Precision design of nanomedicines to restore gemcitabine chemosensitivity for personalized pancreatic ductal adenocarcinoma treatment

Xiao Zhao, Xiuchao Wang, Wei Sun, Keman Cheng, Hao Qin, Xuexiang Han, Yu Lin, Yongwei Wang, Jiayan Lang, Ruifang Zhao, Xiaowei Zheng, Ying Zhao, Jian shi, Jihui Hao, Qing Robert Miao, Guangjun Nie, He Ren

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)44-55
Number of pages12
JournalBiomaterials
Volume158
DOIs
StatePublished - Mar 2018

Keywords

  • Gemcitabine
  • Nanocarriers
  • Pancreatic ductal adenocarcinoma
  • RRM2
  • hENT1

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

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