingchao Li
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China
| | - Jiyong Liu
- Department of pharmacy, Fudan University Shanghai Cancer Center, Shanghai, 200433, China
| | - Mengnan Yang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China
| | - Honglan Wang
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China
| | - Xuxin Chu
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China
| | - Jianping Zhou
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
| | - Meirong Huo
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
| | - Tingjie Yin
- State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, China.
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Yan D, Wei H, Lai X, Ge Y, Xu S, Meng J, Wen T, Liu J, Zhang W, Wang J, Xu H. Co-delivery of homoharringtonine and doxorubicin boosts therapeutic efficacy of refractory acute myeloid leukemia. J Control Release 2020; 327:766-778. [DOI: 10.1016/j.jconrel.2020.09.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 09/12/2020] [Accepted: 09/15/2020] [Indexed: 12/13/2022]
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Sun Y, Liu L, Zhou L, Yu S, Lan Y, Liang Q, Liu J, Cao A, Liu Y. Tumor Microenvironment-Triggered Charge Reversal Polymetformin-Based Nanosystem Co-Delivered Doxorubicin and IL-12 Cytokine Gene for Chemo-Gene Combination Therapy on Metastatic Breast Cancer. ACS APPLIED MATERIALS & INTERFACES 2020; 12:45873-45890. [PMID: 32924511 DOI: 10.1021/acsami.0c14405] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Cancer metastasis is the leading cause of high mortality and disease recurrence in breast cancer. In this study, a novel tumor microenvironment charge reversal polymetformin (PMet)-based nanosystem co-delivering doxorubicin (DOX) and plasmid encoding IL-12 gene (pIL-12) was developed for chemo-gene combination therapy on metastatic breast cancer. Cationic PMet was readily self-assembled into micelles for DOX physical encapsulation and pIL-12 complexation, and a hyaluronidase-sensitive thiolated hyaluronic acid (HA-SH) was then collaboratively assembled to the pIL-12/DOX-PMet micelleplexes, abbreviated as HA/pIL-12/DOX-PMet. DOX/pIL-12 loaded in HA/pIL-12/DOX-PMet micelleplexes presented prolonged circulation in blood, efficient accumulation in tumors, and internalization in tumor cells via CD44 receptor-mediated tumor specific-targeting, and DOX/pIL-12 was co-released in endo/lysosomes tumor microenvironment followed by HAase-triggered HA-SH deshielding from HA/pIL-12/DOX-PMet micelleplexes. Moreover, HA/PMet micelleplexes displayed excellent pIL-12 transfection and IL-12 expression in tumors of 4T1 tumor-bearing mice. Importantly, HA/pIL-12/DOX-PMet micelleplexes synergistically enhanced the NK cells and tumor infiltrated cytotoxic T lymphocytes and modulated the polarization from protumor M2 macrophages to activated antitumor M1 macrophages, with concomitant decreasing of the immunosuppressive regulatory T (Treg) cells, accompanied by an increase in the cytokines expression of IL-12, IFN-γ and TNF-α, consequently showing an improved antitumor and antimetastasis activity in 4T1 breast cancer lung metastasis mice model. In conclusion, the tumor microenvironment charge reversal HA/PMet nanosystem holds great promise for DOX/pIL-12 co-delivery and exploitation in chemo-gene combination therapy on metastatic breast cancer.
