Synergistic effect of tumor chemo-immunotherapy induced by leukocyte-hitchhiking thermal-sensitive micelles

Jing Qi, Feiyang Jin, Yuchan You, Yan Du, Di Liu, Xiaoling Xu (), Jun Wang, Luwen Zhu, Minjiang Chen, Gaofeng Shu, Liming Wu (), Jiansong Ji () and Yongzhong Du ()
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Jing Qi: College of Pharmaceutical Sciences, Zhejiang University
Feiyang Jin: College of Pharmaceutical Sciences, Zhejiang University
Yuchan You: College of Pharmaceutical Sciences, Zhejiang University
Yan Du: College of Pharmaceutical Sciences, Zhejiang University
Di Liu: College of Pharmaceutical Sciences, Zhejiang University
Xiaoling Xu: College of Pharmaceutical Sciences, Zhejiang University
Jun Wang: College of Pharmaceutical Sciences, Zhejiang University
Luwen Zhu: College of Pharmaceutical Sciences, Zhejiang University
Minjiang Chen: College of Pharmaceutical Sciences, Zhejiang University
Gaofeng Shu: Lishui Hospital of Zhejiang University
Liming Wu: The First Affiliated Hospital, Zhejiang University School of Medicine
Jiansong Ji: Lishui Hospital of Zhejiang University
Yongzhong Du: College of Pharmaceutical Sciences, Zhejiang University

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Some specific chemotherapeutic drugs are able to enhance tumor immunogenicity and facilitate antitumor immunity by inducing immunogenic cell death (ICD). However, tumor immunosuppression induced by the adenosine pathway hampers this effect. In this study, E-selectin-modified thermal-sensitive micelles are designed to co-deliver a chemotherapeutic drug (doxorubicin, DOX) and an A2A adenosine receptor antagonist (SCH 58261), which simultaneously exhibit chemo-immunotherapeutic effects when applied with microwave irradiation. After intravenous injection, the fabricated micelles effectively adhere to the surface of leukocytes in peripheral blood mediated by E-selectin, and thereby hitchhiking with leukocytes to achieve a higher accumulation at the tumor site. Further, local microwave irradiation is applied to induce hyperthermia and accelerates the release rate of drugs from micelles. Rapidly released DOX induces tumor ICD and elicits tumor-specific immunity, while SCH 58261 alleviates immunosuppression caused by the adenosine pathway, further enhancing DOX-induced antitumor immunity. In conclusion, this study presents a strategy to increase the tumor accumulation of drugs by hitchhiking with leukocytes, and the synergistic strategy of chemo-immunotherapy not only effectively arrested primary tumor growth, but also exhibited superior effects in terms of antimetastasis, antirecurrence and antirechallenge.

Date: 2021
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DOI: 10.1038/s41467-021-24902-2

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