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Isreb A, Alhnan MA, Mkia A, Al-Jammal K, Yaghi AM, Oga EF, Timmins P, Bonner M, Forbes RT. Evaluation of Drug-Polymer and Drug-Drug Interaction in Cellulosic Multi-Drug Delivery Matrices. Methods Protoc 2025; 8:4. [PMID: 39846690 PMCID: PMC11755489 DOI: 10.3390/mps8010004] [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: 10/14/2024] [Revised: 12/25/2024] [Accepted: 12/31/2024] [Indexed: 01/24/2025] Open
Abstract
Multi-drug delivery systems have gained increasing interest from the pharmaceutical industry. Alongside this is the interest in amorphous solid dispersions as an approach to achieve effective oral delivery of compounds with solubility-limited bioavailability. Despite this, there is limited information regarding predicting the behavior of two or more drugs (in amorphous forms) in a polymeric carrier and whether molecular interactions between the compounds, between each compound, and if the polymer have any effect on the physical properties of the system. This work studies the interaction between model drug combinations (two of ibuprofen, malonic acid, flurbiprofen, or naproxen) dispersed in a polymeric matrix of hypromellose acetate succinate (HPMCAS) using a solvent evaporation technique. Hildebrand and Hansen calculations were used to predict the miscibility of compounds as long as the difference in their solubility parameter values was not greater than 7 MPa1/2. It was observed that the selected APIs (malonic acid, ibuprofen, naproxen, and flurbiprofen) were miscible within the formed polymeric matrix. Adding the API caused depression in the Tg of the polymer to certain concentrations (17%, 23%, 13%) for polymeric matrices loaded with malonic acid, ibuprofen, and naproxen, respectively. Above this, large crystals started to form, and phase separation was seen. Adding two APIs to the same matrix resulted in reducing the saturation concentration of one of the APIs. A trend was observed and linked to Hildebrand and Hansen solubility parameters (HSP).
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Affiliation(s)
- Abdullah Isreb
- Department of Clinical Sciences, Liverpool John Moores University, Liverpool L3 3AF, UK
| | - Mohamed A. Alhnan
- Department of Life Science and Medicine, Kings College University, London SE1 9NH, UK;
| | - Abdulrahman Mkia
- Department of Pharmacy, Al-Ahliyya Amman University, Amman 19111, Jordan;
| | - Khaled Al-Jammal
- Quay Pharma Ltd., Deeside Industrial Park, Quay House, 28 Parkway, Deeside CH5 2NS, UK;
| | - Abdallah M. Yaghi
- Department of Information, University of Sheffield, Sheffield S10 2AH, UK;
| | - Enoche Florence Oga
- Department of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK; (E.F.O.); (R.T.F.)
| | - Peter Timmins
- Department of Pharmacy, University of Huddersfield, Huddersfield HD1 3DH, UK;
| | - Michael Bonner
- Department of Life Sciences, University of Bradford, Bradford BD7 1DP, UK;
| | - Robert T. Forbes
- Department of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK; (E.F.O.); (R.T.F.)
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Lee HG, Lim GH, An JH, Park SM, Seo KW, Youn HY. In vitro evaluation of the antitumor activity of axitinib in canine mammary gland tumor cell lines. J Vet Sci 2024; 25:e1. [PMID: 38311316 PMCID: PMC10839173 DOI: 10.4142/jvs.23191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 11/07/2023] [Accepted: 11/09/2023] [Indexed: 02/07/2024] Open
Abstract
BACKGROUND Axitinib, a potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptor (VEGFR) tyrosine kinase 1,2 and 3, is used in chemotherapy because it inhibits tumor angiogenesis by blocking the VEGF/VEGFR pathway. In veterinary medicine, attempts have been made to apply tyrosine kinase inhibitors with anti-angiogenic effects to tumor patients, but there are no studies on axitinib in canine mammary gland tumors (MGTs). OBJECTIVES This study aimed to confirm the antitumor activity of axitinib in canine mammary gland cell lines. METHODS We treated canine MGT cell lines (CIPp and CIPm) with axitinib and conducted CCK, wound healing, apoptosis, and cell cycle assays. Additionally, we evaluated the expression levels of angiogenesis-associated factors, including VEGFs, PDGF-A, FGF-2, and TGF-β1, using quantitative real-time polymerase chain reaction. Furthermore, we collected canine peripheral blood mononuclear cells (PBMCs), activated them with concanavalin A (ConA) and lipopolysaccharide (LPS), and then treated them with axitinib to investigate changes in viability. RESULTS When axitinib was administered to CIPp and CIPm, cell viability significantly decreased at 24, 48, and 72 h (p < 0.001), and migration was markedly reduced (6 h, p < 0.05; 12 h, p < 0.005). The apoptosis rate significantly increased (p < 0.01), and the G2/M phase ratio showed a significant increase (p < 0.001). Additionally, there was no significant change in the viability of canine PBMCs treated with LPS and ConA. CONCLUSION In this study, we confirmed the antitumor activity of axitinib against canine MGT cell lines. Accordingly, we suggest that axitinib can be applied as a new treatment for patients with canine MGTs.
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Affiliation(s)
- Hye-Gyu Lee
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Ga-Hyun Lim
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Ju-Hyun An
- Department of Veterinary Emergency and Critical Care Medicine and Institute of Veterinary Science, College of Veterinary Medicine, Kangwon National University, Chuncheon 24341, Korea
| | - Su-Min Park
- Haemaru Referral Animal Hospital, Seongnam 13590, Korea
| | - Kyoung-Won Seo
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea
| | - Hwa-Young Youn
- Laboratory of Veterinary Internal Medicine, Department of Veterinary Clinical Science, College of Veterinary Medicine, Seoul National University, Seoul 08826, Korea.
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Anakha J, Dobariya P, Sharma SS, Pande AH. Recombinant human endostatin as a potential anti-angiogenic agent: therapeutic perspective and current status. Med Oncol 2023; 41:24. [PMID: 38123873 DOI: 10.1007/s12032-023-02245-w] [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: 08/01/2023] [Accepted: 11/09/2023] [Indexed: 12/23/2023]
Abstract
Angiogenesis is the physiological process that results in the formation of new blood vessels develop from pre-existing vasculature and plays a significant role in several physiological and pathological processes. Inhibiting angiogenesis, a crucial mechanism in the growth and metastasis of cancer, has been proposed as a potential anticancer therapy. Different studies showed the beneficial effects of angiogenesis inhibitors either in patients suffering from different cancers, alone or in combination with conventional therapies. Even though there are currently a number of efficient anti-angiogenic drugs, including monoclonal antibodies and kinase inhibitors, the associated toxicity profile and their affordability constraints are prompting researchers to search for a safe and affordable angiostatic agent for cancer treatment. Endostatin is one of the endogenous anti-angiogenic candidates that have been extensively pursued for the treatment of cancer, but even over three decades after its discovery, we have not made much advancement in employing it as an anticancer therapeutic despite of its remarkable anti-angiogenic effect with low toxicity profile. A recombinant human endostatin (rh-Es) variant for non-small cell lung cancer was approved by China in 2006 and has since been used effectively. Several other successful clinical trials related to endostatin for various malignancies are either ongoing or have already been completed with promising results. Thus, in this review, we have provided an overview of existing anti-angiogenic drugs developed for cancer therapy, with a summary of tumour angiogenesis in the context of Endostatin, and clinical status of rh-Es in cancer treatment. Furthermore, we briefly discuss the various strategies to improve endostatin features (poor pharmacokinetic properties) for developing rh-Es as a safe and effective agent for cancer treatment.
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Affiliation(s)
- J Anakha
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab, 160062, India
| | - Prakashkumar Dobariya
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab, 160062, India
| | - Shyam Sunder Sharma
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab, 160062, India
| | - Abhay H Pande
- Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Mohali, Punjab, 160062, India.
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Hu X, Yu L, Bian Y, Zeng X, Luo S, Wen Q, Chen P. Paclitaxel-loaded tumor cell-derived microparticles improve radiotherapy efficacy in triple-negative breast cancer by enhancing cell killing and stimulating immunity. Int J Pharm 2023; 632:122560. [PMID: 36586632 DOI: 10.1016/j.ijpharm.2022.122560] [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: 08/10/2022] [Revised: 12/03/2022] [Accepted: 12/25/2022] [Indexed: 12/29/2022]
Abstract
Triple-negative breast cancer (TNBC) is a highly heterogeneous tumor characterized by high recurrence and metastasis, with a very poor prognosis, and there are still great challenges in its clinical treatment. Here, we describe the development of a novel modality for the treatment of TNBC with tumor cell-derived microparticles loaded with paclitaxel (MP-PTX) in combination with radiotherapy. We show that MP can deliver agents to tumor cells by homologous targeting, thereby increasing the absorption rate of the chemotherapeutic agent and enhancing its killing effects on tumor cells. We further demonstrate that MP-PTX combined with radiotherapy shows a synergistic antitumor effect by enhancing the inhibition of tumor cell proliferation, promoting tumor cell apoptosis, reducing the immunosuppressive microenvironment at the tumor site, and activating the antitumor immune response. Altogether, this study provides a referable and optional method for the clinical treatment of refractory tumors such as TNBC based on the combination of T-MP-delivered chemotherapeutic drugs and radiotherapy. Chemical compounds: paclitaxel (PTX), paclitaxel-loaded tumor cell-derived microparticles (MP-PTX).
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Affiliation(s)
- Xiao Hu
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Li Yu
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Yuan Bian
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Xiaonan Zeng
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Shan Luo
- Chengdu Institute of Biological Products Co., Ltd, Chengdu 610023, China
| | - Qinglian Wen
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou 646000, China.
| | - Ping Chen
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou 646000, China; Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, Luzhou 646000, China.
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5
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Akbarian M, Bertassoni LE, Tayebi L. Biological aspects in controlling angiogenesis: current progress. Cell Mol Life Sci 2022; 79:349. [PMID: 35672585 PMCID: PMC10171722 DOI: 10.1007/s00018-022-04348-5] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/01/2022] [Accepted: 05/03/2022] [Indexed: 12/25/2022]
Abstract
All living beings continue their life by receiving energy and by excreting waste products. In animals, the arteries are the pathways of these transfers to the cells. Angiogenesis, the formation of the arteries by the development of pre-existed parental blood vessels, is a phenomenon that occurs naturally during puberty due to certain physiological processes such as menstruation, wound healing, or the adaptation of athletes' bodies during exercise. Nonetheless, the same life-giving process also occurs frequently in some patients and, conversely, occurs slowly in some physiological problems, such as cancer and diabetes, so inhibiting angiogenesis has been considered to be one of the important strategies to fight these diseases. Accordingly, in tissue engineering and regenerative medicine, the highly controlled process of angiogenesis is very important in tissue repairing. Excessive angiogenesis can promote tumor progression and lack of enough angiogensis can hinder tissue repair. Thereby, both excessive and deficient angiogenesis can be problematic, this review article introduces and describes the types of factors involved in controlling angiogenesis. Considering all of the existing strategies, we will try to lay out the latest knowledge that deals with stimulating/inhibiting the angiogenesis. At the end of the article, owing to the early-reviewed mechanical aspects that overshadow angiogenesis, the strategies of angiogenesis in tissue engineering will be discussed.
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Affiliation(s)
- Mohsen Akbarian
- Department of Chemistry, National Cheng Kung University, Tainan, 701, Taiwan
| | - Luiz E Bertassoni
- Division of Biomaterials and Biomechanics, Department of Restorative Dentistry, School of Dentistry, Oregon Health and Science University, Portland, OR, USA
| | - Lobat Tayebi
- Marquette University School of Dentistry, Milwaukee, WI, 53233, USA.
