Normalization of Tumor Vessels by Lenvatinib‐Based Metallo‐Nanodrugs Alleviates Hypoxia and Enhances Calreticulin‐Mediated Immune Responses in Orthotopic HCC and Organoids

钙网蛋白 癌症研究 医学 免疫疗法 肿瘤缺氧 类有机物 免疫系统 免疫学 内科学 生物 放射治疗 细胞生物学 内质网
作者
Da Zhang,Chenwei Jiang,Xiaoyuan Zheng,Zhiwen Lin,Qiuyu Zhuang,Huanzhang Xie,Yuzhi Liang,Yu Kang T. Xu,Linsheng Cui,Xiaolong Liu,Yongyi Zeng
出处
期刊:Small [Wiley]
卷期号:19 (29) 被引量:10
标识
DOI:10.1002/smll.202207786
摘要

Abstract Immunocheckpoint inhibitors combined with Lenvatinib is the first line treatment for hepatocellular carcinoma (HCC), but their potency is hampered by the low response rate and adverse events. Herein, a targeted therapeutic strategy through the coassembly of Lenvatinib, Adriamycin, Fe 3+ ion, and a natural polyphenol (metallo‐nanodrugs) is presented by coordination effect for potentiating tumor vascular normalization and systematic chemo‐immunotherapy to effectively inhibit the progression of HCC in both orthotopic model and patients‐derived organoids. In mice with orthotopic HCC, the obtained metallo‐nanodrugs efficiently increase the drug accumulation in orthotopic tumors and can respond to acidic tumor environment. The promotion of tumor vascular normalization by metallo‐nanodrugs is observed, which enhances the infiltrating T lymphocytes in tumor, and reinforces the calreticulin‐mediated antitumor immunity through alleviating hypoxia, reducing regulatory T cells, and down‐regulating PDL1 expression of tumors. The excellent therapeutic efficiency with complete remission of orthotopic tumors (3/6) and long‐term survival of mice (4/6, 42 days) are also achieved. Furthermore, the excellent therapeutic effect of metallo‐nanodrugs is also validated in 5 patient‐derived organoids, and hence can provide a marvelous systemic chemo‐immunotherapy strategy for enhancing HCC treatment.
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