期刊
BIOMATERIALS
卷 158, 期 -, 页码 44-55出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2017.12.015
关键词
Nanocarriers; Gemcitabine; Pancreatic ductal adenocarcinoma; hENT1; RRM2
资金
- National Distinguished Young Scientists program [31325010]
- Innovation Research Group of National Natural Science Foundation [11621505]
- Key Research Project of Frontier science of the Chinese Academy of Sciences [QYZDJ-SSW-SLH022]
- Key Research Program of the Chinese Academy of Sciences [KGZD-EW-T06]
- National Postdoctoral Program for Innovative Talents [BX201600042]
- Chinese Postdoctoral Science Foundation [2017M610839]
- National Natural Science Foundation of China [51673051, 81672431, 81672435, 31300822, 91543127, 81525021, 81502067, 81572618, 31471340, 31470957]
- Academy of Medical Sciences Newton Advanced Fellowship
- Academy of Medical Sciences (AMS) [NAF003\\1002] Funding Source: researchfish
Low chemosensitivity considerably restricts the therapeutic efficacy of gemcitabine (GEM) in pancreatic cancer treatment. Using immunohistochemical evaluation, we investigated that decreased expression of human equilibrative nucleoside transporter-1 (hENT1, which is the major GEM transporter across cell membranes) and increased expression of ribonucleotide reductase subunit 2 (RRM2, which decreases the cytotoxicity of GEM) was associated with low GEM chemosensitivity. To solve these problems, we employed a nanomedicine-based formulation of cationic liposomes for co-delivery of GEM along with siRNA targeting RRM2. Due to the specific endocytic uptake mechanism of nanocarriers and gene silencing effect of RRM2 siRNA, this nanomedicine formulation significantly increased GEM chemosensitivity in tumor models of genetically engineered Panc1 cells with low hENT1 or high RRM2 expression. Moreover, in a series of patient-derived cancer cells, we demonstrated that the therapeutic benefits of the nanomedicine formulations were associated with the expression levels of hENT1 and RRM2. In summary, we found that the essential factors of GEM chemosensitivity were the expression levels of hENT1 and RRM2, and synthesized nanoformulations can overcome these problems. This unique design of nanomedicine not only provides a universal platform to enhance chemosensitivity but also contributes to the precision design and personalized treatment in nanomedicine. (C) 2017 Elsevier Ltd. All rights reserved.
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