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Tytuł pozycji:

Reduction-responsive RNAi nanoplatform to reprogram tumor lipid metabolism and repolarize macrophage for combination pancreatic cancer therapy.

Tytuł:
Reduction-responsive RNAi nanoplatform to reprogram tumor lipid metabolism and repolarize macrophage for combination pancreatic cancer therapy.
Autorzy:
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: .
Źródło:
Biomaterials [Biomaterials] 2022 Jan; Vol. 280, pp. 121264. Date of Electronic Publication: 2021 Nov 19.
Typ publikacji:
Journal Article; Research Support, Non-U.S. Gov't
Język:
English
Imprint Name(s):
Publication: <1995-> : Amsterdam : Elsevier Science
Original Publication: [Guilford, England] : IPC Science and Technology Press, 1980-
MeSH Terms:
Lipid Metabolism*
Pancreatic Neoplasms*/metabolism
Pancreatic Neoplasms*/therapy
Humans ; Immunotherapy ; Macrophages/metabolism ; RNA Interference ; Tumor Microenvironment
Contributed Indexing:
Keywords: Combination PAC therapy; Lipid metabolism; Nanoplatform; TAMs; siRNA delivery
Entry Date(s):
Date Created: 20211126 Date Completed: 20220314 Latest Revision: 20220314
Update Code:
20240105
DOI:
10.1016/j.biomaterials.2021.121264
PMID:
34823884
Czasopismo naukowe
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.)

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