Roles of ligand and TPGS of micelles in regulating internalization,penetration and accumulation against sensitive or resistant tumor and therapy for multidrug resistant tumors |
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Institution: | 1. Department of Biomedical Engineering, University of California, Irvine, CA 92697-2715, USA;2. Department of Chemical Engineering and Materials Science, University of California, Irvine, CA 92697-2575, USA;3. Department of Computer Science, University of California, Irvine, CA 92697-3435, USA;1. Department of Pharmaceutics, College of Pharmacy, Shandong University, Jinan 250012, China;2. College of Medicine and Nursing, Dezhou University, Dezhou 253023, China;3. School of Health Sciences, Macao Polytechnic Institute, Macao, China;4. Department of Pharmacy, Linyi People''s Hospital Affiliated to Shandong University, Linyi 276003, China;1. Department of Chemical and Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore;2. International Joint Cancer Institute, The Second Military Medical University, 800, Xiang Yin Road, Shanghai 200433, PR China;3. NUS Graduate School for Integrative Science and Engineering, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore;4. Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India;1. Departamento de Tecnología Farmacéutica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina;2. Departamento de Farmacología, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Argentina;3. National Science Research Council (CONICET), Buenos Aires, Argentina;1. Université catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Avenue Mounier 73 bte B1 73.12, B-1200 Brussels, Belgium;2. Université catholique de Louvain, Institut de recherche expérimentale et Clinique, Pôle de Pharmacologie et thérapeutique, Avenue Mounier 53 bte B1.53.09, B-1200 Brussels, Belgium;1. Department of Chemical & Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117585, Singapore;2. Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India;3. International Joint Cancer Institute, The Second Military Medical University, 800 Xiang Yin Road, Shanghai 200433, China |
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Abstract: | There are several obstacles in the process of successful treatment of malignant tumors, including toxicity to normal cells, inefficiency of drug permeation and accumulation into the deep tissue of solid tumor, and multidrug resistance (MDR). In this work, we prepared docetaxel (DTX)-loaded hybrid micelles with DSPE–PEG and TPGS (TPGS/DTX-M), where TPGS serves as an effective P-gp inhibitor for overcoming MDR, and active targeting hybrid micelles (FA@TPGS/DTX-M) with targeting ligand of folate on the hybrid micelles surface offering active targeting to folate receptor-overexpressed tumor cells. A systematic comparative evaluation of these micelles on cellular internalization, sub-cellular distribution, antiproliferation, mitochondrial membrane potential, cell apoptosis and cell cycle, permeation and inhibition on 3-dimensional multicellular tumor spheroids, as well as antitumor efficacy and safety assay in vivo were well performed between sensitive KB tumors and resistant KBv tumors, and among P-gp substrate or not. We found that the roles of folate and TPGS varied due to the sensitivity of tumors and the loaded molecules in the micelles. Folate and folate receptor-mediated endocytosis played a leading role in internalization, permeation and accumulation for sensitive tumors and non-substrates of P-gp. On the contrary, TPGS played the predominant role which dramatically decreased the efflux of drugs both when the tumor is resistant and for P-gp substrate. These findings are very meaningful for guiding the design of carrier delivery system to treat tumors. The antitumor efficacy in xenograft nude mice model and safety assay showed that the TPGS/DTX-M and FA@TPGS/DTX-M significantly exhibited higher antitumor activity against resistant KBv tumors than the marketed formulation and normal micelles owing to the small size (approximately 20 nm), hydrophilic PEGylation, TPGS inhibition of P-gp function, and folate receptor-modified endocytosis, permeation and accumulation in solid tumor, as well as synergistic effects of DTX-induced cell division inhibition, growth restraint and TPGS-triggered mitochondrial apoptosis in tumor cells. In conclusion, folate-modified TPGS hybrid micelles provide a synergistic strategy for effective delivery of DTX into KBv cells and overcoming MDR. |
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Keywords: | Hybrid micelles Multidrug resistance P-gp function Permeation and accumulation in solid tumor Mitochondrial membrane potential Synergistic effect |
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