Lipid-conjugated siRNA hitchhikes endogenous albumin for tumor immunotherapy |
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| Institution: | 1. School of Life Science; Advanced Research Institute of Multidisciplinary Science; School of Medical Technology; Key Laboratory of Molecular Medicine and Biotherapy; Key Laboratory of Medical Molecule Science and Pharmaceutics Engineering; Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceuticals, Beijing Institute of Technology, Beijing 100081, China;2. School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, China;3. NHC Key Laboratory of Nuclear Medicine, Jiangsu Key Laboratory of Molecular Nuclear Medicine, Jiangsu Institute of Nuclear Medicine, Wuxi 214063, China;4. Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China;5. School of Materials and the Environment, Beijing Institute of Technology, Zhuhai 519085, China;6. Rigerna Therapeutics, Suzhou 215127, China;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. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China;3. Department of Immuno-oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang 050011, China;4. Department of Pharmacy, Clinical Trial Research Center, China-Japan Friendship Hospital, Beijing 100029, China;5. Laboratory of innovative formulations and pharmaceutical excipients, Ningbo Institute of Marine Medicine, Peking University, Ningbo 315832, China;1. Department of Urology, Longgang District People''s Hospital of Shenzhen, Shenzhen 518000, China;2. Key Laboratory for Polymeric Composite & Functional Materials of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, China;3. Department of Urology, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen 518107, China;4. Affiliated Dongguan Hospital, Southern Medical University, Dongguan 523059, China;5. Department of Urology, Shenzhen Samii Medical Center, Shenzhen 518000, China;6. Department of Paediatrics, Longgang District People''s Hospital of Shenzhen, Shenzhen 518000, China;1. School of Pharmacy, Second Military Medical University, Shanghai 200433, China;2. Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (MOE), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji''nan 250012, China;1. College of Nuclear Science and Technology, Harbin Engineering University, Harbin 150001, China;2. Laboratory of Nuclear Energy Chemistry, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China;3. China Institute of Atomic Energy, Beijing 102413, China;4. State Key Laboratory of Nuclear Resources and Environment, School of Nuclear Science and Technology, East China University of Technology, Nanchang 330013, China;5. School of Chemistry, University of the Punjab, Lahore 54590, Pakistan |
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| Abstract: | With the development of a small interfering RNA (siRNA) delivery strategy, increasing siRNA therapeutics for tumor treatment appeared in clinical trials and pre-clinical development. However, the test results of such therapeutics unveiled that efficient siRNA delivery to tumor tissues is still challenging. Albumin is considered an ideal carrier for delivering hydrophobic agents into tumor tissue because it is highly concentrated and long-circulating in blood and has propensity of tumor enrichment. Herein, we synthesized lipid conjugated siRNAs (LsiRNAs), which showed high affinity to albumin. Mechanistically, LsiRNAs non-covalently bind to the hydrophobic core of albumin through its octadecyl tails. The small size of albumin/LsiRNAs allows the complex to penetrate tumor tissue efficiently. Biodistribution test proved that albumin extremely prolonged circulation time and increased tumor retention of associated LsiRNAs. Notably, LsiRNA against programmed death ligand-1 (Pdl1) efficiently suppressed tumor growth as well as prolonged survival time of tumor bearing mice by increasing infiltration of CD8+ T cells as well as promoted the maturation of dendritic cells both in tumor and lymph. Together, LsiRNAs provide a simple but effective way for siRNA tumor delivery that “hitchhikes” on albumin. |
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