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Lai V, Neshat SY, Rakoski A, Pitingolo J, Doloff JC. Drug delivery strategies in maximizing anti-angiogenesis and anti-tumor immunity. Adv Drug Deliv Rev 2021; 179:113920. [PMID: 34384826 DOI: 10.1016/j.addr.2021.113920] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/04/2021] [Accepted: 08/06/2021] [Indexed: 12/15/2022]
Abstract
Metronomic chemotherapy has been shown to elicit anti-tumor immune response and block tumor angiogenesis distinct from that observed with maximal tolerated dose (MTD) therapy. This review delves into the mechanisms behind anti-tumor immunity and seeks to identify the differential effect of dosing regimens, including daily low-dose and medium-dose intermittent chemotherapy (MEDIC), on both innate and adaptive immune populations involved in observed anti-tumor immune response. Given reports of VEGF/VEGFR blockade antagonizing anti-tumor immunity, drug choice, dose, and selective delivery determined by advanced formulations/vehicles are highlighted as potential sources of innovation for identifying anti-angiogenic modalities that may be combined with metronomic regimens without interrupting key immune players in the anti-tumor response. Engineered drug delivery mechanisms that exhibit extended and local release of anti-angiogenic agents both alone and in combination with chemotherapeutic treatments have also been demonstrated to elicit a potent and potentially systemic anti-tumor immune response, favoring tumor regression and stasis over progression. This review examines this interplay between various cancer models, the host immune response, and select anti-cancer agents depending on drug dosing, scheduling/regimen, and delivery modality.
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Affiliation(s)
- Victoria Lai
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Sarah Y Neshat
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Amanda Rakoski
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - James Pitingolo
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA
| | - Joshua C Doloff
- Department of Biomedical Engineering, Translational Tissue Engineering Center, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Materials Science and Engineering, Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Oncology, Division of Cancer Immunology, Sidney Kimmel Comprehensive Cancer Center and the Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
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7
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Sokolov AV, Dostdar SA, Attwood MM, Krasilnikova AA, Ilina AA, Nabieva AS, Lisitsyna AA, Chubarev VN, Tarasov VV, Schiöth HB. Brain Cancer Drug Discovery: Clinical Trials, Drug Classes, Targets, and Combinatorial Therapies. Pharmacol Rev 2021; 73:1-32. [PMID: 34663683 DOI: 10.1124/pharmrev.121.000317] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Brain cancer is a formidable challenge for drug development, and drugs derived from many cutting-edge technologies are being tested in clinical trials. We manually characterized 981 clinical trials on brain tumors that were registered in ClinicalTrials.gov from 2010 to 2020. We identified 582 unique therapeutic entities targeting 581 unique drug targets and 557 unique treatment combinations involving drugs. We performed the classification of both the drugs and drug targets based on pharmacological and structural classifications. Our analysis demonstrates a large diversity of agents and targets. Currently, we identified 32 different pharmacological directions for therapies that are based on 42 structural classes of agents. Our analysis shows that kinase inhibitors, chemotherapeutic agents, and cancer vaccines are the three most common classes of agents identified in trials. Agents in clinical trials demonstrated uneven distribution in combination approaches; chemotherapy agents, proteasome inhibitors, and immune modulators frequently appeared in combinations, whereas kinase inhibitors, modified immune effector cells did not as was shown by combination networks and descriptive statistics. This analysis provides an extensive overview of the drug discovery field in brain cancer, shifts that have been happening in recent years, and challenges that are likely to come. SIGNIFICANCE STATEMENT: This review provides comprehensive quantitative analysis and discussion of the brain cancer drug discovery field, including classification of drug, targets, and therapies.
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Affiliation(s)
- Aleksandr V Sokolov
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Samira A Dostdar
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Misty M Attwood
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Aleksandra A Krasilnikova
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Anastasia A Ilina
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Amina Sh Nabieva
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Anna A Lisitsyna
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Vladimir N Chubarev
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Vadim V Tarasov
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Helgi B Schiöth
- Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden (A.V.S., S.A.D., M.M.A., H.B.S.); and Department of Pharmacology, Institute of Pharmacy (A.V.S., S.A.D., A.A.K., A.A.I., A.S.N., A.A.L., V.N.C., V.V.T.) and Institute of Translational Medicine and Biotechnology (V.V.T., H.B.S.), I. M. Sechenov First Moscow State Medical University, Moscow, Russia
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8
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Vyas KM, Sharma D, Magani SKJ, Mobin SM, Mukhopadhyay S. In vitro evaluation of cytotoxicity and antimetastatic properties of novel arene ruthenium(II)‐tetrazolato compounds on human cancer cell lines. Appl Organomet Chem 2021. [DOI: 10.1002/aoc.6187] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Komal M. Vyas
- Discipline of Chemistry Indian Institute of Technology Indore Khandwa Road, Simrol Indore 453552 India
- Department of Chemistry Sardar Patel University Vallabh Vidyanagar 388120 India
| | - Deepu Sharma
- Department of Life Sciences, School of Natural Sciences Shiv Nadar University Greater Noida Uttar Pradesh 201314 India
| | - Sri Krishna Jayadev Magani
- Department of Life Sciences, School of Natural Sciences Shiv Nadar University Greater Noida Uttar Pradesh 201314 India
| | - Shaikh M. Mobin
- Discipline of Chemistry Indian Institute of Technology Indore Khandwa Road, Simrol Indore 453552 India
| | - Suman Mukhopadhyay
- Discipline of Chemistry Indian Institute of Technology Indore Khandwa Road, Simrol Indore 453552 India
- Discipline of Biosciences and Biomedical Engineering, School of Engineering Indian Institute of Technology Khandwa Road, Simrol Indore 453552 India
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9
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Meng B, Strawbridge RR, Tichauer K, Samkoe KS, Davis SC. Monitoring cancer cell surface receptor expression during anti-angiogenesis therapy in vivo. PROCEEDINGS OF SPIE--THE INTERNATIONAL SOCIETY FOR OPTICAL ENGINEERING 2021; 11625:116250Q. [PMID: 34446980 PMCID: PMC8386322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Concurrent administration of cancer therapeutics with tumor vasculature targeting treatment has been shown to improve overall survival in multiple human cancer types, as such combinations aim to destroy different compartments of tumors. Anti-angiogenesis therapeutics designed to inhibit tumor induced vessel sprouting have also been shown to re-model the tumor vasculature through a transient vessel normalization effect, which leads to improved perfusion of oxygen and drug in tumor. However, the effects that this normalized vasculature has on the availability of cancer receptor, such as EGFR, is unknown. Herein, we examined the use of MRI-PAFT to estimate cancer surface receptor availability in response to anti-angiogenesis therapy, using MRI-coupled paired agent fluorescence tomography. Bevacizumab treated tumors showed increase in RA compared to control tumors, but this was not statistically significant.
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Affiliation(s)
- Boyu Meng
- Thayer School of Engineering, Dartmouth College, Hanover, NH 03755
| | | | - Kenneth Tichauer
- Armour College of Engineering, Illinois Institute of Technology, Chicago, IL 60616
| | | | - Scott C Davis
- Thayer School of Engineering, Dartmouth College, Hanover, NH 03755
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10
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Buzdin A, Sorokin M, Garazha A, Glusker A, Aleshin A, Poddubskaya E, Sekacheva M, Kim E, Gaifullin N, Giese A, Seryakov A, Rumiantsev P, Moshkovskii S, Moiseev A. RNA sequencing for research and diagnostics in clinical oncology. Semin Cancer Biol 2019; 60:311-323. [PMID: 31412295 DOI: 10.1016/j.semcancer.2019.07.010] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 07/16/2019] [Indexed: 12/26/2022]
Abstract
Molecular diagnostics is becoming one of the major drivers of personalized oncology. With hundreds of different approved anticancer drugs and regimens of their administration, selecting the proper treatment for a patient is at least nontrivial task. This is especially sound for the cases of recurrent and metastatic cancers where the standard lines of therapy failed. Recent trials demonstrated that mutation assays have a strong limitation in personalized selection of therapeutics, consequently, most of the drugs cannot be ranked and only a small percentage of patients can benefit from the screening. Other approaches are, therefore, needed to address a problem of finding proper targeted therapies. The analysis of RNA expression (transcriptomic) profiles presents a reasonable solution because transcriptomics stands a few steps closer to tumor phenotype than the genome analysis. Several recent studies pioneered using transcriptomics for practical oncology and showed truly encouraging clinical results. The possibility of directly measuring of expression levels of molecular drugs' targets and profiling activation of the relevant molecular pathways enables personalized prioritizing for all types of molecular-targeted therapies. RNA sequencing is the most robust tool for the high throughput quantitative transcriptomics. Its use, potentials, and limitations for the clinical oncology will be reviewed here along with the technical aspects such as optimal types of biosamples, RNA sequencing profile normalization, quality controls and several levels of data analysis.
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Affiliation(s)
- Anton Buzdin
- I.M. Sechenov First Moscow State Medical University, Moscow, Russia; Omicsway Corp., Walnut, CA, USA; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia.
| | - Maxim Sorokin
- I.M. Sechenov First Moscow State Medical University, Moscow, Russia; Omicsway Corp., Walnut, CA, USA; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
| | | | | | - Alex Aleshin
- Stanford University School of Medicine, Stanford, 94305, CA, USA
| | - Elena Poddubskaya
- I.M. Sechenov First Moscow State Medical University, Moscow, Russia; Vitamed Oncological Clinics, Moscow, Russia
| | - Marina Sekacheva
- I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Ella Kim
- Johannes Gutenberg University Mainz, Mainz, Germany
| | - Nurshat Gaifullin
- Lomonosov Moscow State University, Faculty of Medicine, Moscow, Russia
| | | | | | | | - Sergey Moshkovskii
- Institute of Biomedical Chemistry, Moscow, 119121, Russia; Pirogov Russian National Research Medical University (RNRMU), Moscow, 117997, Russia
| | - Alexey Moiseev
- I.M. Sechenov First Moscow State Medical University, Moscow, Russia
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The combination of cantharidin and antiangiogenic therapeutics presents additive antitumor effects against pancreatic cancer. Oncogenesis 2018; 7:94. [PMID: 30478299 PMCID: PMC6255842 DOI: 10.1038/s41389-018-0102-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2018] [Revised: 07/14/2018] [Accepted: 11/09/2018] [Indexed: 01/02/2023] Open
Abstract
Cantharidin, one of the active components of mylabris, is believed to have antitumor activity. Cantharidin selectively inhibits protein phosphatase 2A (PP2A), which can repress multiple oncogenic kinases (ERK, JNK, PKC, and NF-κB). Researches in vitro have shown that cantharidin suppresses cell viability and metastasis in pancreatic cancer cells. This study aims to investigate the effects of cantharidin on pancreatic cancer xenografts in vivo. Xenograft models were established using cells stably expressing luciferase. Xenograft growth was evaluated by living imaging. Gene expression was determined using a microarray, real-time PCR, a RayBiotech antibody array, and the Milliplex assay. Surprisingly, cantharidin significantly accelerated xenograft growth. Living imaging showed a rapid distribution of D-luciferin in cantharidin-treated xenografts, suggesting a rich blood supply. Immunohistochemistry confirmed increased angiogenesis. Microarray and antibody array identified upregulated proangiogenic and downregulated antiangiogenic factors. The Milliplex assay suggested elevated secretion of IL-6, IL-8, TNF-α, and VEGF. Inhibitors of ERK, JNK, PKC, and NF-κB pathway attenuated the cantharidin-induced changes to proangiogenic gene expression. PKC pathway-inhibiting tamoxifen or antiangiogenic therapeutics, including Ginsenoside Rg3, bevacizumab, Apatinib, and Endostar, antagonized the proangiogenic effect of cantharidin or its derivatives. These regimens presented remarkable additive antitumor effects in vivo. Although cantharidin presents antitumor effects in vitro and has been applied in clinical practice, we revealed an unfavorable proangiogenic side effect. We recommend that the clinical application of cantharidin should be performed on the premise of antivascularization therapy.
