Chemically engineered mTOR-nanoparticle blockers enhance antitumour efficacy

作者：Hong Tang, Dilinuer Dilimulati, Zhentao Yang, Ke Zhou, Xiaona Chen, Ruiqi Sun, Ning Wang, Zhi Liang, Suchen Bian, Jialing Zhao, Penghong Song, Shusen Zheng, Hangxiang Wang, Haiyang Xie · 发表于：EBioMedicine · 年份：2024 · DOI：10.1016/j.ebiom.2024.105099 · 被引用次数：11 · 研究领域：Cancer, Stress, Anesthesia, and Immune Response、Nanoplatforms for cancer theranostics、Hepatocellular Carcinoma Treatment and Prognosis

Background Hepatocellular carcinoma (HCC) is a highly prevalent and deadly type of cancer, and although pharmacotherapy remains the cornerstone of treatment, therapeutic outcomes are often unsatisfactory. Pharmacological inhibition of mammalian target of rapamycin (mTOR) has been closely associated with HCC regression. Methods Herein, we covalently conjugated AZD8055, a potent mTORC1/2 blocker, with a small panel of unsaturated fatty acids via a dynamically activating linkage to enable aqueous self-assembly of prodrug conjugates to form mTOR nanoblockers. Cell-based experiments were carried out to evaluate the effects of the nanoblocker against hepatocellular carcinoma (HCC) cells. The orthotopic and subcutaneous HCC mouse models were established to examine its antitumour activity. Findings Among several fatty acids as promoieties, linoleic acid-conjugated self-assembling nanoblocker exhibited optimal size distribution and superior physiochemical properties. Compared with free agents, PEGylated AZD8055 nanoblocker (termed AZD NB) was pharmacokinetically optimized after intravenous administration. In vivo investigations confirmed that AZD NB significantly suppressed tumour outgrowth in subcutaneous HCCLM3 xenograft, Hepatoma-22, and orthotopic Hepa1-6 liver tumour models. Strikingly, treatment with AZD NB, but not free agent, increased intratumour infiltration of IFN-γ + CD8 + T cells and CD8 + memory T cells, suggesting a potential role of the mTOR nanoblocker to remodel the ...