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  3. New path to treating pancreatic cancer: TRAIL gene delivery targeting the fibroblast-enriched tumor microenvironment

New path to treating pancreatic cancer: TRAIL gene delivery targeting the fibroblast-enriched tumor microenvironment

  • J Control Release. 2018 Sep 28;286:254-263. doi: 10.1016/j.jconrel.2018.07.047.
Haiping Jiang 1,  Sujuan Wang 2,  Xuefei Zhou 2,  Liying Wang 2,  Lidan Ye 2,  Zhuxian Zhou 2,  Jianbin Tang 2,  Xiangrui Liu 3,  Lisong Teng 4,  Youqing Shen 2
Affiliations

Affiliations

  • 1 Department of Medical Oncology, the First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, People's Republic of China.
  • 2 Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
  • 3 Key Laboratory of Biomass Chemical Engineering of Ministry of Education and Center for Bionanoengineering, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China. Electronic address: xiangrui@zju.edu.cn.
  • 4 Department of Surgical Oncology, the First Affiliated Hospital of Medical School of Zhejiang University, Hangzhou, People's Republic of China.
PMID: 30075209 DOI: 10.1016/j.jconrel.2018.07.047
Abstract

Gene therapy has shown promise in antitumor strategies for advanced Cancer. However, efficient and safe delivery of potent therapeutic gene expressing in specific tumor tissues remains elusive, especially when there exist stromal obstacles. Here we report a non-viral gene delivery approach targeting pancreatic stellate cells (PSCs) as the transfection host in the fibroblast-enriched tumor microenvironment of pancreatic Cancer. Plasmid DNA (pDNA) encapsulated in branched polyethylenemine (BPEI) was found to selectively transfect PSCs rather than pancreatic Cancer cells and other fibroblast cell lines. Mechanism investigations reveal that the highly expressed Fibroblast Growth Factor receptors (FGFRs) in PSCs facilitated the cellular uptake of polyplexes in PSCs. This delivery platform carrying gene encoding of TNF-related apoptosis-inducing ligand (TRAIL) displayed effective by-stander effect and tumor cell-selective cytotoxicity. More importantly, the therapeutic efficacy was proved in a PSC-enriched orthotopic pancreatic tumor model. Thus, this gene delivery strategy smartly converts PSCs as the microenvironment obstacle for Drug Delivery into the producer and reservoir of selective tumor-killing proteins.

Keywords

Cancer associated fibroblasts; Gene delivery; Pancreatic cancer; Pancreatic stellate cells; TRAIL.

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