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Ameratunga M, Pavlakis N, Wheeler H, Grant R, Simes J, Khasraw M, Cochrane Gynaecological, Neuro‐oncology and Orphan Cancer Group. Anti-angiogenic therapy for high-grade glioma. Cochrane Database Syst Rev 2018; 11:CD008218. [PMID: 30480778 PMCID: PMC6516839 DOI: 10.1002/14651858.cd008218.pub4] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND This is an updated version of the original Cochrane Review published in September 2014. The most common primary brain tumours in adults are gliomas. Gliomas span a spectrum from low to high grade and are graded pathologically on a scale of one to four according to the World Health Organization (WHO) classification. High-grade glioma (HGG) carries a poor prognosis. Grade IV glioma is known as glioblastoma and carries a median survival in treated patients of about 15 months. Glioblastomas are rich in blood vessels (i.e. highly vascular) and also rich in a protein known as vascular endothelial growth factor (VEGF) that promotes new blood vessel formation (the process of angiogenesis). Anti-angiogenic agents inhibit the process of new blood vessel formation and promote regression of existing vessels. Several anti-angiogenic agents have been investigated in clinical trials, both in newly diagnosed and recurrent HGG, showing preliminary promising results. This review was undertaken to report on the benefits and harms associated with the use of anti-angiogenic agents in the treatment of HGGs. OBJECTIVES To evaluate the efficacy and toxicity of anti-angiogenic therapy in people with high-grade glioma (HGG). The intervention can be used in two broad groups: at first diagnosis as part of 'adjuvant' therapy, or in the setting of recurrent disease. SEARCH METHODS We conducted updated searches to identify published and unpublished randomised controlled trials (RCTs), including the Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 9), MEDLINE and Embase to October 2018. We handsearched proceedings of relevant oncology conferences up to 2018. We also searched trial registries for ongoing studies. SELECTION CRITERIA RCTs evaluating the use of anti-angiogenic therapy to treat HGG versus the same therapy without anti-angiogenic therapy. DATA COLLECTION AND ANALYSIS Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles. MAIN RESULTS After a comprehensive literature search, we identified 11 eligible RCTs (3743 participants), of which 7 were included in the original review (2987 participants). There was significant design heterogeneity in the included studies, especially in the response assessment criteria used. All eligible studies were restricted to glioblastomas and there were no eligible studies evaluating other HGGs. Ten studies were available as fully published peer-reviewed manuscripts, and one study was available in abstract form. The overall risk of bias in included studies was low. This risk was based upon low rates of selection bias, detection bias, attrition bias and reporting bias. The 11 studies included in this review did not show an improvement in overall survival with the addition of anti-angiogenic therapy (pooled hazard ratio (HR) of 0.95, 95% confidence interval (CI) 0.88 to 1.02; P = 0.16; 11 studies, 3743 participants; high-certainty evidence). However, pooled analysis from 10 studies (3595 participants) showed improvement in progression-free survival with the addition of anti-angiogenic therapy (HR 0.73, 95% CI 0.68 to 0.79; P < 0.00001; high-certainty evidence).We carried out additional analyses of overall survival and progression-free survival according to treatment setting and for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy alone. Pooled analysis of overall survival in either the adjuvant or recurrent setting did not show an improvement (HR 0.93, 95% CI 0.86 to 1.02; P = 0.12; 8 studies, 2833 participants; high-certainty evidence and HR 0.99, 95% CI 0.85 to 1.16; P = 0.90; 3 studies, 910 participants; moderate-certainty evidence, respectively). Pooled analysis of overall survival for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy also did not clearly show an improvement (HR 0.92, 95% CI 0.85 to 1.00; P = 0.05; 11 studies, 3506 participants; low-certainty evidence). The progression-free survival in the subgroups all showed findings that demonstrated improvements in progression-free survival with the addition of anti-angiogenic therapy. Pooled analysis of progression-free survival in both the adjuvant and recurrent setting showed an improvement (HR 0.75, 95% CI 0.69 to 0.82; P < 0.00001; 8 studies, 2833 participants; high-certainty evidence and HR 0.64, 95% CI 0.54 to 0.76; P < 0.00001; 2 studies, 762 participants; moderate-certainty evidence, respectively). Pooled analysis of progression-free survival for anti-angiogenic therapy combined with chemotherapy compared to chemotherapy alone showed an improvement (HR 0.72, 95% CI 0.66 to 0.77; P < 0.00001; 10 studies, 3464 participants). Similar to trials of anti-angiogenic therapies in other solid tumours, adverse events related to this class of therapy included hypertension and proteinuria, poor wound healing, and the potential for thromboembolic events, although generally, the rate of grade 3 and 4 adverse events was low (< 14.1%) and in keeping with the literature. The impact of anti-angiogenic therapy on quality of life varied between studies. AUTHORS' CONCLUSIONS The use of anti-angiogenic therapy does not significantly improve overall survival in newly diagnosed people with glioblastoma. Thus, there is insufficient evidence to support the use of anti-angiogenic therapy for people with newly diagnosed glioblastoma at this time. Overall there is a lack of evidence of a survival advantage for anti-angiogenic therapy over chemotherapy in recurrent glioblastoma. When considering the combination anti-angiogenic therapy with chemotherapy compared with the same chemotherapy alone, there may possibly be a small improvement in overall survival. While there is strong evidence that bevacizumab (an anti-angiogenic drug) prolongs progression-free survival in newly diagnosed and recurrent glioblastoma, the impact of this on quality of life and net clinical benefit for patients remains unclear. Not addressed here is whether subsets of people with glioblastoma may benefit from anti-angiogenic therapies, nor their utility in other HGG histologies.
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Affiliation(s)
- Malaka Ameratunga
- Alfred HospitalMedical OncologyCommercial RoadMelbourneVictoriaAustralia3004
| | - Nick Pavlakis
- Royal North Shore HospitalDepartment of Medical OncologyPacific HighwaySt LeonardsNew South WalesAustralia2065
| | - Helen Wheeler
- Royal North Shore HospitalDepartment of Medical OncologyPacific HighwaySt LeonardsNew South WalesAustralia2065
| | - Robin Grant
- Western General HospitalEdinburgh Centre for Neuro‐Oncology (ECNO)Crewe RoadEdinburghScotlandUKEH4 2XU
| | - John Simes
- The University of SydneyNHMRC Clinical Trials CentreLocked Bag 77CamperdownNSWAustralia1450
| | - Mustafa Khasraw
- NHMRC Clinical Trials Centre, The University of SydneyCamperdownAustralia
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Wang F, Molina J, Satele D, Yin J, Lim VS, Adjei AA. A phase I study of the vascular endothelial growth factor inhibitor Vatalanib in combination with Pemetrexed disodium in patients with advanced solid tumors. Invest New Drugs 2018; 37:658-665. [PMID: 30382439 DOI: 10.1007/s10637-018-0690-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Accepted: 10/25/2018] [Indexed: 02/07/2023]
Abstract
Introduction Vatalanib is an oral receptor tyrosine kinase inhibitor that blocks all known VEGF, PDGF, and c-Kit receptors. This phase I study evaluated the safety, tolerability, and biologic activity of the combination of vatalanib with pemetrexed disodium in patients with advanced solid tumors. Methods Patients were administered escalating twice daily doses of vatalanib in combination with pemetrexed disodium in 21-day cycles. A dose expansion cohort was enrolled to further define the maximum tolerated dose (MTD) and further evaluate efficacy. Results A total of 29 patients were enrolled in the study (dose escalation, 9; dose expansion, 20). Dose-limiting toxicities included grade 4 thrombocytopenia (6.9%) and febrile neutropenia, anorexia, constipation, and dehydration. Other common adverse events were fatigue (75%), nausea (66%), vomiting (48%), oral mucositis (31%) and diarrhea (28%). The majority of these toxicities were Grade 1-2. The MTD was reached at vatalanib 250 mg twice daily continuously combined with pemetrexed disodium 500 mg/m2 day 1. Overall, 2 patients (6.9%) had partial responses, 8 (27.6%) had stable disease for at least 4 cycles, 5 had progressive disease (17.2%) and 5 went off study before disease assessment. Conclusion The combination of vatalanib with pemetrexed disodium was feasible, but not well tolerated. The modest efficacy results are consistent with other results obtained from combinations of chemotherapy and a large number of VEGF tyrosine kinase inhibitors. This combination should not be developed further unless predictive biomarkers can be identified.
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Affiliation(s)
- Fen Wang
- Department of Oncology, Peking University Shenzhen Hospital, Shenzhen, Guangdong, China
| | - Julian Molina
- Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, United States
| | - Daniel Satele
- Department of Health Sciences Research, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, United States
| | - Jun Yin
- Department of Health Sciences Research, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, United States
| | - Vun-Sin Lim
- Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, United States
| | - Alex A Adjei
- Department of Oncology, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, United States.
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Characterization of Small Molecules Inhibiting the Pro-Angiogenic Activity of the Zinc Finger Transcription Factor Vezf1. Molecules 2018; 23:molecules23071615. [PMID: 29970794 PMCID: PMC6100598 DOI: 10.3390/molecules23071615] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 06/23/2018] [Accepted: 06/24/2018] [Indexed: 02/01/2023] Open
Abstract
Discovery of inhibitors for endothelial-related transcription factors can contribute to the development of anti-angiogenic therapies that treat various diseases, including cancer. The role of transcription factor Vezf1 in vascular development and regulation of angiogenesis has been defined by several earlier studies. Through construction of a computational model for Vezf1, work here has identified a novel small molecule drug capable of inhibiting Vezf1 from binding to its cognate DNA binding site. Using structure-based design and virtual screening of the NCI Diversity Compound Library, 12 shortlisted compounds were tested for their ability to interfere with the binding of Vezf1 to DNA using electrophoretic gel mobility shift assays. We identified one compound, T4, which has an IC50 of 20 μM. Using murine endothelial cells, MSS31, we tested the effect of T4 on endothelial cell viability and angiogenesis by using tube formation assay. Our data show that addition of T4 in cell culture medium does not affect cell viability at concentrations lower or equal to its IC 50 but strongly inhibits the network formation by MSS31 in the tube formation assays. Given its potential efficacy, this inhibitor has significant therapeutic potential in several human diseases.
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15
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Synthesis, cytotoxicity and anti-metastatic properties of new pyridyl-thiazole arene ruthenium(II) complexes. Appl Organomet Chem 2018. [DOI: 10.1002/aoc.4311] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
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Hilberg F, Tontsch-Grunt U, Baum A, Le AT, Doebele RC, Lieb S, Gianni D, Voss T, Garin-Chesa P, Haslinger C, Kraut N. Triple Angiokinase Inhibitor Nintedanib Directly Inhibits Tumor Cell Growth and Induces Tumor Shrinkage via Blocking Oncogenic Receptor Tyrosine Kinases. J Pharmacol Exp Ther 2018; 364:494-503. [PMID: 29263244 PMCID: PMC6040086 DOI: 10.1124/jpet.117.244129] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2017] [Accepted: 12/11/2017] [Indexed: 12/11/2022] Open
Abstract
The triple-angiokinase inhibitor nintedanib is an orally available, potent, and selective inhibitor of tumor angiogenesis by blocking the tyrosine kinase activities of vascular endothelial growth factor receptor (VEGFR) 1-3, platelet-derived growth factor receptor (PDGFR)-α and -β, and fibroblast growth factor receptor (FGFR) 1-3. Nintedanib has received regulatory approval as second-line treatment of adenocarcinoma non-small cell lung cancer (NSCLC), in combination with docetaxel. In addition, nintedanib has been approved for the treatment of idiopathic lung fibrosis. Here we report the results from a broad kinase screen that identified additional kinases as targets for nintedanib in the low nanomolar range. Several of these kinases are known to be mutated or overexpressed and are involved in tumor development (discoidin domain receptor family, member 1 and 2, tropomyosin receptor kinase A (TRKA) and C, rearranged during transfection proto-oncogene [RET proto oncogene]), as well as in fibrotic diseases (e.g., DDRs). In tumor cell lines displaying molecular alterations in potential nintedanib targets, the inhibitor demonstrates direct antiproliferative effects: in the NSCLC cell line NCI-H1703 carrying a PDGFRα amplification (ampl.); the gastric cancer cell line KatoIII and the breast cancer cell line MFM223, both driven by a FGFR2 amplification; AN3CA (endometrial carcinoma) bearing a mutated FGFR2; the acute myeloid leukemia cell lines MOLM-13 and MV-4-11-B with FLT3 mutations; and the NSCLC adenocarcinoma LC-2/ad harboring a CCDC6-RET fusion. Potent kinase inhibition does not, however, strictly translate into antiproliferative activity, as demonstrated in the TRKA-dependent cell lines CUTO-3 and KM-12. Importantly, nintedanib treatment of NCI-H1703 tumor xenografts triggered effective tumor shrinkage, indicating a direct effect on the tumor cells in addition to the antiangiogenic effect on the tumor stroma. These findings will be instructive in guiding future genome-based clinical trials of nintedanib.
