Local sustained release of PD-1 monoclonal antibody and lenvatinib by thermo-sensitive hydrogel for improving tumor immunotherapy |
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| Affiliation: | 1. Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China;2. Department of Pharmaceutical Analysis, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China;3. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Hepato-Pancreato-Biliary Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China;1. Institute of Environmental and Energy Catalysis, School of Materials Science and Chemical Engineering, Xi''an Technological University, Xi''an 710021, China;2. School of Sciences, Xi''an Technological University, Xi''an 710021, China;1. Institute for New Energy Materials & Low Carbon Technologies, School of Chemistry and Chemical Engineering, Tianjin University of Technology, Tianjin 300384, China;2. School of Chemistry, Chemical Engineering and Materials, Jining University, Qufu 273100, China;1. PCFM, LIFM Lab, School of Chemistry, Sun Yat-sen University, Guangzhou 510275, China;2. Guangdong Provincial Key Laboratory of Optical Chemicals, Xinhuayue Group, Maoming 525000, China;3. Shenzhen Grubbs Institute, Department of Chemistry, Southern University of Science and Technology, Shenzhen 518055, China;4. Pohang Accelerator Laboratory, Postech, Pohang, Gyeongbuk, Korea;1. School of Chemistry and Chemical Engineering, Yangzhou University, Yangzhou 225002, China;2. College of Environmental Science and Engineering, Yangzhou University, Yangzhou 225002, China;1. School of Petrochemical Engineering, Changzhou University, Changzhou 213164, China;2. Department of Chemistry, Maynooth University, National University of Ireland, Maynooth, Co. Kildare, Ireland;3. State Key Laboratory of Analytical Chemistry for Life Science, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China;1. State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, China;2. Economical Forest Cultivation and Utilization of 2011 Collaborative Innovation Center in Hunan Province, Hunan Key Laboratory of Green Chemistry and Application of Biological Nanotechnology, Hunan University of Technology, Zhuzhou 412007, China |
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| Abstract: | In clinic, the combination of intravenous pembrolizumab (PD-1 monoclonal antibody) with oral Lenvatinib (LEN) exhibited an enhanced synergistic benefit for cancer therapy. However, the clinical outcomes were always limited by the problems of inconsistent pharmacokinetic profiles of two drugs, lower drug accumulation in tumor and obvious side effects during the combination therapy. Here, in situ-forming thermosensitive hydrogels based on PLGA-PEG-PLGA triblock copolymers were prepared for local administration of anti-PD1 and LEN (P&L@Gel) to improve therapeutic efficacy and safety. After peritumoral or surgical resection site injection, the significant increased concentrations of both drugs in tumor were observed with the local sustained release of P&L@Gel. In comparison with the group of intraperitoneal anti-PD1 plus oral LEN (P-ip&L-po), significantly higher tumor inhibition efficiency on CT26 tumor models could be obtained in P&L@Gel group, even at the dose of one-eighth of the former, same tumor-inhibition effects could be achieved. The enhanced antitumor efficacy of P&L@Gel group was probably associated with the 2.2 folds of increased level of CD8+ T cells and the polarization of tumor associated macrophage from M2 to M1 along with the increased drug accumulation. Moreover, compared with the obvious side effects of P-ip&L-po group, no significant changes of PLT, ALT and UA in blood, as well as IL-1α and IL-1β in mice paws were observed between P&L@Gel group and untreated group. These results suggested that local administration of anti-PD1 and LEN with thermosensitive hydrogel could offer a potential strategy for tumors or tumor postoperative adjuvant treatment. |
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