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Research Article

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

Miao Xie1,§, Qiushuang Zhang1,§, Yuanyuan Guo2, Lijuan Zhu3, Xinyuan Zhu1, Chuan Zhang1( )
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

§ Miao Xie and Qiushuang Zhang contributed equally to this work.

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Graphical Abstract

An EGFR-targeted chemogene is rationally designed for potential pancreatic cancer treatment. With gemcitabine embedded in the chemogene construct empowered with anti-Bcl-2 sequence, this targeted chemogene exhibits enhanced anti-tumor efficacy in a pancreatic tumor-bearing mouse model.

Abstract

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.

Keywords

antisense oligonucleotidechemogenenanobodydrug delivery systempancreatic cancer

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Nano Research
Volume 17 Issue 2,
February 2024
Pages 848-857
DOI: 10.1007/s12274-023-6245-2
Cite this article:
Xie M, Zhang Q, Guo Y, et al. EGFR-targeted and gemcitabine-incorporated chemogene for combinatorial pancreatic cancer treatment. Nano Research, 2024, 17(2): 848-857. https://doi.org/10.1007/s12274-023-6245-2
Topics:
Gene therapy Targeted drug delivery
Part of a topical collection:
NR45 Awards in Bio-inspired Nanomaterials, 2023

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Received: 08 August 2023
Revised: 04 October 2023
Accepted: 06 October 2023
Published: 17 November 2023
© Tsinghua University Press 2023
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