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Affiliation(s)
- Yue Sun
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Lu Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Liyue Zhou
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Shuangyu Yu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Yang Lan
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Qiangwei Liang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Jinxia Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Aichen Cao
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Yanhua Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
- Key Laboratory of Hui Ethnic Medicine Modernization, Ningxia Medical University, Yinchuan 750004, China
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Poly-(Lactic-co-Glycolic) Acid Nanoparticles for Synergistic Delivery of Epirubicin and Paclitaxel to Human Lung Cancer Cells. Molecules 2020; 25:molecules25184243. [PMID: 32947799 PMCID: PMC7570462 DOI: 10.3390/molecules25184243] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2020] [Revised: 09/11/2020] [Accepted: 09/12/2020] [Indexed: 12/21/2022] Open
Abstract
Combination therapy using chemically distinct drugs has appeared as one of the promising strategies to improve anticancer treatment efficiency. In the present investigation, poly-(lactic-co-glycolic) acid (PLGA) nanoparticles electrostatically conjugated with polyethylenimine (PEI)-based co-delivery system for epirubicin and paclitaxel (PLGA-PEI-EPI-PTX NPs) has been developed. The PLGA-PEI-EPI-PTX NPs exhibited a monodispersed size distribution with an average size of 240.93 ± 12.70 nm as measured through DLS and 70.8-145 nm using AFM. The zeta potential of 41.95 ± 0.65 mV from -17.45 ± 2.15 mV further confirmed the colloidal stability and PEI modification on PLGA nanoparticles. Encapsulation and loading efficiency along with in vitro release of drug for nanoparticles were done spectrophotometrically. The FTIR analysis of PLGA-PEI-EPI-PTX NPs revealed the involvement of amide moiety between polymer PLGA and PEI. The effect of nanoparticles on the cell migration was also corroborated through wound healing assay. The MTT assay demonstrated that PLGA-PEI-EPI-PTX NPs exhibited considerable anticancer potential as compared to the naïve drugs. Further, p53 protein expression analysed through western blot showed enhanced expression. This study suggests that combination therapy using PLGA-PEI-EPI-PTX NPs represent a potential approach and could offer clinical benefits in the future for lung cancer patients.
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Mao W, Hu C, Zheng H, Xie J, Shi X, Du Y, Wang F. A Functionalized Polydopamine Theranostic Nanoprobe for Efficient Imaging of miRNA-21 and In Vivo Synergetic Cancer Therapy. MOLECULAR THERAPY. NUCLEIC ACIDS 2020; 22:27-37. [PMID: 32911342 PMCID: PMC7490455 DOI: 10.1016/j.omtn.2020.08.007] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 07/20/2020] [Accepted: 08/07/2020] [Indexed: 11/16/2022]
Abstract
MicroRNAs (miRNAs) are emerging as vital biomarkers since their abnormal expression is associated with various disease types including cancer. Therefore, it is essential to develop a sensitive and specific platform to monitor the dynamic expression of miRNAs for early clinical diagnosis and treatment. In this study, we designed a functionalized polydopamine (PDA)-based theranostic nanoprobe for efficient detection of miRNA-21 and in vivo synergistic cancer therapy. PDA was modified with polyethylene glycol (PEG) and the obtained PDA-PEG nanoparticles showed good stability in different solutions. PDA-PEG nanoparticles were loaded with fluorescein isothiocyanate (FITC)-labeled hairpin DNA (hpDNA) and an anticancer drug doxorubicin (DOX). In the absence of miRNA-21, PDA effectively quenched the fluorescence of FITC-labeled hpDNA. The presence of miRNA-21 specifically recognized hpDNA and induced the dissociation of hpDNA from PDA-PEG and subsequently recovered the fluorescence signals. Upon cellular uptake of these nanoprobes, a dose-dependent fluorescence activation and synergetic cytotoxic effect were observed due to the release of DOX and inhibition of miRNA-21 function. Furthermore, PDA-PEG-DOX-hpDNA nanoparticles can afford long-term monitoring of miRNA-21 and combined therapeutic efficacy in the nude mice bearing 4T1 tumors. Our results demonstrate the capability of PDA-PEG-DOX-hpDNA as a theranostic nanoprobe for continuously tracking of miRNAs and synergetic cancer therapy.
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Affiliation(s)
- Wenjie Mao
- Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710071, China
| | - Chong Hu
- Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710071, China
| | - Haifeng Zheng
- Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710071, China
| | - Jinrong Xie
- Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710071, China
| | - Xiaorui Shi
- Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710071, China
| | - Yarong Du
- Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710071, China
| | - Fu Wang
- Engineering Research Center of Molecular and Neuro Imaging, Ministry of Education, School of Life Science and Technology, Xidian University, Xi'an, Shaanxi 710071, China.
