背景:肝细胞癌(HCC)是一种非常普遍和致命的癌症类型,尽管药物治疗仍然是治疗的基石,治疗结果往往不能令人满意.哺乳动物雷帕霉素靶蛋白(mTOR)的药理学抑制与HCC的消退密切相关。
方法:这里,我们共价结合AZD8055,一种有效的mTORC1/2阻断剂,与一组不饱和脂肪酸通过动态激活连接,使前药缀合物的水性自组装形成mTOR纳米阻滞剂。进行基于细胞的实验以评估纳米锁定剂对肝细胞癌(HCC)细胞的作用。建立原位和皮下HCC小鼠模型以检查其抗肿瘤活性。
结果:在几种脂肪酸中,亚油酸共轭自组装纳米受体具有最佳的尺寸分布和优异的理化性质。与自由球员相比,在静脉内施用后,对PEG化AZD8055纳米阻滞剂(称为AZDNB)进行药代动力学优化。体内研究证实,AZDNB显着抑制皮下HCCLM3异种移植物中的肿瘤生长,肝癌-22和原位Hepa1-6肝肿瘤模型。引人注目的是,用AZDNB治疗,但不是自由球员,IFN-γ+CD8+T细胞和CD8+记忆T细胞的肿瘤内浸润增加,提示mTOR纳米受体在重塑肿瘤微环境中的潜在作用。总的来说,与脂肪酸的单一缀合将疏水性mTOR阻断剂转化为可系统注射的纳米药物,代表了提高基于mTOR抑制的癌症治疗的治疗指数的简便和可推广的策略。
结论:与原始药物相比,本文提出的化学工程纳米阻滞剂对mTOR的抑制作用增强了对肿瘤的疗效,因此具有改善HCC患者生存结局的潜力。此外,这种来自小分子前药实体共组装的新纳米系统可以作为不同药物协同共给药的递送平台。
背景:这项工作得到了国家自然科学基金(32171368,81721091)的支持,浙江省自然科学基金(LZ21H180001),济南市微生态生物医学实验室研究项目(JNL-2022039c和JNL-2022010B),传染病诊治国家重点实验室(zz202310),山东省自然科学基金(ZR2023ZD59).
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.
RESULTS: 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 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.
CONCLUSIONS: 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.
BACKGROUND: 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).