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

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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.

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Acknowledgements

This work was financially 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), and the Shanghai Pilot Program for Basic Research-Shanghai Jiao Tong University (No. 21TQ1400219).

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

Authors and Affiliations

  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

    Miao Xie, Qiushuang Zhang, Xinyuan Zhu & Chuan Zhang

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

    Yuanyuan Guo

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

    Lijuan Zhu

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  1. Miao Xie
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Correspondence to Chuan Zhang.

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Xie, M., Zhang, Q., Guo, Y. et al. EGFR-targeted and gemcitabine-incorporated chemogene for combinatorial pancreatic cancer treatment. Nano Res. 17, 848–857 (2024). https://doi.org/10.1007/s12274-023-6245-2

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