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Zhang J, Tang X, Huang C, Liu Z, Ye Y. Oleic Acid Copolymer as A Novel Upconversion Nanomaterial to Make Doxorubicin-Loaded Nanomicelles with Dual Responsiveness to pH and NIR. Pharmaceutics 2020; 12:pharmaceutics12070680. [PMID: 32698309 PMCID: PMC7408047 DOI: 10.3390/pharmaceutics12070680] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 07/16/2020] [Accepted: 07/17/2020] [Indexed: 12/29/2022] Open
Abstract
Oleic acid (OA) as main component of plant oil is an important solvent but seldom used in the nanocarrier of anticancer drugs because of strong hydrophobicity and little drug release. In order to develop a new type of OA nanomaterial with dual responses to pH and near infrared light (NIR) to achieve the intelligent delivery of anticancer drugs. The novel OA copolymer (mPEG-PEI-(NBS, OA)) was synthesized by grafting OA and o-nitrobenzyl succinate (NBS) onto mPEGylated polyethyleneimine (mPEG-PEI) by amidation reaction. It was further conjugated with NaYF4:Yb3+/Er3+ nanoparticles, and encapsulated doxorubicin (DOX) through self-assembly to make upconversion nanomicelles with dual response to pH and NIR. Drug release behavior of DOX, physicochemical characteristics of the nanomicelles were evaluated, along with its cytotoxic profile, as well as the degree of cellular uptake in A549 cells. The encapsulation efficiency and drug loading capacity of DOX in the nanomicelles were 73.84% ± 0.58% and 4.62% ± 0.28%, respectively, and the encapsulated DOX was quickly released in an acidic environment exposed to irradiation at 980 nm. The blank nanomicelles exhibited low cytotoxicity and excellent biocompatibility by MTT assay against A549 cells. The DOX-loaded nanomicelles showed remarkable cytotoxicity to A549 cells under NIR, and promoted the cellular uptake of DOX into the cytoplasm and nucleus of cancer cells. OA copolymer can effectively deliver DOX to cancer cells and achieve tumor targeting through a dual response to pH and NIR.
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Affiliation(s)
| | | | | | | | - Yong Ye
- Correspondence: ; Tel.: +86-20-87110234
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Lan Y, Liang Q, Sun Y, Cao A, Liu L, Yu S, Zhou L, Liu J, Zhu R, Liu Y. Codelivered Chemotherapeutic Doxorubicin via a Dual-Functional Immunostimulatory Polymeric Prodrug for Breast Cancer Immunochemotherapy. ACS APPLIED MATERIALS & INTERFACES 2020; 12:31904-31921. [PMID: 32551517 DOI: 10.1021/acsami.0c06120] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Immunochemotherapy is viewed as a promising approach for cancer therapy via combination treatment with immune-modulating drugs and chemotherapeutic drugs. A novel dual-functional immunostimulatory polymeric prodrug carrier PEG2k-Fmoc-1-MT was developed for simultaneously delivering 1-methyl tryptophan (1-MT) of an indoleamine 2,3-dioxygenase (IDO) inhibitor and chemotherapeutic doxorubicin (DOX) for breast cancer immunochemotherapy. DOX/PEG2k-Fmoc-1-MT micelles were more effective in cell proliferation inhibition and apoptosis induction in 4T1 cells. PEG2k-Fmoc-1-MT prodrug micelles presented enhanced inhibition ability of IDO with decreased kynurenine production and increased the proliferation in dose-dependent manners of effector CD4+ and CD8+ T cells. DOX/PEG2k-Fmoc-1-MT micelles exhibited prolonged blood circulation time and superior accumulation of DOX and 1-MT in tumors compared to that of DOX and 1-MT solutions. A significantly enhanced immune response of the DOX/PEG2k-Fmoc-1-MT micelles was observed with the decreasing tryptophan/kynurenine ratio in blood and tumor tissue, promoting effector CD4+ and CD8+ T cells while reducing regulatory T cell (Tregs) expression. Meanwhile, the coreleased DOX-triggered immunogenic cell death action combined with the cleaved 1-MT promoted the related cytokine secretion of tumor necrosis factor-α, interleukin-2, and interferon-γ, further facilitating the T cell-mediated immune responses. More importantly, the DOX-loaded micelles led to a significantly improved inhibition on tumor growth and prolonged animal survival rate in a 4T1 murine breast cancer model. In conclusion, DOX codelivered by a PEG2k-Fmoc-1-MT immunostimulatory polymeric prodrug showed a maximum immunochemotherapy efficacy against breast cancer.
