Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Hangzhou, Zhejiang Province 310003, China.
EBioMedicine. 2024 May;103:105099. doi: 10.1016/j.ebiom.2024.105099. Epub 2024 Apr 10.
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.
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.
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-γCD8 T cells and CD8 memory T cells, suggesting a potential role of the mTOR nanoblocker to remodel the tumour microenvironment. Overall, a single conjugation with fatty acid transformed a hydrophobic mTOR blocker into a systemically injectable nanomedicine, representing a facile and generalizable strategy for improving the therapeutic index of mTOR inhibition-based cancer therapy.
The mTOR inhibition by chemically engineered nanoblocker presented here had enhanced efficacy against tumours compared with the pristine drug and thus has the potential to improve the survival outcomes of patients with HCC. Additionally, this new nanosystem derived from co-assembling of small-molecule prodrug entities can serve as a delivery platform for the synergistic co-administration of distinct pharmaceutical agents.
This work was supported by the National Natural Science Foundation of China (32171368,81721091), the Zhejiang Provincial Natural Science Foundation of China (LZ21H180001), the Jinan Provincial Laboratory Research Project of Microecological Biomedicine (JNL-2022039c and JNL-2022010B), State Key Laboratory for Diagnosis and Treatment of Infectious Diseases (zz202310), and Natural Science Foundation of Shandong Province (ZR2023ZD59).
肝细胞癌（HCC）是一种高发且致命的癌症，尽管药物治疗仍是治疗的基石，但治疗效果往往不尽人意。哺乳动物雷帕霉素靶蛋白（mTOR）的药理学抑制与 HCC 消退密切相关。
本文通过动态激活连接，将强效 mTORC1/2 抑制剂 AZD8055 与一系列不饱和脂肪酸共价连接，使前药缀合物在水溶液中自组装形成 mTOR 纳米阻断剂。进行细胞实验以评估纳米阻断剂对肝癌（HCC）细胞的作用。建立了原位和皮下 HCC 小鼠模型，以研究其抗肿瘤活性。
在几种作为促进剂的脂肪酸中，亚油酸偶联的自组装纳米阻断剂表现出最佳的粒径分布和优越的物理化学性质。与游离药物相比，PEG 化 AZD8055 纳米阻断剂（称为 AZD NB）在静脉给药后具有更好的药代动力学特性。体内研究证实，AZD NB 可显著抑制皮下 HCCLM3 异种移植、Hepa-22 和原位 Hepa1-6 肝肿瘤模型中的肿瘤生长。引人注目的是，与游离药物相比，AZD NB 治疗可增加肿瘤内 IFN-γCD8 T 细胞和 CD8 记忆 T 细胞的浸润，提示 mTOR 纳米阻断剂具有重塑肿瘤微环境的潜力。总体而言，通过与脂肪酸的简单偶联，将疏水性 mTOR 抑制剂转化为可系统注射的纳米药物，代表了一种提高基于 mTOR 抑制的癌症治疗治疗指数的简便且可推广的策略。
与原始药物相比，本文通过化学工程设计的纳米阻断剂对肿瘤的抑制作用增强，因此有可能提高 HCC 患者的生存结果。此外，这种源自小分子前药实体共组装的新型纳米系统可以作为协同给予不同药物制剂的递药平台。
本工作得到了国家自然科学基金（32171368、81721091）、浙江省自然科学基金（LZ21H180001）、济南市实验室研究项目微生态生物医学（JNL-2022039c 和 JNL-2022010B）、传染病诊治国家重点实验室（zz202310）和山东省自然科学基金（ZR2023ZD59）的支持。
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