Precision design of nanomedicines to restore gemcitabine chemosensitivity for personalized pancreatic ductal adenocarcinoma treatment. Biomaterials 2018 Mar;158:44-55
Date
12/25/2017Pubmed ID
29275122DOI
10.1016/j.biomaterials.2017.12.015Scopus ID
2-s2.0-85038856565 (requires institutional sign-in at Scopus site) 31 CitationsAbstract
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.
Author List
Zhao X, Wang X, Sun W, Cheng K, Qin H, Han X, Lin Y, Wang Y, Lang J, Zhao R, Zheng X, Zhao Y, Shi J, Hao J, Miao QR, Nie G, Ren HMESH terms used to index this publication - Major topics in bold
AnimalsCarcinoma, Pancreatic Ductal
Cell Line, Tumor
Deoxycytidine
Equilibrative Nucleoside Transporter 1
Female
Gene Expression Regulation, Neoplastic
Humans
Liposomes
Mice
Precision Medicine
RNA, Small Interfering
Ribonucleotide Reductases