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Affiliation(s)
- Yang Lan
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Qiangwei Liang
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Yue Sun
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Aichen Cao
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Lu Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Shuangyu Yu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Liyue Zhou
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Jinxia Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
| | - Rongyue Zhu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
- Key Laboratory of Hui Ethnic Medicine Modernization, Ningxia Medical University, Yinchuan 750004, China
| | - Yanhua Liu
- Department of Pharmaceutics, School of Pharmacy, Ningxia Medical University, No. 1160, Shengli Street, Yinchuan 750004, China
- Key Laboratory of Hui Ethnic Medicine Modernization, Ningxia Medical University, Yinchuan 750004, China
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Lv H, Tan R, Liao J, Hao Z, Yang X, Liu Y, Xia Y. Doxorubicin contributes to thrombus formation and vascular injury by interfering with platelet function. Am J Physiol Heart Circ Physiol 2020; 319:H133-H143. [PMID: 32469636 DOI: 10.1152/ajpheart.00456.2019] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
In clinical studies, platelet aggregation and risk of thrombosis are increased in patients after doxorubicin treatment. However, the exact role of doxorubicin in platelet functions and thrombus formation in vivo remain unclear. The present study is to investigate the role of doxorubicin in platelet function in relation to thrombus formation and vascular toxicity, as well as the efficacy of antiplatelet therapy. Mice were treated with doxorubicin or vehicle (5 mg/kg iv, 4 wk), and the following parameters were determined: platelet count and size, platelet surface adhesive receptors by flow cytometry, density of granules by electron microscopy, platelet aggregation and degranulation at resting or agonist-stimulated state, platelet adhesion on fibrinogen or endothelial cells, and thrombus formation on collagen matrix. The efficacy of clopidogrel (15 mg·kg-1·day-1, followed by 5 mg·kg-1·day-1) on doxorubicin-induced changes in the aforementioned parameters as well as vascular injury were also determined. Whereas platelet count and size were similar between doxorubicin-treated and vehicle-treated mice, doxorubicin promoted thrombus formation evidenced by greater platelet aggregation, degranulation, and adhesion to endothelial cells evoked by agonists. Clopidogrel treatment attenuated the enhanced platelet activity and thrombus formation by doxorubicin, as well as vascular platelet infiltration and reactive oxygen species generation. Collectively, this study demonstrates that platelet functions are enhanced after long-term doxorubicin administration, which leads to thrombus formation and vascular toxicity, and that doxorubicin-induced changes in the functionality of platelets can be effectively inhibited by antiplatelet drugs.NEW & NOTEWORTHY Doxorubicin therapy in mice (antitumor dosage) markedly enhanced platelet functions measured as agonist-induced platelet aggregation, degranulation, and adhesion to endothelial cells, actions leading to thrombus formation and thrombosis-independent vascular injury. Clopidogrel treatment ameliorated thrombus formation and vascular toxicity induced by doxorubicin via inhibiting platelet activity.
