A Tumor Microenvironments‐Adapted Polypeptide Hydrogel/Nanogel Composite Boosts Antitumor Molecularly Targeted Inhibition and Immunoactivation. Issue 21 (17th April 2022)

• Record Type: Journal Article
• Authors: Li, Zhongmin; Xu, Weiguo; Yang, Jiazhen; Wang, Juan; Wang, Jialiang; Zhu, Ge; Li, Di; Ding, Jianxun; Sun, Tianmeng
• Is Part Of: Advanced materials. Volume 34:Issue 21(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-04-17
• Subjects: polypeptides -- reactive oxygen species responsive nanogels -- sequential drug delivery -- synergistic cancer therapy -- thermosensitive hydrogel; Materials -- Periodicals; Chemical vapor deposition -- Periodicals; 620.11
• DOI: 10.1002/adma.202200449
• Languages: English
• ISSNs: 0935-9648

Abstract

Abstract: Various macro/microscopic biomaterials have been developed for controlled drug delivery in the combination therapy of malignancies. However, uncertain loading ratio, release sequence, and spatiotemporal distribution of drugs hinder their synergistic therapeutic effects and clinical applications. In this work, a tumor microenvironments‐adapted composite consisting of a thermosensitive hydrogel and a reactive oxygen species (ROS)‐responsive nanogel is developed for precisely sequential drug release to enhance molecularly targeted therapy and amplify immune activation. LY3200882 (LY), a selective transforming growth factor‐β (TGF‐β) inhibitor, is encapsulated in the ROS‐responsive nanogel and dispersed uniformly with regorafenib (REG) in a thermosensitive hydrogel (Gel/(REG+NG/LY)). After in situ administration, REG is preferentially released from the hydrogel to inhibit tumor growth and promote ROS generation, which triggers the subsequent on‐demand release of LY from the nanogel. LY contributes to preventing the epithelial–mesenchymal transition and immune escape of tumor cells induced by elevated TGF‐β. In subcutaneous and orthotopic colorectal tumor bearing mouse models, Gel/(REG+NG/LY) effectively inhibits tumor growth and liver metastases by increasing the tumor infiltration of CD8 + T cells, reducing the recruitment of tumor‐associated macrophages and myeloid‐derived suppressor cells, and promoting the polarization of macrophages from M2 to M1 type, indicating the significant potential in improving the prognosis of advanced cancer patients. Abstract : A tumor microenvironments‐adapted composite consisting of a thermosensitive hydrogel and a reactive oxygen species (ROS)‐responsive nanogel achieves sequential release of molecularly targeted drug and TGF‐β inhibitor in the tumor cells, blocks the proliferation of tumor cells, reverses the epithelial–mesenchymal transition caused by elevated TGF‐β, and regulates the tumor immune microenvironments, thereby effectively inhibiting tumor growth and metastases.