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Tytuł:
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Reduction-responsive RNAi nanoplatform to reprogram tumor lipid metabolism and repolarize macrophage for combination pancreatic cancer therapy.
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Autorzy:
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Cao S; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China; RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China.
Saw PE; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China; RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China.
Shen Q; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China; The Second Affiliated Hospital, Department of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, PR China.
Li R; The Second Affiliated Hospital, Department of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, PR China.
Liu Y; School of Pharmacy, Guangdong Medical University, Dongguan, 523808, PR China.
Xu X; Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China; RNA Biomedical Institute, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, PR China; The Second Affiliated Hospital, Department of Clinical Pharmacology, Hengyang Medical School, University of South China, Hengyang, 421001, PR China. Electronic address: .
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Źródło:
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Biomaterials [Biomaterials] 2022 Jan; Vol. 280, pp. 121264. Date of Electronic Publication: 2021 Nov 19.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: <1995-> : Amsterdam : Elsevier Science
Original Publication: [Guilford, England] : IPC Science and Technology Press, 1980-
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MeSH Terms:
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Lipid Metabolism*
Pancreatic Neoplasms*/metabolism
Pancreatic Neoplasms*/therapy
Humans ; Immunotherapy ; Macrophages/metabolism ; RNA Interference ; Tumor Microenvironment
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Contributed Indexing:
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Keywords: Combination PAC therapy; Lipid metabolism; Nanoplatform; TAMs; siRNA delivery
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Entry Date(s):
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Date Created: 20211126 Date Completed: 20220314 Latest Revision: 20220314
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Update Code:
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20240105
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DOI:
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10.1016/j.biomaterials.2021.121264
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PMID:
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34823884
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Pancreatic cancer (PAC) is one of the most lethal malignant neoplasms with poor prognosis and high mortality. Emerging evidence has revealed that abnormal tumor lipid metabolism and tumor-associated macrophages (TAMs) significantly contribute to PAC development and progression. Therefore, concurrently reprogramming tumor lipid metabolism and regulating TAMs function could be a promising strategy for effective PAC therapy. Herein, we identified an important enzyme catabolizing lipids (monoacylglycerol lipase, MGLL) and a key receptor regulating macrophage phenotype (endocannabinoid receptor-2, CB-2) that are over-expressed in PAC cells and on TAMs, respectively. Based on this finding, we developed a reduction-responsive poly (disulfide amide) (PDSA)-based nanoplatform for systemic co-delivery of MGLL siRNA (siMGLL) and CB-2 siRNA (siCB-2). This nanoplatform could utilize its reduction-responsive characteristic to rapidly release siRNA for efficient silencing of MGLL and CB-2, inducing concurrent suppression of free fatty acids (FFAs) generation in PAC cells and repolarization of TAMs into tumor-inhibiting M1-like phenotype. With this suppressed FFAs generation to inhibit nutrient supply for tumor cells and repolarized TAMs to secrete tumoricidal cytokines such as TNF-α and IL-12, a combinational anticancer effect could be achieved in both xenograft and orthotopic PAC tumor models.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)