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Research Article

Addressing chemoresistance with a lipid gemcitabine nanotherapeutic strategy for effective treatment of pancreatic cancer

Jiawei Hong1, Shiyun Xian1, Shusen Zheng1( ), Hangxiang Wang1,2( ), Donghai Jiang1( )
The First Affiliated Hospital, NHC Key Laboratory of Combined Multi-Organ Transplantation, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou 310003, China
Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250117, China
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Graphical Abstract

By employing a simple fatty acid conjugation and subsequent aqueous nanoassembly, a nanoparticle formulation of gemcitabine (Nano GEM) was developed. Nano GEM has demonstrated a more pronounced cytotoxic effect on gemcitabine-resistant pancreatic cancer cells, while also exhibiting favorable biosafety.

Abstract

Resistance to gemcitabine in pancreatic cancer poses a significant clinical challenge. Further investigation is warranted to assess whether nano-formulation strategy can be employed to enhance the sensitivity of resistant strains to gemcitabine therapy. In this study, using gemcitabine-resistant pancreatic cancer cell lines, we examined the therapeutic potential of a gemcitabine nanodelivery platform and assessed the ability to overcome drug resistance against resistant strains. Silencing of human equilibrative nucleoside transporter 1 (hENT1) led to reduced cellular uptake of gemcitabine, resulting in chemoresistance in pancreatic cancer. Gemcitabine nanoparticles circumvented the entry blockade caused by hENT1 silencing through endocytosis. Nanoparticle entry via clathrin-mediated endocytosis increased intracellular gemcitabine accumulation in gemcitabine-resistant pancreatic cancer cells. Moreover, gemcitabine nanoparticles are preferential in vivo delivery to tumor tissues, likely due to the enhanced permeability and retention effect. In comparison to free gemcitabine, gemcitabine nanoparticles demonstrate a more pronounced cytotoxic effect on gemcitabine-resistant pancreatic cancer cells, with favorable biosafety. This study improved the efficacy of gemcitabine through nanotechnology, providing a novel strategy to address gemcitabine-resistant pancreatic cancer.

Keywords

pancreatic cancergemcitabine resistancegemcitabine nanoparticlehuman equilibrative nucleoside transporter 1

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Nano Research
Volume 17 Issue 9,
September 2024
Pages 8377-8388
DOI: 10.1007/s12274-024-6860-6
Cite this article:
Hong J, Xian S, Zheng S, et al. Addressing chemoresistance with a lipid gemcitabine nanotherapeutic strategy for effective treatment of pancreatic cancer. Nano Research, 2024, 17(9): 8377-8388. https://doi.org/10.1007/s12274-024-6860-6
Topics:
Nano biology

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Received: 28 March 2024
Revised: 01 July 2024
Accepted: 02 July 2024
Published: 01 August 2024
© Tsinghua University Press 2024
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