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Affiliation(s)
- Frank Hilberg
- Boehringer Ingelheim RCV GmbH Co KG, Vienna, Austria (F.H., U.T.-G., A.B., S.L., D.G., T.V., P.G.-C., C.H., N.K.); University of Colorado, School of Medicine, Division of Medical Oncology, Aurora, Colorado (A.T.L., R.C.D.); and AstraZeneca - Innovative Medicines and Early Development, Discovery Sciences, Cambridge Science Park, Milton, Cambridge (D.G.)
| | - Ulrike Tontsch-Grunt
- Boehringer Ingelheim RCV GmbH Co KG, Vienna, Austria (F.H., U.T.-G., A.B., S.L., D.G., T.V., P.G.-C., C.H., N.K.); University of Colorado, School of Medicine, Division of Medical Oncology, Aurora, Colorado (A.T.L., R.C.D.); and AstraZeneca - Innovative Medicines and Early Development, Discovery Sciences, Cambridge Science Park, Milton, Cambridge (D.G.)
| | - Anke Baum
- Boehringer Ingelheim RCV GmbH Co KG, Vienna, Austria (F.H., U.T.-G., A.B., S.L., D.G., T.V., P.G.-C., C.H., N.K.); University of Colorado, School of Medicine, Division of Medical Oncology, Aurora, Colorado (A.T.L., R.C.D.); and AstraZeneca - Innovative Medicines and Early Development, Discovery Sciences, Cambridge Science Park, Milton, Cambridge (D.G.)
| | - Anh T Le
- Boehringer Ingelheim RCV GmbH Co KG, Vienna, Austria (F.H., U.T.-G., A.B., S.L., D.G., T.V., P.G.-C., C.H., N.K.); University of Colorado, School of Medicine, Division of Medical Oncology, Aurora, Colorado (A.T.L., R.C.D.); and AstraZeneca - Innovative Medicines and Early Development, Discovery Sciences, Cambridge Science Park, Milton, Cambridge (D.G.)
| | - Robert C Doebele
- Boehringer Ingelheim RCV GmbH Co KG, Vienna, Austria (F.H., U.T.-G., A.B., S.L., D.G., T.V., P.G.-C., C.H., N.K.); University of Colorado, School of Medicine, Division of Medical Oncology, Aurora, Colorado (A.T.L., R.C.D.); and AstraZeneca - Innovative Medicines and Early Development, Discovery Sciences, Cambridge Science Park, Milton, Cambridge (D.G.)
| | - Simone Lieb
- Boehringer Ingelheim RCV GmbH Co KG, Vienna, Austria (F.H., U.T.-G., A.B., S.L., D.G., T.V., P.G.-C., C.H., N.K.); University of Colorado, School of Medicine, Division of Medical Oncology, Aurora, Colorado (A.T.L., R.C.D.); and AstraZeneca - Innovative Medicines and Early Development, Discovery Sciences, Cambridge Science Park, Milton, Cambridge (D.G.)
| | - Davide Gianni
- Boehringer Ingelheim RCV GmbH Co KG, Vienna, Austria (F.H., U.T.-G., A.B., S.L., D.G., T.V., P.G.-C., C.H., N.K.); University of Colorado, School of Medicine, Division of Medical Oncology, Aurora, Colorado (A.T.L., R.C.D.); and AstraZeneca - Innovative Medicines and Early Development, Discovery Sciences, Cambridge Science Park, Milton, Cambridge (D.G.)
| | - Tilman Voss
- Boehringer Ingelheim RCV GmbH Co KG, Vienna, Austria (F.H., U.T.-G., A.B., S.L., D.G., T.V., P.G.-C., C.H., N.K.); University of Colorado, School of Medicine, Division of Medical Oncology, Aurora, Colorado (A.T.L., R.C.D.); and AstraZeneca - Innovative Medicines and Early Development, Discovery Sciences, Cambridge Science Park, Milton, Cambridge (D.G.)
| | - Pilar Garin-Chesa
- Boehringer Ingelheim RCV GmbH Co KG, Vienna, Austria (F.H., U.T.-G., A.B., S.L., D.G., T.V., P.G.-C., C.H., N.K.); University of Colorado, School of Medicine, Division of Medical Oncology, Aurora, Colorado (A.T.L., R.C.D.); and AstraZeneca - Innovative Medicines and Early Development, Discovery Sciences, Cambridge Science Park, Milton, Cambridge (D.G.)
| | - Christian Haslinger
- Boehringer Ingelheim RCV GmbH Co KG, Vienna, Austria (F.H., U.T.-G., A.B., S.L., D.G., T.V., P.G.-C., C.H., N.K.); University of Colorado, School of Medicine, Division of Medical Oncology, Aurora, Colorado (A.T.L., R.C.D.); and AstraZeneca - Innovative Medicines and Early Development, Discovery Sciences, Cambridge Science Park, Milton, Cambridge (D.G.)
| | - Norbert Kraut
- Boehringer Ingelheim RCV GmbH Co KG, Vienna, Austria (F.H., U.T.-G., A.B., S.L., D.G., T.V., P.G.-C., C.H., N.K.); University of Colorado, School of Medicine, Division of Medical Oncology, Aurora, Colorado (A.T.L., R.C.D.); and AstraZeneca - Innovative Medicines and Early Development, Discovery Sciences, Cambridge Science Park, Milton, Cambridge (D.G.)
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Fan Y, Sun W, Shi X. Design and Biomedical Applications of Poly(amidoamine)‐Dendrimer‐Based Hybrid Nanoarchitectures. SMALL METHODS 2017; 1. [DOI: 10.1002/smtd.201700224] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
AbstractDendrimers, especially poly(amidoamine) (PAMAM) dendrimers, possess unique properties such as 3D architecture, monodispersity, highly branched macromolecular characteristics, and tunable terminal functionalities. These properties allow them to be used for controlled synthesis and assembly of hybrid nanoarchitectures with a range of properties suitable for biomedical applications. Here, the recent advances in the design of different PAMAM‐dendrimer‐based hybrid nanoarchitectures for various biomedical applications, in particular for molecular imaging, nonviral gene delivery, and theranostics, are summarized and discussed; future perspectives are also briefly illustrated.
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Affiliation(s)
- Yu Fan
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials College of Chemistry Chemical Engineering and Biotechnology Donghua University Shanghai 201620 P. R. China
| | - Wenjie Sun
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials College of Chemistry Chemical Engineering and Biotechnology Donghua University Shanghai 201620 P. R. China
| | - Xiangyang Shi
- State Key Laboratory for Modification of Chemical Fibers and Polymer Materials College of Chemistry Chemical Engineering and Biotechnology Donghua University Shanghai 201620 P. R. China
- CQM‐Centro de Química da Madeira Universidade da Madeira Campus da Penteada 9000‐390 Funchal Portugal
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Zhang J, Li J, Shi Z, Yang Y, Xie X, Lee SM, Wang Y, Leong KW, Chen M. pH-sensitive polymeric nanoparticles for co-delivery of doxorubicin and curcumin to treat cancer via enhanced pro-apoptotic and anti-angiogenic activities. Acta Biomater 2017; 58:349-364. [PMID: 28455219 DOI: 10.1016/j.actbio.2017.04.029] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 04/22/2017] [Accepted: 04/24/2017] [Indexed: 01/24/2023]
Abstract
Co-delivery of multiple drugs with complementary anticancer mechanisms by nano-carriers offers an effective strategy to treat cancer. The combination of drugs with pro-apoptotic and anti-angiogenic activities is potentially effective in treating human hepatocellular carcinoma (HCC). Herein, we developed a co-delivery system for doxorubicin (Dox), a pro-apoptotic drug, and curcumin (Cur), a potent drug for antiangiogenesis, in pH-sensitive nanoparticles (NPs) constituted with amphiphilic poly(β-amino ester) copolymer. Dox & Cur co-loaded NPs ((D+C)/NPs) were prepared with optimized drug ratio, showing low polydispersity, high encapsulation efficiency, and enhanced release in the acidic environment of cancer cells. Furthermore, enhanced cellular internalization of cargoes delivered from (D+C)/NPs were observed in human liver cancer SMMC 7721 cells and human umbilical vein endothelial cells (HUVECs) compared to the use of free drugs. The (D+C)/NPs induced a high rate of apoptosis in SMMC 7721 cells through decreased mitochondrial membrane potential. Additionally, (D+C)/NPs exhibited stronger anti-angiogenic effects including inhibition of HUVEC proliferation, migration, invasion, and tube formation mediated VEGF pathway modulation in vitro and in vivo. Taken together, encapsulation of the pro-apoptotic drug Dox and antiangiogenic agent Cur in pH-sensitive NPs provides a promising strategy to effectively inhibit HCC progression in a synergistic manner. STATEMENT OF SIGNIFICANCE The combination of multiple drugs has been demonstrated to be more effective than single treatment. However, the different physicochemical and pharmacokinetic profiles of each drug render optimal delivery challenging. In view of the great delivery advantage of nanocarriers to unify the multiple drugs in vivo, stimulus-responsive nano-carriers are more crucial to increase efficacy and reduce toxicity from off-target exposure. Therefore, herein the pH-sensitive nanoparticles, composed by d-α-tocopheryl polyethylene glycol 1000-block-poly (β-amino ester) (TPGS-PAE) polymers, have been fabricated for doxorubicin (Dox) and curcumin (Cur) co-delivery, which exhibited diverse anticancer approaches, i.e. pro-apoptosis and antiangiogenesis. The precise intracellular target site and effective drug combination concentration result in the enhanced antitumor efficiency and the reduced systematic toxicity of Dox. The co-encapsulation of the pro-apoptotic drug and antiangiogenic agent in pH-sensitive NPs provides a promising strategy to effectively inhibit malignant neoplasm progression in a synergistic manner.
