Li Zhongmin, Xu Weiguo, Yang Jiazhen, Wang Juan, Wang Jialiang, Zhu Ge, Li Di, Ding Jianxun, Sun Tianmeng
Key Laboratory of Organ Regeneration and Transplantation of Ministry of Education, National-Local Joint Engineering Laboratory of Animal Models for Human Diseases, Jilin University, 1 Xinmin Street, Changchun, 130061, P. R. China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, 130022, P. R. China.
Adv Mater. 2022 May;34(21):e2200449. doi: 10.1002/adma.202200449. Epub 2022 Apr 17.
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.
为了在恶性肿瘤的联合治疗中实现可控药物递送，人们开发了各种宏观/微观生物材料。然而，药物的负载率、释放顺序以及时空分布不确定，这阻碍了它们的协同治疗效果和临床应用。在这项工作中，我们开发了一种由热敏水凝胶和活性氧（ROS）响应纳米凝胶组成的适应肿瘤微环境的复合材料，用于精确的顺序药物释放，以增强分子靶向治疗并放大免疫激活。选择性转化生长因子-β（TGF-β）抑制剂LY3200882（LY）被封装在ROS响应纳米凝胶中，并与瑞戈非尼（REG）均匀分散在热敏水凝胶中（Gel/(REG+NG/LY)）。原位给药后，REG优先从水凝胶中释放以抑制肿瘤生长并促进ROS生成，这触发了LY随后从纳米凝胶中的按需释放。LY有助于防止由升高的TGF-β诱导的肿瘤细胞上皮-间质转化和免疫逃逸。在皮下和原位结直肠癌荷瘤小鼠模型中，Gel/(REG+NG/LY)通过增加CD8 T细胞的肿瘤浸润、减少肿瘤相关巨噬细胞和髓源性抑制细胞的募集以及促进巨噬细胞从M2型向M1型极化，有效抑制肿瘤生长和肝转移，表明其在改善晚期癌症患者预后方面具有巨大潜力。
