Reversal of multidrug resistance by co-delivery of paclitaxel and lonidamine using a TPGS and hyaluronic acid dual-functionalized liposome for cancer treatment |
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| Affiliation: | 1. State Key Laboratory of Natural Medicines and Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, Center of Drug Discovery, China Pharmaceutical University, Nanjing 210009, China;2. UFR Pharmacie, Faculté des Sciences de la Santé, Université d''Abomey-Calavi, 01 BP 188 Cotonou, Benin;3. Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China;4. Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia;1. Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China;2. Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 210009, China;3. Shanghai Institute of Materia Medica, Shanghai Institutes for Biological Sciences, Chinese Academy of Science, Shanghai 201203, China;4. Center of Pharmacokinetics, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, China;5. College of Pharmacy, University of Manitoba, Winnipeg, MB R3E 0T5, Canada;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;1. The First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China;2. Suzhou Integrated of Chinese and Western Medicine Hospital, Suzhou, People’s Republic of China;3. Jiangsu Cancer Hospital, Nanjing, People’s Republic of China;4. Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing, People’s Republic of China;1. State Key Laboratory of Natural Medicines, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, PR China;2. Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009, PR China;3. College of Chemistry and Bio-engineering, Yichun University, Yichun 336000, PR China;4. Department of Hematology, The Affiliated Zhongda Hospital of Southeast University, Nanjing 210009, PR China;1. Maliba Pharmacy College, UKA Tarsadia University, Gopal-Vidyanagar Campus, Surat 394350, Gujarat, India;2. Chemistry Department, Veer Narmad South Gujarat University, Surat 395007, Gujarat, India |
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| Abstract: | Multidrug resistance (MDR) remains the primary issue in cancer therapy, which is characterized by the overexpressed P-glycoprotein (P-gp)-included efflux pump or the upregulated anti-apoptotic proteins. In this study, a D-alpha-tocopheryl poly (ethylene glycol 1000) succinate (TPGS) and hyaluronic acid (HA) dual-functionalized cationic liposome containing a synthetic cationic lipid, 1,5-dioctadecyl-N-histidyl-l-glutamate (HG2C18) was developed for co-delivery of a small-molecule chemotherapeutic drug, paclitaxel (PTX) with a chemosensitizing agent, lonidamine (LND) to treat the MDR cancer. It was demonstrated that the HG2C18 lipid contributes to the endo-lysosomal escape of the liposome following internalization for efficient intracellular delivery. The TPGS component was confirmed able to elevate the intracellular accumulation of PTX by inhibiting the P-gp efflux, and to facilitate the mitochondrial-targeting of the liposome. The intracellularly released LND suppressed the intracellular ATP production by interfering with the mitochondrial function for enhanced P-gp inhibition, and additionally, sensitized the MDR breast cancer (MCF-7/MDR) cells to PTX for promoted induction of apoptosis through a synergistic effect. Functionalized with the outer HA shell, the liposome preferentially accumulated at the tumor site and showed a superior antitumor efficacy in the xenograft MCF-7/MDR tumor mice models. These findings suggest that this dual-functional liposome for co-delivery of a cytotoxic drug and an MDR modulator provides a promising strategy for reversal of MDR in cancer treatment. |
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| Keywords: | Liposome Paclitaxel Lonidamine Combination therapy Multidrug resistance |
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