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Strozyk MS, Carregal-Romero S, Henriksen-Lacey M, Brust M, Liz-Marzán LM. Biocompatible, Multiresponsive Nanogel Composites for Codelivery of Antiangiogenic and Chemotherapeutic Agents. CHEMISTRY OF MATERIALS 2017; 29:2303-2313. [DOI: 10.1021/acs.chemmater.6b05471] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Affiliation(s)
- Malte S. Strozyk
- Bionanoplasmonics
Laboratory, CIC biomaGUNE, Paseo de Miramón 182, 20014 Donostia-San Sebastián, Spain
- Department
of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom
| | - Susana Carregal-Romero
- Bionanoplasmonics
Laboratory, CIC biomaGUNE, Paseo de Miramón 182, 20014 Donostia-San Sebastián, Spain
| | - Malou Henriksen-Lacey
- Bionanoplasmonics
Laboratory, CIC biomaGUNE, Paseo de Miramón 182, 20014 Donostia-San Sebastián, Spain
- CIBER
de Bioingenierı́a, Biomateriales y Nanomedicina, 20014 Donostia-San Sebastián, Spain
| | - Mathias Brust
- Department
of Chemistry, University of Liverpool, Liverpool L69 7ZD, United Kingdom
| | - Luis M. Liz-Marzán
- Bionanoplasmonics
Laboratory, CIC biomaGUNE, Paseo de Miramón 182, 20014 Donostia-San Sebastián, Spain
- Ikerbasque, Basque
Foundation for Science, 48013 Bilbao, Spain
- CIBER
de Bioingenierı́a, Biomateriales y Nanomedicina, 20014 Donostia-San Sebastián, Spain
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Sun J, Jiang L, Lin Y, Gerhard EM, Jiang X, Li L, Yang J, Gu Z. Enhanced anticancer efficacy of paclitaxel through multistage tumor-targeting liposomes modified with RGD and KLA peptides. Int J Nanomedicine 2017; 12:1517-1537. [PMID: 28280323 PMCID: PMC5338999 DOI: 10.2147/ijn.s122859] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Mitochondria serve as both “energy factories” and “suicide weapon stores” of cells. Targeted delivery of cytotoxic drugs to the mitochondria of tumor cells and tumor vascular cells is a promising strategy to improve the efficacy of chemotherapy. Here, multistage tumor-targeting liposomes containing two targeted peptide-modified lipids, cRGD-PEG2000-DSPE and KLA-PEG2000-DSPE, were developed for encapsulation of the anticancer drug paclitaxel (PTX, RGD-KLA/PTX-Lips). Compared with Taxol (free PTX), RGD/PTX-Lips and KLA/PTX-Lips, the half-maximal inhibitory concentration (IC50) value of RGD-KLA/PTX-Lips in vitro was 1.9-, 36.7- and 22.7-fold lower with 4T1 cells, respectively, because of higher levels of cellular uptake. Similar results were also observed with human umbilical vascular endothelial cells (HUVECs). An apoptosis assay showed that the total apoptotic ratio of RGD-KLA/PTX-Lips was the highest because of the mitochondria-targeted drug delivery and the activation of mitochondrial apoptosis pathways, as evidenced by visible mitochondrial localization, decreased mitochondrial membrane potential, release of cytochrome c and increased activities of caspase-9 and caspase-3. The strongest tumor growth inhibition (TGI; 80.6%) and antiangiogenesis effects without systemic toxicity were also observed in RGD-KLA/PTX-Lip-treated 4T1 tumor xenograft BALB/c mice. In conclusion, these multistage tumor-targeting liposomes represent a promising anticancer drug delivery system (DDS) capable of maximizing anticancer therapeutic efficacy and minimizing systemic toxicity.
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Affiliation(s)
- Jiawei Sun
- West China School of Pharmacy, Sichuan University, Chengdu, Sichuan
| | - Lei Jiang
- Department of Pharmaceutics, China Pharmaceutical University, Nanjing, Jiangsu
| | - Yi Lin
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Ethan Michael Gerhard
- Department of Biomedical Engineering Materials Research Institute, The Huck Institutes of The Life Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Xuehua Jiang
- West China School of Pharmacy, Sichuan University, Chengdu, Sichuan
| | - Li Li
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Jian Yang
- Department of Biomedical Engineering Materials Research Institute, The Huck Institutes of The Life Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Zhongwei Gu
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, Sichuan, People's Republic of China
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Klamka J, Maurer H, Swierniak A. Local controllability and optimal control for a model of combined anticancer therapy with control delays. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2017; 14:195-216. [PMID: 27879128 DOI: 10.3934/mbe.2017013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
We study some control properties of a class of two-compartmental models of response to anticancer treatment which combines anti-angiogenic and cytotoxic drugs and take into account multiple control delays. We formulate sufficient local controllability conditions for semilinear systems resulting from these models. The control delays are related to PK/PD effects and some clinical recommendations, e.g., normalization of the vascular network. The optimized protocols of the combined therapy for the model, considered as solutions to an optimal control problem with delays in control, are found using necessary conditions of optimality and numerical computations. Our numerical approach uses dicretization and nonlinear programming methods as well as the direct optimization of switching times. The structural sensitivity of the considered control properties and optimal solutions is also discussed.
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Affiliation(s)
- Jerzy Klamka
- Silesian University of Technology, Department of Automatic Control, Akademicka 16, 44101 Gliwice, Poland.
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Lombardi G, Pambuku A, Bellu L, Farina M, Della Puppa A, Denaro L, Zagonel V. Effectiveness of antiangiogenic drugs in glioblastoma patients: A systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol 2017; 111:94-102. [PMID: 28259301 DOI: 10.1016/j.critrevonc.2017.01.018] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2016] [Revised: 01/17/2017] [Accepted: 01/24/2017] [Indexed: 12/01/2022] Open
Abstract
BACKGROUND glioblastomas are highly vascularized tumors and various antiangiogenic drugs have been investigated in clinical trials showing unclear results. We performed a systematic review and a meta-analysis to clarify and evaluate their effectiveness in glioblastoma patients. PATIENTS AND METHODS we searched relevant published and unpublished randomized clinical trials analyzing antiangiogenic drugs versus chemotherapy in glioblastoma patients from January 2006 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. RESULTS fourteen randomized clinical trials were identified (7 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) including 4330 patients. Antiangiogenic drugs showed no improvement in overall survival with a pooled HR of 1.00, a trend for an inferior outcome, in terms of overall survival, was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR=1.24, p=0.056). Bevacizumab did not improve overall survival. Twelve trials (4113 patients) were analyzed for progression-free survival. Among antiangiogenic drugs, only bevacizumab demonstrated an improvement of progression-free survival (HR=0.63, p<0.001), both alone (HR=0.60, p=0.003) or in combination to chemotherapy (HR=0.63; p<0.001), both as first-line treatment (HR=0.70, p<0.001) or in recurrent disease (HR=0.52, p<0.001). CONCLUSIONS antiangiogenic drugs did not improve overall survival in glioblastoma patients, either as first or second-line treatment, and either as single agent or in combination with chemotherapy. Among antiangiogenic drugs, only bevacizumab improved progression-free survival regardless of treatment line, both as single agent or in combination with chemotherapy.
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Affiliation(s)
- Giuseppe Lombardi
- Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology, IOV - IRCCS, Padua, Italy.
| | - Ardi Pambuku
- Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology, IOV - IRCCS, Padua, Italy
| | - Luisa Bellu
- Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology, IOV - IRCCS, Padua, Italy
| | - Miriam Farina
- Clinical Trials and Biostatistics Unit, Veneto Institute of Oncology, IOV - IRCCS, Padua, Italy
| | | | - Luca Denaro
- Neurosurgery Department, University of Padua, Padua, Italy
| | - Vittorina Zagonel
- Department of Clinical and Experimental Oncology, Medical Oncology 1, Veneto Institute of Oncology, IOV - IRCCS, Padua, Italy
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Rocha TGR, Lopes SCDA, Cassali GD, Ferreira Ê, Veloso ES, Leite EA, Braga FC, Ferreira LAM, Balvay D, Garofalakis A, Oliveira MC, Tavitian B. Evaluation of Antitumor Activity of Long-Circulating and pH-Sensitive Liposomes Containing Ursolic Acid in Animal Models of Breast Tumor and Gliosarcoma. Integr Cancer Ther 2016; 15:512-524. [PMID: 27130721 PMCID: PMC5739155 DOI: 10.1177/1534735416628273] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Revised: 12/01/2015] [Accepted: 12/11/2015] [Indexed: 01/05/2023] Open
Abstract
Background Ursolic acid (UA) is a triterpene found in different plant species, possessing antitumor activity, which may be a result of its antiangiogenic effect. However, UA has low water solubility, which limits its use because the bioavailability is impaired. To overcome this inconvenience, we developed long-circulating and pH-sensitive liposomes containing ursolic acid (SpHL-UA). We investigated the antiangiogenic effect of free UA and SpHL-UA in murine brain cancer and human breast tumor models by means of determination of the relative tumor volume, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and histopathological analysis. Methods The animals were treated with dimethyl sulfoxide in 0.9% (w/v) NaCl, free UA, long-circulating and pH-sensitive liposomes without drug (SpHL), or SpHL-UA. The animals were submitted to each treatment by intraperitoneal injection for 5 days. The dose of free UA or SpHL-UA was equal to 23 mg/kg. Results Tumor growth inhibition was not observed in human breast tumor-bearing animals. For murine gliosarcoma-bearing animals, a slight tumor growth inhibition was observed in the groups treated with free UA or SpHL-UA (9% and 15%, respectively). No significant change in any of the parameters evaluated by DCE-MRI for both experimental models could be observed. Nevertheless, the evaluation of the mean values of magnetic resonance parameters of human breast tumor-bearing animals showed evidence of a possible antiangiogenic effect induced by SpHL-UA. Histopathological analysis did not present significant change for any treatment. Conclusion SpHL-UA did not show antiangiogenic activity in a gliosarcoma model and seemed to induce an antiangiogenic effect in the human breast tumor model.
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Affiliation(s)
| | | | | | - Ênio Ferreira
- Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
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25
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Kumar M, Dhatwalia SK, Dhawan DK. Role of angiogenic factors of herbal origin in regulation of molecular pathways that control tumor angiogenesis. Tumour Biol 2016; 37:14341-14354. [DOI: 10.1007/s13277-016-5330-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2016] [Accepted: 09/06/2016] [Indexed: 12/19/2022] Open
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Xu X, Li L, Zhou Z, Sun W, Huang Y. Dual-pH responsive micelle platform for co-delivery of axitinib and doxorubicin. Int J Pharm 2016; 507:50-60. [DOI: 10.1016/j.ijpharm.2016.04.060] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 04/22/2016] [Accepted: 04/23/2016] [Indexed: 12/14/2022]
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Ma Y, Mou Q, Wang D, Zhu X, Yan D. Dendritic Polymers for Theranostics. Theranostics 2016; 6:930-47. [PMID: 27217829 PMCID: PMC4876620 DOI: 10.7150/thno.14855] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 03/09/2016] [Indexed: 12/14/2022] Open
Abstract
Dendritic polymers are highly branched polymers with controllable structures, which possess a large population of terminal functional groups, low solution or melt viscosity, and good solubility. Their size, degree of branching and functionality can be adjusted and controlled through the synthetic procedures. These tunable structures correspond to application-related properties, such as biodegradability, biocompatibility, stimuli-responsiveness and self-assembly ability, which are the key points for theranostic applications, including chemotherapeutic theranostics, biotherapeutic theranostics, phototherapeutic theranostics, radiotherapeutic theranostics and combined therapeutic theranostics. Up to now, significant progress has been made for the dendritic polymers in solving some of the fundamental and technical questions toward their theranostic applications. In this review, we briefly summarize how to control the structures of dendritic polymers, the theranostics-related properties derived from their structures and their theranostics-related applications.