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Affiliation(s)
- Haichen Lv
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Ruopeng Tan
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jiawei Liao
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Zhujing Hao
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xiaolei Yang
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yang Liu
- Institute of Cardiovascular Diseases, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Yunlong Xia
- Department of Cardiology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
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47
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Pourjavadi A, Asgari S, Hosseini SH. Graphene oxide functionalized with oxygen-rich polymers as a pH-sensitive carrier for co-delivery of hydrophobic and hydrophilic drugs. J Drug Deliv Sci Technol 2020. [DOI: 10.1016/j.jddst.2020.101542] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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48
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Gao W, Li L, Zhang X, Luo L, He Y, Cong C, Gao D. Nanomagnetic liposome-encapsulated parthenolide and indocyanine green for targeting and chemo-photothermal antitumor therapy. Nanomedicine (Lond) 2020; 15:871-890. [PMID: 32223505 DOI: 10.2217/nnm-2019-0038] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Aim: To synthesize a drug-delivery system with chemo-photothermal function and magnetic targeting, to validate its antitumor effect. Materials & methods: Parthenolide (PTL), employing chemotherapy and indocyanine green (ICG) providing phototherapy, were encased separately in the lipid and aqueous phases of liposomes (Lips). The Fe3O4 nanoparticles (MNPs), endowing magnetic targeting, were modified on the surface of Lips. The antitumor effects were investigated in vitro and in vivo. Results: ICG-PTL-Lips@MNPs showed outstanding synergistic antitumor efficacy in vitro and in vivo. Especially, after 14-day treatment, the tumor volumes decreased significantly and the biotoxicity was very low. Conclusion: The designed ICG-PTL-Lips@MNPs possess synergistic effects of chemotherapy, photothermal and targeting therapy, which are expected to provide an alternative way to further improve antitumor efficacy.
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Affiliation(s)
- Wenbin Gao
- Applying Chemistry Key Laboratory of Hebei Province, Department of Bioengineer, Yanshan University, No. 438 Hebei Street, Qinhuangdao, 066004, PR China
| | - Lei Li
- Applying Chemistry Key Laboratory of Hebei Province, Department of Bioengineer, Yanshan University, No. 438 Hebei Street, Qinhuangdao, 066004, PR China.,State Key Laboratory of Metastable Materials Science & Technology, Yanshan University, No. 438 Hebei Street, Qinhuangdao, 066004, PR China
| | - Xuwu Zhang
- Applying Chemistry Key Laboratory of Hebei Province, Department of Bioengineer, Yanshan University, No. 438 Hebei Street, Qinhuangdao, 066004, PR China
| | - Liyao Luo
- Applying Chemistry Key Laboratory of Hebei Province, Department of Bioengineer, Yanshan University, No. 438 Hebei Street, Qinhuangdao, 066004, PR China
| | - Yuchu He
- Applying Chemistry Key Laboratory of Hebei Province, Department of Bioengineer, Yanshan University, No. 438 Hebei Street, Qinhuangdao, 066004, PR China
| | - Cong Cong
- Applying Chemistry Key Laboratory of Hebei Province, Department of Bioengineer, Yanshan University, No. 438 Hebei Street, Qinhuangdao, 066004, PR China.,Hebei Province Asparagus Industry Technology Research Institute, No. 12 Donghai Road, Qinhuangdao, 066318, PR China
| | - Dawei Gao
- Applying Chemistry Key Laboratory of Hebei Province, Department of Bioengineer, Yanshan University, No. 438 Hebei Street, Qinhuangdao, 066004, PR China.,State Key Laboratory of Metastable Materials Science & Technology, Yanshan University, No. 438 Hebei Street, Qinhuangdao, 066004, PR China.,Hebei Province Asparagus Industry Technology Research Institute, No. 12 Donghai Road, Qinhuangdao, 066318, PR China
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Visentin S, Sedić M, Pavelić SK, Pavelić K. Targeting Tumour Metastasis: The Emerging Role of Nanotechnology. Curr Med Chem 2020; 27:1367-1381. [DOI: 10.2174/0929867326666181220095343] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Revised: 02/13/2018] [Accepted: 11/12/2018] [Indexed: 12/29/2022]
Abstract
The metastatic process has still not been completely elucidated, probably due to insufficient knowledge of the underlying mechanisms. Here, we provide an overview of the current findings that shed light on specific molecular alterations associated with metastasis and present novel concepts in the treatment of the metastatic process. In particular, we discuss novel pharmacological approaches in the clinical setting that target metastatic progression. New insights into the process of metastasis allow optimisation and design of new treatment strategies, especially in view of the fact that metastatic cells share common features with stem cells. Nano- and micro-technologies are herein elaborated in details as a promising therapeutic concept in targeted drug delivery for metastatic cancer. Progression in the field could provide a more efficient way to tackle metastasis and thus bring about advancements in the treatment and management of patients with advanced cancer.
