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A prodrug nanoplatform via esterification of STING agonist and IDO inhibitor for synergistic cancer immunotherapy

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Abstract

Cancer immunotherapy has made significant progress in the last few decades, revolutionizing oncology. However, low patient response rates and potential immune-related adverse events continue to be major clinical challenges. Cancer nanomedicine, by virtue of its regulated delivery and modular flexibility, has shown the potential to strengthen antitumor immune responses and sensitize tumors to immunotherapy. In this study, we developed tumor microenvironment (TME) responsive nanomedicine to achieve specific and localized amplification of the immune response in tumor tissue in a safe and effective manner, while simultaneously reducing immune-related side effects. We synthesized the TME responsive prodrug by coupling MSA-2, a stimulator of interferon genes (STING) agonist, and NLG-919, an indoleamine 2,3 dioxygenase (IDO) inhibitor. The prodrug was assembled into nanoparticles to enhance the solubility and bioavailability. By synthesizing a TME responsive prodrug, we aim to explore the therapeutic efficacy of combined regimen (STING agonist and IDO inhibitor) for cancer, and reduce the unwanted side effects of STING agonism on normal tissues. Free prodrug and nanoparticles were characterized by mass spectrometry, dynamic light scattering (DLS), and transmission electron microscopy (TEM). Following that, we investigated the tumor accumulation, anti-tumor activity, and toxicity in vitro and in vivo. Prodrug nanoparticles demonstrated the ability to inhibit the tumor growth and activate antitumor immune response by modulating immune cells populations in tumor microenvironment. The TME responsive nanomedicine provided an effective tool for precise targeting, promoting antitumor immunity, and efficient tumor growth inhibition with safety. Outcomes of this study may have implications for future clinical trials.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (Nos. 81920108001 and 81870007) and Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents.

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Authors and Affiliations

  1. International Institutes of Medicine, the Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, 322000, China

    Madiha Zahra Syeda, Tu Hong, Yanfei Han, Xiaoling Zhu, Songmin Ying & Longguang Tang

  2. Department of Pharmacology and Department of Respiratory and Critical Care Medicine of the Second Affiliated Hospital, Zhejiang University School of Medicine, Key Laboratory of Respiratory Disease of Zhejiang Province, Hangzhou, 310009, China

    Madiha Zahra Syeda, Min Zhang & Songmin Ying

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  1. Madiha Zahra Syeda
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  2. Tu Hong
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  5. Xiaoling Zhu
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  6. Songmin Ying
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Correspondence to Songmin Ying or Longguang Tang.

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Syeda, M.Z., Hong, T., Zhang, M. et al. A prodrug nanoplatform via esterification of STING agonist and IDO inhibitor for synergistic cancer immunotherapy. Nano Res. 15, 9215–9222 (2022). https://doi.org/10.1007/s12274-022-4598-6

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  • DOI: https://doi.org/10.1007/s12274-022-4598-6

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