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Affiliation(s)
- Yuan Ma
- School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Quanbing Mou
- School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Dali Wang
- School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Xinyuan Zhu
- School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
| | - Deyue Yan
- School of Chemistry and Chemical Engineering, State Key Laboratory of Metal Matrix Composites, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, P. R. China
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Cesca M, Morosi L, Berndt A, Nerini IF, Frapolli R, Richter P, Decio A, Dirsch O, Micotti E, Giordano S, D'Incalci M, Davoli E, Zucchetti M, Giavazzi R. Bevacizumab-Induced Inhibition of Angiogenesis Promotes a More Homogeneous Intratumoral Distribution of Paclitaxel, Improving the Antitumor Response. Mol Cancer Ther 2015; 15:125-35. [DOI: 10.1158/1535-7163.mct-15-0063] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 10/09/2015] [Indexed: 11/16/2022]
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Gandin V, Trenti A, Porchia M, Tisato F, Giorgetti M, Zanusso I, Trevisi L, Marzano C. Homoleptic phosphino copper(I) complexes with in vitro and in vivo dual cytotoxic and anti-angiogenic activity. Metallomics 2015; 7:1497-507. [PMID: 26190698 DOI: 10.1039/c5mt00163c] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Homoleptic, tetrahedral Cu(i) complexes of the type [Cu(P)4]BF4 (1-3), where P are the phosphine ligands, 1,3,5-triaza-7-phosphaadamantane (PTA), 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane (DAPTA) and 2-thia-1,3,5-triaza-phosphoaadamantane-2,2-dioxide (PTA-SO2), have been prepared. Novel complexes [Cu(DAPTA)4]BF42 and [Cu(PTA-SO2)4]BF43 have been fully characterized by means of spectroscopic methods, corroborated by XAS-EXAFS analysis of 2. In vitro cell culture experiments revealed a significant antiproliferative activity for Cu(i) compounds against several human cancer cell lines derived from solid tumors with preferential cell growth inhibition towards tumour compared to non-malignant cells. In vitro monitoring of migration and capillary-like tube formation of human umbilical vein endothelial cells (HUVECs) showed an anti-angiogenic effect of copper(i) complexes at sub-cytotoxic concentrations. In vivo studies on the antitumor efficacy and ability to inhibit angiogenesis confirmed the dual cytotoxic and anti-angiogenic properties of Cu(i) derivatives.
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Affiliation(s)
- V Gandin
- Dipartimento di Scienze del Farmaco, Università di Padova, via Marzolo 5, 35131 Padova, Italy.
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Li W, Luo T, Yang Y, Tan X, Liu L. Formation of controllable hydrophilic/hydrophobic drug delivery systems by electrospinning of vesicles. LANGMUIR : THE ACS JOURNAL OF SURFACES AND COLLOIDS 2015; 31:5141-5146. [PMID: 25897828 DOI: 10.1021/la504796v] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2023]
Abstract
Novel multifunctional poly(ethylene oxide) (PEO) nanofibrous membrane, which contains vesicles constructed by mixed surfactant cetyltrimethylammonium bromide (CTAB)/sodium dodecylbenzenesulfonate (SDBS), has been designed as dual drug-delivery system and fabricated via the electrospinning process. 5-FU and paeonolum, which are hydrophilic and hydrophobic anticancer model drugs, can be dissolved in vesicle solution's bond water and lipid bilayer membranes, respectively. The physicochemical properties of the electrospun nanofibrous membrane were systematically studied using scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FTIR), and X-ray diffraction (XRD). Drug release behaviors of the electrospun nanofibrous membrane fabricated with different molar ratio of CTAB/SDBS vesicle solution were investigated. The result showed that the releasing amount of hydrophilic drug presented an ascending release manner, while the hydrophobic one showed a descending release behavior with increasing of the molar ratio of CTAB/SDBS. Moreover, the release amount of drugs from drug delivery system can be controlled by the molar ratio of CTAB/SDBS in the vesicle solution easily and conveniently. The distinct properties can be utilized to encapsulate environmental demanding and quantificational materials.
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Affiliation(s)
- Wei Li
- Department of Chemistry, Capital Normal University, Beijing 100048, China
| | - Tian Luo
- Department of Chemistry, Capital Normal University, Beijing 100048, China
| | - Yanjuan Yang
- Department of Chemistry, Capital Normal University, Beijing 100048, China
| | - Xiuniang Tan
- Department of Chemistry, Capital Normal University, Beijing 100048, China
| | - Lifei Liu
- Department of Chemistry, Capital Normal University, Beijing 100048, China
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Anti-angiogenic Effects of Bumetanide Revealed by DCE-MRI with a Biodegradable Macromolecular Contrast Agent in a Colon Cancer Model. Pharm Res 2015; 32:3029-43. [PMID: 25840948 DOI: 10.1007/s11095-015-1684-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 03/19/2015] [Indexed: 10/23/2022]
Abstract
PURPOSE To assess the antiangiogenic effect of bumetanide with dynamic contrast enhanced (DCE)-MRI and a biodegradable macromolecular MRI contrast agent. METHODS A new polydisulfide containing macrocyclic gadolinium (Gd(III)) chelates, poly([(Gd-DOTA)-DETA]-co-DTBP) (GODP), was synthesized as a safe biodegradable macromolecular MRI contrast agent for DCE-MRI. Nude mice bearing flank HT29 colon cancer xenografts were then treated daily with either bumetanide or saline for a total of 3 weeks. DCE-MRI was performed before and after the treatment weekly. The DCE-MRI data were analyzed using the adiabiatic approximation to the tissue homogeneity (AATH) model to assess the change of tumor vascularity in response to the treatment. Immunohistochemistry (IHC) and western blot were performed to study tumor angiogenic biomarkers and hypoxia. RESULTS DCE-MRI with GODP revealed that bumetanide reduced vascular permeability and plasma volume fraction by a significantly greater extent than the saline control therapy after 3 weeks of therapy. These changes were verified by the significant decline of CD31 and VEGF expression in the bumetanide treatment group. Despite a significant regression in vascularity, the tumors remained highly proliferative. Overexpression of the transcription factor HIF-1α in response to elevated hypoxia is thought to be the driving force behind the uninterrupted tumor expansion. CONCLUSION This study demonstrated the effectiveness of DCE-MRI with GODP in detecting vascular changes following the administration of bumetanide. Bumetanide has the potential to curtail growth of the tumor vasculature and can be employed in future therapeutic strategies.
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Sajeesh S, Choe JY, Lee TY, Lee DK. Guanidine modified polyethyleneimine-g-polyethylene glycol nanocarriers for long interfering RNA (liRNA) based advanced anticancer therapy. J Mater Chem B 2015; 3:207-216. [DOI: 10.1039/c4tb01621a] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Long interfering RNA mediated advanced anticancer therapy.
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Affiliation(s)
- S. Sajeesh
- Global Research Laboratory for RNAi Medicine
- Department of Chemistry
- Sungkyunkwan University
- Suwon 440-746
- Republic of Korea
| | - Jeong Yong Choe
- Global Research Laboratory for RNAi Medicine
- Department of Chemistry
- Sungkyunkwan University
- Suwon 440-746
- Republic of Korea
| | - Tae Yeon Lee
- Global Research Laboratory for RNAi Medicine
- Department of Chemistry
- Sungkyunkwan University
- Suwon 440-746
- Republic of Korea
| | - Dong-ki Lee
- Global Research Laboratory for RNAi Medicine
- Department of Chemistry
- Sungkyunkwan University
- Suwon 440-746
- Republic of Korea
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Wang X, Li S, Shi Y, Chuan X, Li J, Zhong T, Zhang H, Dai W, He B, Zhang Q. The development of site-specific drug delivery nanocarriers based on receptor mediation. J Control Release 2014; 193:139-53. [DOI: 10.1016/j.jconrel.2014.05.028] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 05/13/2014] [Accepted: 05/17/2014] [Indexed: 01/28/2023]
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Abstract
BACKGROUND The most common primary brain tumours in adults are gliomas. Gliomas span a spectrum from low to high-grade and are graded pathologically on a scale of one to four according to the World Health Organization (WHO) classification. High-grade glioma (HGG) carries a poor prognosis. Grade IV glioma is known as glioblastoma (GBM) and carries a median survival in treated patients of about 15 months. GBMs are rich in blood vessels (i.e. highly vascular) and in a protein known as vascular endothelial growth factor (VEGF), which promotes new blood vessel formation (the process of angiogenesis). Antiangiogenic agents inhibit the process of new blood vessel formation and promote regression of existing vessels. Several antiangiogenic agents have been investigated in clinical trials in newly diagnosed and recurrent HGG, showing promising preliminary results. This review was undertaken to report on the benefits and harms associated with the use of antiangiogenic agents in the treatment of HGGs. OBJECTIVES To evaluate the efficacy and toxicity of antiangiogenic therapy in patients with high-grade glioma. This intervention can be used in two broad groups of patients: those with first diagnosis as part of 'adjuvant' therapy, and those with recurrent or progressive disease. Comparisons will include the following.• Treatment with antiangiogenic therapy versus placebo.• Treatment (such as chemotherapy or chemoradiotherapy) with antiangiogenic therapy added versus the same treatment without the addition of antiangiogenic therapy. SEARCH METHODS Searches were conducted to identify published and unpublished Randomised Controlled Trials (RCTs) starting in 2000; the following databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 3, 2014; MEDLINE to April 2014 and EMBASE to April 2014. Proceedings of relevant oncology conferences since 2000 were handsearched. SELECTION CRITERIA RCTs evaluating the use of antiangiogenic therapy versus control treatment without antiangiogenic therapy in the treatment of HGG. DATA COLLECTION AND ANALYSIS Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles. MAIN RESULTS After a comprehensive literature search, seven eligible RCTs were identified (total of 2987 participants). Significant design heterogeneity was noted in the included studies, especially in the response assessment criteria used. All eligible studies were restricted to GBMs, and no eligible studies evaluated other HGGs. Four studies were available only in abstract form. We have reserved an overall assessment of the quality of the evidence until the final study publications are received. The three studies that have been published in full were judged to have low risk of bias. The seven trials of 2987 participants included in this systematic review did not show improvement in OS with the addition of antiangiogenic therapy (pooled hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.86 to 1.02; P value 0.16). However, pooled analysis of PFS from six studies (2847 participants) showed improvement in PFS with the addition of antiangiogenic therapy (HR 0.74, 95% CI 0.68 to 0.81; P value < 0.00001). Bevacizumab was the antiangiogenic therapy more likely to yield favourable results. Pooled HR for PFS for bevacizumab studies (three studies with 1712 participants) was significant at 0.66 (95% CI 0.59 to 0.74; P value < 0.00001), and this was reflected in the lower hazard ratio reported in the pooled analysis of bevacizumab studies compared with the overall analysis. Nevertheless, this finding was not significant for OS (HR 0.92, 95% CI 0.83 to 1.02; P value 0.12). Similar to trials of antiangiogenic therapies in other solid tumours, adverse events related to this class of therapy included hypertension and proteinuria, poor wound healing and the potential for thromboembolic events, although generally, the occurrence of grade 3 events of this kind was low (< 14.1%), consistent with reported findings of studies of bevacizumab in other tumours. AUTHORS' CONCLUSIONS In patients with newly diagnosed GBM, the use of antiangiogenic therapy does not improve survival, despite evidence of improved progression-free survival. Thus at this time, evidence is insufficient to support the use of antiangiogenic therapy in patients with newly diagnosed GBM on the basis of effects on survival.Bevacizumab may confer a progression-free survival benefit in GBM; however evidence in favour of using other antiangiogenic therapies in recurrent GBM is insufficient.Although bevacizumab appears to prolong progression-free survival in newly diagnosed and recurrent GBM, the impact of this on quality of life remains unclear.Adequately powered, randomised, placebo-controlled studies of bevacizumab in recurrent GBM (or HGG) are needed.Not addressed here is whether subsets of patients with newly diagnosed GBM may benefit from antiangiogenic therapies and whether these therapies are useful in other high-grade glioma histologies.