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Affiliation(s)
- Sarah Visentin
- Department of Biotechnology, University of Rijeka, Centre for High-Throughput Technologies, Radmile Matejcic 2, 51 000 Rijeka, Croatia
| | - Mirela Sedić
- Department of Biotechnology, University of Rijeka, Centre for High-Throughput Technologies, Radmile Matejcic 2, 51 000 Rijeka, Croatia
| | - Sandra Kraljević Pavelić
- Department of Biotechnology, University of Rijeka, Centre for High-Throughput Technologies, Radmile Matejcic 2, 51 000 Rijeka, Croatia
| | - Krešimir Pavelić
- Faculty of Medicine, Juraj Dobrila University of Pula, Zagrebacka 30, 52 100 Pula, Croatia
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50
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Zheng K, Liu H, Liu X, Wang Y, Li L, Li S, Xue J, Huang M. Tumor Targeting Chemo- and Photodynamic Therapy Packaged in Albumin for Enhanced Anti-Tumor Efficacy. Int J Nanomedicine 2020; 15:151-167. [PMID: 32021171 PMCID: PMC6968805 DOI: 10.2147/ijn.s227144] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 12/16/2019] [Indexed: 12/21/2022] Open
Abstract
PURPOSE Combination therapy for tumors is an important and promising strategy to improve therapeutic efficiency. This study aims at combining tumor targeting, chemo-, and photodynamic therapies to improve the anti-tumor performance. PATIENTS AND METHODS Human serum albumin (HSA), as a nontoxic and biodegradable drug carrier, was used to load hydrophobic photosensitizers (mono-substituted β-4-pyridyloxy phthalocyanine zinc, mPPZ) by a dilution-incubation-purification (DIP) strategy to form molecular complex HSA:mPPZ. This complex was cross-linked as nanoparticles, and then chemotherapy drug doxorubicin (DOX) was adsorbed into the nanoparticles to achieve combined photodynamic therapy and chemotherapy. Next, the surface of the obtained composite was modified by a tumor surface receptor (urokinase receptor) targeting agent (ATF-HSA) using a noncovalent method to obtain the final product (ATF-HSA@HSA:mPPZ:DOX nanoparticles, AHmDN). RESULTS AHmDN exhibited strong stability, remarkable cytotoxicity and higher uptake to tumor cells. Cell imaging analysis indicated that DOX was separated from AHmDN and uniformly distributed in cell nucleus while mPPZ localized in cytoplasm. The PDT activity of all the samples had been confirmed by the detection of intracellular ROS. In animal experiments, AHmDN was demonstrated to have a prominent tumor-targeting effect using a 3D imaging system. In addition, the enhanced antitumor effect of AHmDN in tumor-bearing mice was also been observed. Importantly, the tumor-targeting effect of such nanoparticles lasted for about 14 days after one injection. CONCLUSION These albumin nanoparticles with combined functions of tumor targeting, chemotherapy and photodynamic therapy can highly enhance the anti-tumor effect. This drug delivery system can be applied to package other hydrophobic photosensitizers and chemotherapy drugs for improving therapeutic efficacy to tumors.
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Affiliation(s)
- Ke Zheng
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong266042, People’s Republic of China
- College of Chemistry, Fuzhou University, Fuzhou, Fujian350118, People’s Republic of China
- Key Laboratory of Pharmaceutical Research for Metabolic Disease, Qingdao University of Science and Technology, Qingdao, Shandong266042, People’s Republic of China
| | - Hongyan Liu
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong266042, People’s Republic of China
| | - Xinxin Liu
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong266042, People’s Republic of China
| | - Ying Wang
- College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, Shandong266042, People’s Republic of China
| | - Linlin Li
- College of Chemistry, Fuzhou University, Fuzhou, Fujian350118, People’s Republic of China
| | - Shijie Li
- College of Chemistry, Fuzhou University, Fuzhou, Fujian350118, People’s Republic of China
| | - Jinping Xue
- College of Chemistry, Fuzhou University, Fuzhou, Fujian350118, People’s Republic of China
| | - Mingdong Huang
- College of Chemistry, Fuzhou University, Fuzhou, Fujian350118, People’s Republic of China
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