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 resist...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.展开更多
基金supported by the National Natural Science Foundation of China(Nos.82273490,82073296,and 81773193 to Hangxiang Wang,No.81721091 to Shusen Zheng)Research Project of Jinan Microecological Biomedicine Shandong Laboratory(No.JNL-2022010B to Hangxiang Wang)+1 种基金Natural Science Foundation of Shandong Province(No.ZR2023ZD59 to Hangxiang Wang)Zhejiang Provincial Natural Science Foundation of China(No.LR19H160002 to Hangxiang Wang).
文摘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.
