Статья

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

Yuxin ZhangDepartment of Radiology, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease‐Related Molecular Network, State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaZaixiang FangDepartment of Radiology, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease‐Related Molecular Network, State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaDayi PanDepartment of Radiology, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease‐Related Molecular Network, State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaYunkun LiDepartment of Radiology, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease‐Related Molecular Network, State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaJie ZhouDepartment of Radiology, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease‐Related Molecular Network, State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaHongying ChenDepartment of Radiology, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease‐Related Molecular Network, State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaZhiqian LiDepartment of Radiology, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease‐Related Molecular Network, State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaMengli ZhuDepartment of Radiology, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease‐Related Molecular Network, State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaCong LiDepartment of Radiology, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease‐Related Molecular Network, State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaLiwen QinDepartment of Radiology, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease‐Related Molecular Network, State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaXiangyi RenDepartment of Radiology, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease‐Related Molecular Network, State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 ChinaQiyong GongDepartment of Radiology West China Xiamen Hospital of Sichuan University Xiamen 361021 ChinaKui LuoDepartment of Radiology, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease‐Related Molecular Network, State Key Laboratory of Biotherapy West China Hospital Sichuan University Chengdu 610041 China

2024en

ABI

Аннотация

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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Идентификаторы

DOI: 10.1002/adma.202401304

Цитирования и источники

Цитирований: 3Использованных источников: 0

Показатели — AkademScholar