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

作　　者：Miao Xie Qiushuang Zhang Yuanyuan Guo Lijuan Zhu Xinyuan Zhu Chuan Zhang 

机构地区：[1]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 [2]Department of Radiology,Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200233,China [3]Institute of Molecular Medicine,Shanghai Jiao Tong University Affiliated Renji Hospital,School of Medicine,Shanghai Jiao Tong University,Shanghai 200127,China

出　　处：《Nano Research》2024年第2期848-857,共10页纳米研究（英文版）

基　　金：supported by the National Key Research and Development Program of China(No.2018YFA0902601);the National Natural Science Foundation of China(Nos.52225302,52103265,and 22175116);the Shanghai Sailing Program(No.21YF1434300);the Natural Science Foundation of Shanghai(No.23ZR1448000);the Shanghai Pilot Program for Basic Research-Shanghai Jiao Tong University(No.21TQ1400219).

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-ASO^(Bcl-2)).Thereafter,Ge-ASO^(Bcl-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.

关 键 词：antisense oligonucleotide chemogene NANOBODY drug delivery system pancreatic cancer 

分 类 号：R735.9[医药卫生—肿瘤]