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Affiliation(s)
- Mustafa Khasraw
- NHMRC Clinical Trials Centre, University of Sydney, University of Sydney, Sydney, Australia
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Gubbi A, Kendrick JE, Finkler NJ. The role of bevacizumab in recurrent, platinum-sensitive ovarian cancer. Expert Rev Anticancer Ther 2014; 14:1105-13. [PMID: 25189201 DOI: 10.1586/14737140.2014.956095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The majority of women with ovarian cancer will experience a recurrence of their disease despite aggressive primary cytoreduction and adjuvant cytotoxic chemotherapy. Notwithstanding the high rate of recurrence, targeted and biologic agents have helped to decrease the dependence on cytotoxic chemotherapy. Bevacizumab, a vascular endothelial growth factor inhibitor, has been shown to cause regression in tumor vasculature, inhibition of angiogenesis and prevention of progenitor cell recruitment. Phase III clinical trials of bevacizumab in patients with primary epithelial ovarian cancer and in patients with platinum-sensitive ovarian cancer have shown an improvement in progression free survival without an appreciable difference in overall survival. The addition of bevacizumab to standard cytotoxic chemotherapy regimens has demonstrated improved response rates, and improved progression free survival. These results have stimulated research in additional angiogenesis inhibitors and trials to further incorporate bevacizumab into the treatment schema for patients with recurrent ovarian cancer.
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Affiliation(s)
- Ajit Gubbi
- Florida Hospital Cancer Institute - Gynecologic Oncology, 2501 North Orange Ave, Orlando, Florida 32804, USA
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Duan CL, Hou GH, Liu YP, Liang T, Song J, Han JK, Zhang C. Tumor vascular homing endgolin-targeted radioimmunotherapy in hepatocellular carcinoma. Tumour Biol 2014; 35:12205-15. [PMID: 25164610 DOI: 10.1007/s13277-014-2529-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2014] [Accepted: 08/20/2014] [Indexed: 12/29/2022] Open
Abstract
Endoglin is a proliferation-associated cell membrane antigen and overexpressed in the angiogenic vasculature of solid tumors. However, the applications of endoglin (ENG)-targeted radioimmunotheray in hepatocellular carcinoma have not been reported yet. Therefore, the aim of this study was the visualization of both the development of hepatocellular carcinoma (HCC) tumor burden and therapeutic effect with ENG-targeted (131)I-anti-ENG mAb (A8), via in vivo noninvasive fluorescence imaging (NIFLI) of SMMC7721-green fluorescent protein (GFP) cells. A8 showed a dose-dependent, time-dependent suppression on the proliferation of SMMC7721-GFP cells and human umbilical vein endothelial cells (HUVECs) in vitro. Tube formation assay showed that (131)I-A8 markedly inhibits HUVECs to form extensive and enclosed tube networks. The results showed that the radiochemical purity of (131)I-A8 was 92.8 % and (131)I-A8 maintained more stable in serum than in saline and had high affinity against SMMC7721-GFP cells. The pharmacokinetics of (131)I-A8 was in accordance with the two-compartment model, with a rapid distribution phase and a slow decline phase. NIFLI exhibited a good relation between the fluorescent signal and tumor volume in vivo. Furthermore, treatment with (131)I-A8 resulted in significant tumor-growth suppression on the basis of the reducing fluorescent signal and a remarkably decreased tumor weight in treated animals. These results were further verified by RT-PCR and immunohistochemistry staining. Our findings indicate that (131)I-A8 can be used as ENG-targeted therapy for hepatocellular carcinoma, and noninvasive fluorescence imaging provides valuable information on tumor burden and effectiveness of therapy.
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Affiliation(s)
- Chong-Ling Duan
- Key Laboratory for Experimental Teratology of the Ministry of Education and Institute of Experimental Nuclear Medicine, School of Medicine, Shandong University, Jinan, China
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Patel AR, Chougule MB, Lim E, Francis KP, Safe S, Singh M. Theranostic tumor homing nanocarriers for the treatment of lung cancer. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2014; 10:1053-1063. [PMID: 24355163 PMCID: PMC4061286 DOI: 10.1016/j.nano.2013.12.002] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2013] [Revised: 11/25/2013] [Accepted: 12/07/2013] [Indexed: 12/31/2022]
Abstract
UNLABELLED The drugs/strategies to selectively inhibit tumor blood supply have generated interest in recent years for enhancement of cancer therapeutics. The objective of this study was to formulate tumor homing PEGylated CREKA peptide conjugated theranostic nanoparticles of DIM-C-pPhC6H5 (DIM-P) and investigate in vivo antitumor activity as well as evaluate the targeted efficiency to lung tumors using imaging techniques. DIM-P loaded Nanoparticles (NCs-D) were prepared using lipids, and DOGS-NTA-Ni and the surface of NCs-D were modified with PEGylated CREKA peptide (PCNCs-D). PCNCs-D showed 3 fold higher binding to clotted plasma proteins in tumor vasculature compared to NCs-D. PCNCs-D showed 26%±4% and 22%±5% increase in tumor reduction compared to NCs-D in metastatic and orthotopic models respectively. In-vivo imaging studies showed ~40 folds higher migration of PCNCs-Di in tumor vasculature than NCs-Di. Our studies demonstrate the role of PCNCs-D as theranostic tumor homing drug delivery and imaging systems for lung cancer diagnosis and treatment. FROM THE CLINICAL EDITOR This study demonstrates a very efficient delivery system to address lung cancer growth through blood supply inhibition.
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Affiliation(s)
- Apurva R Patel
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, USA
| | - Mahavir B Chougule
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Hawai'i at Hilo, Hilo, HI, USA
| | - Ed Lim
- Calipers-Life Sciences & Technology, A Perkin Elmer Company, Alameda, CA, USA
| | - Kevin P Francis
- Calipers-Life Sciences & Technology, A Perkin Elmer Company, Alameda, CA, USA
| | - Stephen Safe
- Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA
| | - Mandip Singh
- College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, USA.
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Detection of vascular endothelial growth factor in colon cancer xenografts using bevacizumab based near infrared fluorophore conjugate. J Biomed Sci 2014; 21:35. [PMID: 24780003 PMCID: PMC4012715 DOI: 10.1186/1423-0127-21-35] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2014] [Accepted: 04/23/2014] [Indexed: 01/06/2023] Open
Abstract
Background The aim of this study was to develop the near infrared fluorescence (NIRF)-based imaging agent for the visualization of vascular endothelial growth factor (VEGF) in colon cancer. AlexaFluor 750 conjugating with bevacizumab, and injected intravenously into nude mice bearing VEGF over-expressing HT29 human colorectal cancer. Optical imaging was performed at 15 min, 24 h and 48 h post injection. Immunofluorescences staining of the tumor sections were performed. HT29 colorectal cancer xenografts were clearly visualized with bevacizumab-AlexaFluor 750. Results Ex vivo analysis showed 2.1 ± 0.4%, 37.6 ± 6.3% and 38.5 ± 6.2% injected dose/g accumulated in the tumors at 15 min, 24 h and 48 h respectively. Tumor uptake was significantly decreased in pretreated with excess of bevacizumab (p = 0.002). Immunofluorescence analysis showed strong staining of anti-CD 31 antibody around the blood vessels. Anti-VEGF-A and bevacizumab showed heterogeneous expression throughout the tumor. Conclusions Current study successfully detected the VEGF expression in HT29 colorectal cancer xenografts, signifying as a potential agent for non-invasive imaging of VEGF expression, which may be applied in clinical practice.
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Combination of docetaxel and TSU-68, an oral antiangiogenic agent, in patients with metastatic breast cancer previously treated with anthracycline: randomized phase II multicenter trial. Invest New Drugs 2014; 32:753-61. [PMID: 24715580 DOI: 10.1007/s10637-014-0093-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Accepted: 03/18/2014] [Indexed: 10/25/2022]
Abstract
The novel oral antiangiogenic agent TSU-68 was investigated in patients with metastatic breast cancer. Patients with anthracycline-pretreated metastatic breast cancer were randomly assigned to receive either TSU-68 400 mg twice daily on days 1-21 plus docetaxel 60 mg/m(2) on day 1 every 3 weeks, or docetaxel 60 mg/m(2) on day 1 every 3 weeks. The primary endpoint was progression-free survival. Between November 2006 and December 2007, 81 patients were included in this study (41 for TSU-68 plus docetaxel and 40 for docetaxel alone). Median progression-free survival was 6.8 months (95 % confidence interval [CI] = 5.4-12.5 months) in the TSU-68 plus docetaxel group and 8.1 months (95 % CI = 4.0-13.7 months) in the docetaxel-alone group (hazard ratio [HR] = 1.0; 95 % CI = 0.6-1.8; p = 0.95). There were no significant differences in the overall response rates and overall survival between groups (p = 0.29 and p = 0.42, respectively). In subgroup analysis, TSU-68 plus docetaxel was associated with better overall survival than docetaxel alone in anthracycline-resistant patients (HR = 0.3; 95 % CI = 0.1-0.8; p = 0.02). The most frequent adverse events were neutropenia and anorexia in both arms. Although both regimens were well tolerated, grade 3/4 non-hematologic toxicity was more frequently observed in the TSU-68 plus docetaxel group. Combination of TSU-68 and docetaxel is well tolerated but failed to demonstrate superior efficacy over docetaxel alone in anthracycline-pretreated breast cancer patients. As TSU-68 was associated with better survival in the anthracycline-resistant subgroup, it should be further explored in this subgroup.
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Karmani L, Bouchat V, Bouzin C, Levêque P, Labar D, Bol A, Deumer G, Marega R, Bonifazi D, Haufroid V, Michiels C, Grégoire V, Feron O, Lucas S, Vander Borght T, Gallez B. (89)Zr-labeled anti-endoglin antibody-targeted gold nanoparticles for imaging cancer: implications for future cancer therapy. Nanomedicine (Lond) 2014; 9:1923-37. [PMID: 24547782 DOI: 10.2217/nnm.13.185] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
AIMS Antibody-labeled gold nanoparticles represent an attractive tool for cancer imaging and therapy. In this study, the anti-CD105 antibody was conjugated with gold nanoparticles (AuNPs) for the first time. The antibody biodistribution in mice before and after conjugation to AuNPs was studied, with a focus on tumor targeting. MATERIALS & METHODS Antibodies were radiolabeled with 89Zr before conjugation to AuNPs (5 nm). Immunonanoconjugates were characterized in vitro in terms of size, stability in plasma and binding to the target. Quantitative PET imaging and ICP-MS analysis assessed in vivo distribution and specific tumor targeting of tracers. RESULTS The tumor uptake of immunoconjugates was preserved up to 24 h after injection, with high tumor contrast and selective tumor targeting. No major tracer accumulation was observed over time in nonspecific organs. ICP-MS analysis confirmed the antibody specificity after nanoparticle conjugation. CONCLUSION The anti-CD105 antibody conjugation to AuNPs did not greatly affect CD105-dependent tumor uptake and the efficacy of tumor targeting for cancer detection.
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Affiliation(s)
- Linda Karmani
- Biomedical Magnetic Resonance Group (REMA), Louvain Drug Research Institute, Université Catholique de Louvain, Avenue Mounier 73, 1200 Brussels, Belgium
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Abstract
The past several decades have revealed certain challenges that are inherent to soft-tissue sarcomas with regards to devising, testing and setting treatment paradigms for such a rare and heterogeneous malignancy. Despite this, significant advances have been made through the efforts of scientists, clinicians and patients alike. We are now entering a molecular era of cancer and current biotechnology is beginning to unravel the pathogenic enigma of these often devastating tumors. As our understanding of these malignancies improves, so does our list of potential treatment options. The impetus now lies with the medical/scientific community to direct translational research and subsequently the development and clinical testing of novel compounds in a fashion that best serves this unique patient population. To do so, we must continue to integrate the lessons of the past with the resources and promise of the future. This review will outline current areas of therapeutic interest in soft-tissue sarcomas with regard to agents that have reached clinical testing.
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Affiliation(s)
- William D Tap
- UCLA Sarcoma Program, Division of Hematology/Oncology, Los Angeles, CA 90095-7059, USA.
