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Enhanced antitumor and anti-metastasis by VEGFR2-targeted doxorubicin immunoliposome synergy with NK cell activation

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Summary

Liposomal doxorubicin exhibits stronger drug accumulation at the tumor site due to the Enhanced Permeability and Retention (EPR) effect. However, the prognosis for the patient is poor due to this drug’s lack of targeting and tumor metastasis during treatment. Vascular epidermal growth factor receptor (VEGFR2) plays an important role in angiogenesis and cancer metastasis. To enhance antitumor efficacy of PEGylated liposomal doxorubicin, we constructed a VEGFR2-targeted and doxorubicin-loaded immunoliposome (Lipo-DOX-C00) by conjugating a VEGFR2-specific, single chain antibody fragment to DSPE-PEG2000-MAL, and then we inserted the antibody-conjugated polymer into liposomal doxorubicin (Lipo-DOX). The immunoliposome was formed uniformly with high affinity for VEGFR2. In vitro, Lipo-DOX-C00 enhanced doxorubicin internalization into LLC and 4T1 cells compared with non-conjugated, liposomal doxorubicin. In vivo, Lipo-DOX-C00 delivered DOX to tumor tissues effectively, which exhibited an improved antitumor and anti-metastasis efficacy in both LLC subcutaneous tumor models and 4T1 tumor models. In addition, the combined therapy of a VEGFR2–MICA bispecific antibody (JZC01) and Lipo-DOX-C00 achieved enhanced inhibition of cancer growth and metastasis due to activation of the immune system. Our study provides a promising approach to clinical application of liposomal doxorubicin.

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Data availability

The data that support the findings of this study are available on request from the corresponding author, upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation (NSFC81973223) and the National College Students Innovation and Entrepreneurship Training Program (202210316062Y, China).

Funding

This work was supported by the National Natural Science Foundation (NSFC81973223) and the National College Students Innovation and Entrepreneurship Training Program (202210316062Y, China).

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Author notes

  1. Mingzhu Pan and Yali Liu contributed equally to this article.

Authors and Affiliations

  1. Antibody Engineering Laboratory, School of Life Science & Technology, China Pharmaceutical University, Nanjing, 211198, China

    Mingzhu Pan, Yali Liu, Tian Sang, Jiajun Xie, Huishu Lin, Jianpeng Wei, Shuai Shao & Juan Zhang

  2. Department of Pathology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China

    Yanying Zheng

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  1. Mingzhu Pan
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Contributions

Material preparation, data collection, and analysis were performed by MP and YL. The manuscript was written by MP and YL. TS and JX performed the recombinant protein preparation and FCA assays. HL, JW, and SS helped with the animal experiments. All authors read and approved the final manuscript.

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Correspondence to Yanying Zheng or Juan Zhang.

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All experimental procedures were conducted in conformity with institutional guidelines for the care and use of laboratory animals at China Pharmaceutical University, Nanjing, China, and procedures conformed to the National Institutes of Regulations for the Administration of Affairs Concerning Experimental Animals.

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Pan, M., Liu, Y., Sang, T. et al. Enhanced antitumor and anti-metastasis by VEGFR2-targeted doxorubicin immunoliposome synergy with NK cell activation. Invest New Drugs 41, 664–676 (2023). https://doi.org/10.1007/s10637-023-01372-5

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