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Dendritic Polymer‐Based Nanomedicines Remodel the Tumor Stroma: Improve Drug Penetration and Enhance Antitumor Immune Response

Zhang, Yuxin, Fang, Zaixiang, Pan, Dayi, Li, Yunkun, Zhou, Jie, Chen, Hongying, Li, Zhiqian, Zhu, Mengli, Li, Cong, Qin, Liwen, Ren, Xiangyi, Gong, Qiyong, Luo, Kui·2024·Advanced Materials
DOI 10.1002/adma.202401304
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Abstract

The dense extracellular matrix (ECM) in solid tumors, contributed by cancer‐associated fibroblasts (CAFs), hinders penetration of drugs and diminishes their therapeutic outcomes. A sequential treatment strategy of remodeling the ECM via a CAF modifier (dasatinib, DAS) is proposed to promote penetration of an immunogenic cell death (ICD) inducer (epirubicin, Epi) via apoptotic vesicles, ultimately enhancing the treatment efficacy against breast cancer. Dendritic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA)‐based nanomedicines (poly[OEGMA‐Dendron(G2)‐Gly‐Phe‐Leu‐Gly‐DAS] (P‐DAS) and poly[OEGMA‐Dendron(G2)‐hydrazone‐Epi] (P‐Epi)) are developed for sequential delivery of DAS and Epi, respectively. P‐DAS reprograms CAFs to reduce collagen by downregulating collagen anabolism and energy metabolism, thereby reducing the ECM deposition. The regulated ECM can enhance tumor penetration of P‐Epi to strengthen its ICD effect, leading to an amplified antitumor immune response. In breast cancer‐bearing mice, this approach alleviates the ECM barrier, resulting in reduced tumor burden and increased cytotoxic T lymphocyte infiltration, and more encouragingly, synergizes effectively with anti‐programmed cell death 1 (PD‐1) therapy, significantly inhibiting tumor growth and preventing lung metastasis. Furthermore, systemic toxicity is barely detectable after sequential treatment with P‐DAS and P‐Epi. This approach opens a new avenue for treating desmoplastic tumors by metabolically targeting CAFs to overcome the ECM barrier.

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Metadata

Authors
Zhang, Y., Fang, Z., Pan, D., Li, Y., Zhou, J., Chen, H., Li, Z., Zhu, M., Li, C., Qin, L., Ren, X., Gong, Q., & Luo, K.
Venue
Advanced Materials
Publisher
Wiley
Published
2024-03-22
Volume
36
Issue
25
ISSN
  • 0935-9648
  • 1521-4095
DOI
10.1002/adma.202401304
Cited by
116
References
2
Language
en
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Funders
  • National Natural Science Foundation of China (32271445, 32271382, 52103175)
  • National Key Research and Development Program of China (2022YFC2009900)
  • National Science and Technology Major Project (2023YFB3810004)
  • Science and Technology Department of Sichuan Province (24NSFJQ0167)

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CoChat. (2026). Citation check: Dendritic Polymer‐Based Nanomedicines Remodel the Tumor Stroma: Improve Drug Penetration and Enhance Antitumor Immune Response. https://app.cochat.ai/papers/10.1002/adma.202401304
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Zhang, Y., Fang, Z., Pan, D., Li, Y., Zhou, J., Chen, H., Li, Z., Zhu, M., Li, C., Qin, L., Ren, X., Gong, Q., & Luo, K. (2024). Dendritic Polymer‐Based Nanomedicines Remodel the Tumor Stroma: Improve Drug Penetration and Enhance Antitumor Immune Response. Advanced Materials. https://doi.org/10.1002/adma.202401304