EGFR-targeted and gemcitabine-incorporated chemogene for combinatorial pancreatic cancer treatment

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外文摘要：Pancreatic cancer stands out as a recognized intractable tumor due to its high malignancy and mortality rates,which are largely attributed to the insensitivity of current clinical chemotherapies or multidrug-resistance.Combinatorial chemo and gene therapy that integrates different therapeutic targets,may increase the chemosensitivity of pancreatic cancer and synergistically enhance the antitumor efficacy.However,conventional co-delivery of gene and chemo drugs is intensively dependent on complex nanoparticle delivery systems,thus would be limited by unstable drug packaging,nonspecific biodistribution,and biosafety problem.Herein,we rationally designed an epidermal growth factor-receptor(EGFR)-targeted and gemcitabine-incorporated oligonucleotide(termed as chemogene)with anti-Bcl-2 sequence,which achieves simple and precise integration of gemcitabine into a gene regulative agent,as well as the EGFR-targeted delivery for pancreatic cancer therapy.Through solid-phase synthesis,gemcitabine,as the first-line chemodrug for pancreatic cancer,is introduced to the antisense oligonucleotide to replace all cytosine nucleosides to obtain the gemcitabine-integrated chemogene(Ge-ASOBcl-2).Thereafter,Ge-ASOBcl-2 is covalently coupled with EGFR nanobody to construct the final targeted chemogene without any exogenous carriers.Notably,this nanobody-conjugated chemogene exhibits remarkable tumor targeting capability and antitumor effects both in vitro and in vivo,which initiates a first step toward the application of combinatorial chemo and gene therapy for future pancreatic cancer treatment.

外文关键词：

antisense oligonucleotidechemogenenanobodydrug delivery systempancreatic cancer

作者：

Miao Xie、Qiushuang Zhang、Yuanyuan Guo、Lijuan Zhu、Xinyuan Zhu、Chuan Zhang

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作者单位：

School of Chemistry and Chemical Engineering,Frontiers Science Center for Transformative Molecules,Institute of Molecular Medicine,Sixth people's Hospital,School of Medicine,Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs,Shanghai Jiao Tong University,Shanghai 200240,China

Department of Radiology,Shanghai Jiao Tong University Affiliated Sixth People's Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200233,China

Institute of Molecular Medicine,Shanghai Jiao Tong University Affiliated Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200127,China

基金：

National Key Research and Development Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaShanghai Sailing ProgramNatural Science Foundation of ShanghaiShanghai Pilot Program for Basic Research-Shanghai Jiao Tong University

项目编号：

2018YFA090260152225302521032652217511621YF143430023ZR144800021TQ1400219

出版年：

2024

DOI：

10.1007/s12274-023-6245-2

纳米研究(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.17(2)

参考文献量49