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Spatially targeting of tumor-associated macrophages and cancer cells for suppression of spontaneously metastatic tumor

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Abstract

The interaction between cancer cells and M2 tumor-associated macrophages (M2-TAMs) facilitates tumor growth and metastasis. However, cancer cells and M2-TAMs have different spatial distribution patterns, which requires distinct drug delivery strategies. Herein, based on different tumor-penetrating ability of nanocarriers, we developed a combinatory strategy that consists of a TAMs-targeting liposome (alanine-alanine-asparagine (AAN)-Lip-regorafenib (Rego)) and a cancer cells-targeting copolymer (internalizing RGD modified with N-(2-hydroxypropyl) methacrylamide-doxorubicin (iRGD-HD)). Our study confirmed AAN-Lip-Rego accumulated at perivascular sites where M2-TAM is located, while iRGD-HD penetrated into deep site of tumor to enter cancer cells. Thereafter, we found iRGD-HD induced cancer cells undergoing immunogenic cell death to enhance tumor infiltration of CD8+ T cells. Meanwhile, AAN-Lip-Rego efficiently repolarized TAMs from M2 into M1 to alleviate tumor immunosuppression, thus reviving CD8+ T cells. Moreover, the repolarization of TAMs led to dramatic downregulation of prometastatic factors expressed on cancer cells. As a result, such combinatory approach elicited robust antitumor immune responses and generated considerable anti-tumor and anti-metastasis efficacy to markedly inhibit primary tumor and spontaneous lung metastasis.

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Acknowledgements

This work was supported by the National Natural Science Foundation for Distinguished Young Scholars (No. 81625023).

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  1. Minglu Zhou and Dandan Xie contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China

    Minglu Zhou, Dandan Xie, Zhou Zhou, Lian Li & Yuan Huang

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  1. Minglu Zhou
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  2. Dandan Xie
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  3. Zhou Zhou
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  4. Lian Li
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Correspondence to Yuan Huang.

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Zhou, M., Xie, D., Zhou, Z. et al. Spatially targeting of tumor-associated macrophages and cancer cells for suppression of spontaneously metastatic tumor. Nano Res. 15, 3446–3457 (2022). https://doi.org/10.1007/s12274-021-3976-9

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