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42
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Holzer TR, Fulford AD, Nedderman DM, Umberger TS, Hozak RR, Joshi A, Melemed SA, Benjamin LE, Plowman GD, Schade AE, Ackermann BL, Konrad RJ, Nasir A. Tumor cell expression of vascular endothelial growth factor receptor 2 is an adverse prognostic factor in patients with squamous cell carcinoma of the lung. PLoS One 2013; 8:e80292. [PMID: 24244672 PMCID: PMC3828187 DOI: 10.1371/journal.pone.0080292] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2013] [Accepted: 10/02/2013] [Indexed: 11/19/2022] Open
Abstract
A robust immunohistochemical (IHC) assay for VEGFR2 was developed to investigate its utility for patient tailoring in clinical trials. The sensitivity, specificity, and selectivity of the IHC assay were established by siRNA knockdown, immunoblotting, mass spectrometry, and pre-absorption experiments. Characterization of the assay included screening a panel of multiple human cancer tissues and an independent cohort of non-small cell lung carcinoma (NSCLC, n = 118) characterized by TTF-1, p63, CK5/6, and CK7 IHC. VEGFR2 immunoreactivity was interpreted qualitatively (VEGFR2 positive/negative) in blood vessels and by semi-quantitative evaluation using H-scores in tumor cells (0-300). Associations were determined among combinations of VEGFR2 expression in blood vessels and tumor cells, and clinico-pathologic characteristics (age, sex, race, histologic subtype, disease stage) and overall survival using Kaplan-Meier analyses and appropriate statistical models. VEGFR2 expression both in blood vessels and in tumor cells in carcinomas of the lung, cervix, larynx, breast, and others was demonstrated. In the validation cohort, 99/118 (83.9%) NSCLC tissues expressed VEGFR2 in the blood vessels and 46/118 (39.0%) showed high tumor cell positivity (H-score ≥10). Vascular and tumor cell expression were inversely correlated (p = 0.0175). High tumor cell expression of VEGFR2 was associated with a 3.7-fold reduction in median overall survival in lung squamous-cell carcinoma (SCC, n = 25, p = 0.0134). The inverse correlation between vascular and tumor cell expression of VEGFR2 and the adverse prognosis associated with high VEGFR2 expression in immunohistochemically characterized pulmonary SCC are new findings with potential therapeutic implications. The robustness of this novel IHC assay will support further evaluation of its utility for patient tailoring in clinical trials of antiangiogenic agents.
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Affiliation(s)
- Timothy R. Holzer
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Angie D. Fulford
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Drew M. Nedderman
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Tara S. Umberger
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Rebecca R. Hozak
- Oncology Statistics-Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Adarsh Joshi
- Oncology Statistics-Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Symantha A. Melemed
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Laura E. Benjamin
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Gregory D. Plowman
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Andrew E. Schade
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Bradley L. Ackermann
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Robert J. Konrad
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
| | - Aejaz Nasir
- Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States of America
- * E-mail:
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43
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Cesca M, Bizzaro F, Zucchetti M, Giavazzi R. Tumor delivery of chemotherapy combined with inhibitors of angiogenesis and vascular targeting agents. Front Oncol 2013; 3:259. [PMID: 24102047 PMCID: PMC3787308 DOI: 10.3389/fonc.2013.00259] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2013] [Accepted: 09/15/2013] [Indexed: 01/24/2023] Open
Abstract
Numerous angiogenesis-vascular targeting agents have been admitted to the ranks of cancer therapeutics; most are used in polytherapy regimens. This review looks at recent progress and our own preclinical experience in combining angiogenesis inhibitors, mainly acting on VEGF/VEGFR pathways, and vascular targeting agents with conventional chemotherapy, discussing the factors that determine the outcome of these treatments. Molecular and morphological modifications of the tumor microenvironment associated with drug distribution and activity are reviewed. Modalities to improve drug delivery and strategies for optimizing combination therapy are examined.
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Affiliation(s)
- Marta Cesca
- Laboratory of Biology and Treatment of Metastases, Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri" , Milan , Italy
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44
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Combined chemotherapy delivered by nanoparticulate systems: an old concept with modern innovations. Ther Deliv 2013; 3:1363-8. [PMID: 23323553 DOI: 10.4155/tde.12.111] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
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Dołbniak M, Swierniak A. Comparison of simple models of periodic protocols for combined anticancer therapy. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2013; 2013:567213. [PMID: 23653666 PMCID: PMC3638653 DOI: 10.1155/2013/567213] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Accepted: 02/27/2013] [Indexed: 11/21/2022]
Abstract
Several simple ordinary differential equation (ODE) models of tumor growth taking into account the development of its vascular network are discussed. Different biological aspects are considered from the simplest model of Hahnfeldt et al. proposed in 1999 to a model which includes drug resistance of cancer cells to chemotherapy. Some of these models can be used in clinical oncology to optimize antiangiogenic and cytostatic drugs delivery so as to ensure maximum efficacy. Simple models of continuous and periodic protocols of combined therapy are implemented. Discussion on the dynamics of the models and their complexity is presented.
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Affiliation(s)
- Marzena Dołbniak
- Department of Automatic Control, Silesian University of Technology, ul. Akademicka 2A, 44-100 Gliwice, Poland.
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46
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Theoretical investigation of the efficacy of antiangiogenic drugs combined to chemotherapy in xenografted mice. J Theor Biol 2013; 320:86-99. [DOI: 10.1016/j.jtbi.2012.12.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Revised: 12/10/2012] [Accepted: 12/12/2012] [Indexed: 11/30/2022]
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47
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Muñoz R, Arias Y, Ferreras JM, Jiménez P, Langa C, Rojo MA, Gayoso MJ, Córdoba-Díaz D, Bernabéu C, Girbés T. In vitro and in vivo effects of an anti-mouse endoglin (CD105)-immunotoxin on the early stages of mouse B16MEL4A5 melanoma tumours. Cancer Immunol Immunother 2013; 62:541-51. [PMID: 23076642 PMCID: PMC11029560 DOI: 10.1007/s00262-012-1357-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2012] [Accepted: 09/25/2012] [Indexed: 10/27/2022]
Abstract
TGF-beta superfamily co-receptors are emerging as targets for cancer therapy, acting both directly on cells and indirectly on the tumour neovasculature. Endoglin (CD105), an accessory component of the TGF-beta receptor complex, is expressed in certain melanoma cell lines and the endothelial cells of tumour neovessels. Targeting endoglin with immunotoxins is an attractive approach for actively suppressing the blood supply to tumours. Here, we report evidence indicating that endoglin is expressed in mouse melanoma B16MEL4A5 and mouse fibroblast L929 cell lines. We prepared an immunotoxin to target endoglin by coupling the rat anti-mouse MJ7/18 (IgG2a) monoclonal antibody (mAb) to the non-toxic type 2 ribosome-inactivating protein nigrin b (Ngb) with N-succinimidyl 3-(2-pyridyldithio)-propionate (SPDP) as a linker with a molar nigrin b at a MJ7/18 stoichiometry of 2:1. The MJ7-Ngb immunotoxin generated killed both cell lines, with IC50 values of 4.2 × 10(-9) M for B16MEL4A5 and 7.7 × 10(-11) M for L929 cells. For in vivo assays of the immunotoxin, B16MEL4A5 cells were injected subcutaneously into the right flanks of 6-week-old C57BL/6 J mice. When the animals developed palpable solid tumours, they were subjected to treatment with the immunotoxin. While treatment with either MJ7/18 mAb or Ngb did not affect tumour development, treatment with the immunotoxin completely and steadily blocked tumour growth up to 7 days, after which some tumours re-grew. Thus, vascular-targeting therapy with this anti-vascular immunotoxin could promote the destruction of newly created tumour vessels at early stages of B16MEL4A5 tumour development and readily accessible CD105+ B16MEL4A5 melanoma cells.
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Affiliation(s)
- Raquel Muñoz
- Facultad de Ciencias, Departamento de Bioquímica y Biología Molecular, Universidad de Valladolid, 47005 Valladolid, Spain
| | - Yolanda Arias
- Facultad de Ciencias, Departamento de Bioquímica y Biología Molecular, Universidad de Valladolid, 47005 Valladolid, Spain
| | - José Miguel Ferreras
- Facultad de Ciencias, Departamento de Bioquímica y Biología Molecular, Universidad de Valladolid, 47005 Valladolid, Spain
| | - Pilar Jiménez
- Nutrición y Bromatología-Facultad de Medicina y Centro de Investigación en Nutrición, Alimentación y Dietética (CINAD), Universidad de Valladolid, 47005 Valladolid, Spain
| | - Carmen Langa
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain
| | - María Angeles Rojo
- Escuela Politécnica, Universidad Europea Miguel de Cervantes, 47012 Valladolid, Spain
| | - Manuel José Gayoso
- Facultad de Medicina, Departamento de Biología Celular, Histología y Farmacología, Universidad de Valladolid, 47005 Valladolid, Spain
| | - Damián Córdoba-Díaz
- Facultad de Farmacia, Departamento de Farmacia y Tecnología Farmacéutica, Universidad Complutense de Madrid, 28040 Madrid, Spain
| | - Carmelo Bernabéu
- Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28040 Madrid, Spain
| | - Tomás Girbés
- Nutrición y Bromatología-Facultad de Medicina y Centro de Investigación en Nutrición, Alimentación y Dietética (CINAD), Universidad de Valladolid, 47005 Valladolid, Spain
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Gasparini G. Antiangiogenic tyrosine kinase inhibitors in non-small-cell-lung cancer: lights and shadows. Transl Lung Cancer Res 2013; 2:E10-2. [PMID: 25806209 DOI: 10.3978/j.issn.2218-6751.2012.08.04] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Accepted: 08/28/2012] [Indexed: 11/14/2022]
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Lin J, Kelly WK. Targeting angiogenesis as a promising modality for the treatment of prostate cancer. Urol Clin North Am 2012; 39:547-60. [PMID: 23084530 DOI: 10.1016/j.ucl.2012.07.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Antiangiogenic therapy has been successful for the treatment of solid tumors. Several strategies have been used to target angiogenesis in prostate cancer. These strategies include blocking proangiogenic factors via monoclonal antibodies or small molecule inhibitors targeting downstream signaling effector pathways, or using agents with immune-modulatory effects. This review examines the general concepts of tumor angiogenesis and the key clinical trials that have used these agents and other novel biologics in prostate cancer. Targeting angiogenesis is still a promising treatment strategy in prostate cancer with a rational trial design and combination approach.
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Affiliation(s)
- Jianqing Lin
- Department of Medical Oncology, Jefferson Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA.
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Kim H, Choi JS, Kim KS, Yang JA, Joo CK, Hahn SK. Flt1 peptide-hyaluronate conjugate micelle-like nanoparticles encapsulating genistein for the treatment of ocular neovascularization. Acta Biomater 2012; 8:3932-40. [PMID: 22824530 DOI: 10.1016/j.actbio.2012.07.016] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2012] [Revised: 06/21/2012] [Accepted: 07/11/2012] [Indexed: 10/28/2022]
Abstract
Flt1 peptide of GNQWFI is an antagonistic peptide for vascular endothelial growth factor receptor 1 (VEGFR1 or Flt1). In this work, Flt1 peptide-hyaluronate (HA) conjugates were successfully synthesized and the resulting micelle-like nanoparticles were exploited to encapsulate genistein, an inhibitor of tyrosine-specific protein kinases, for the treatment of ocular neovascularization. The mean diameter of genistein-loaded Flt1 peptide-HA conjugate micelles was measured to be 172.0±18.7 nm, with a drug-loading efficiency of 40-50%. In vitro release tests of genistein from the genistein-loaded Flt1 peptide-HA conjugate micelles exhibited the controlled release for longer than 24h. In vitro biological activity of genistein/Flt1 peptide-HA micelles was corroborated from the synergistic anti-proliferation of human umbilical vein endothelial cells (HUVECs). Furthermore, we could confirm the anti-angiogenic effect of genistein/Flt1 peptide-HA micelles from the statistically significant suppression of corneal neovascularization in silver nitrate cauterized corneas of SD rats. The retinal vascular hyperpermeability was also drastically reduced by the treatment in diabetic retinopathy model rats.
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