Cancer Cell Preferential Penetration and pH-Responsive Drug Delivery of Oligorutin
Cancer Cell Preferential Penetration and pH-Responsive Drug Delivery of Oligorutin
复制标题
寡芦丁的癌细胞优先渗透和 pH 响应性药物递送
DOI：
10.1021/acs.biomac.1c00268
复制
发表时间：
2021
影响因子：
6.2
通讯作者：
Xu Li
中科院分区：
文献类型：
--
作者：
Hong Weiying;Liu Chang-Cheng;Zhang Henan;Chen Zhiyong;Xiao Min;Xu Li
我们在此报告了一种新的递送系统，源自于酶促低聚寡聚蛋白（OR）的合成，用于癌细胞靶向和ph反应性药物递送。在本研究中，我们证明OR可以通过脂质筏介导的内吞途径优先渗透癌细胞，而细胞膜胆固醇对OR的内化至关重要。体内生物分布研究进一步证实了OR在肿瘤区域的积累。考虑到OR的肿瘤靶向性，将OR上的儿茶酚基团通过ph敏感的硼酸酯键与抗肿瘤药物硼替佐米（BTZ）共价偶联，开发了一种ph响应性药物递送系统（OR - BTZ）。OR-BTZ对肝癌细胞具有细胞毒性，抑制肝癌细胞的迁移和侵袭，对正常肝细胞无明显的细胞毒性。OR-BTZs在小鼠肝细胞癌模型中也表现出显著的治疗效果和较低的系统毒性。据我们所知，这项研究首次尝试利用低聚类黄酮在癌细胞靶向药物递送方面的潜力，并将推动类黄酮及其衍生物作为肿瘤靶向治疗的新型生物材料的发展。
We report herein a novel delivery system, derived from the facile enzymatic synthesis of oligorutin (OR), for cancer cell targeting and pH-responsive drug delivery. In this study, we demonstrate that OR could preferentially penetrate cancer cells via the lipid raft-mediated endocytosis pathway, and cell membrane cholesterol was critical to the internalization of OR. The accumulation of OR in the tumor region was further confirmed by an in vivo biodistribution study. Considering the tumor-targeting property of OR, a pH-responsive drug delivery system (OR–BTZ) was developed by covalent conjugation of the catechol groups on OR with antitumor drug bortezomib (BTZ) through a pH-sensitive borate ester bond. OR–BTZ exerted cytotoxicity as well as inhibition of the migration and invasion to hepatoma carcinoma cells and showed no apparent cytotoxicity with liver normal cells. The OR–BTZs also presented significant therapeutic efficacy and low systematic toxicity in the murine hepatocellular carcinoma model. To our knowledge, this study presents the first attempt to exploit the potential of oligoflavonoids for cancer cell-targeted drug delivery and will motivate the development of flavonoids and their derivatives as a new type of biomaterials for tumor-targeted therapy.