Cancer cell-targeted cisplatin prodrug delivery in vivo via metabolic labeling and bioorthogonal click reaction
Cancer cell-targeted cisplatin prodrug delivery in vivo via metabolic labeling and bioorthogonal click reaction
复制标题
通过代谢标记和生物正交点击反应体内癌细胞靶向顺铂前药递送
DOI：
10.1039/d0bm01709d
复制
发表时间：
2021
影响因子：
6.6
通讯作者：
Yin Lichen
中科院分区：
文献类型：
--
作者：
Liu Xun;Wu Fan;Cai Kaimin;Zhao Ziyin;Zhang Zhimin;Chen Yongbing;Liu Yong;Cheng Jianjun;Yin Lichen
癌细胞和非癌细胞表面受体的差异性一直被认为是肿瘤靶向治疗的支柱。然而，由于肿瘤细胞的异质性和肿瘤细胞表面受体水平不足，癌细胞靶向治疗的成功在很大程度上受到限制。先前开发了组蛋白脱乙酰酶/组织蛋白酶L-响应性乙酰化叠氮甘露糖（DCL-AAM），以通过糖代谢用反应性叠氮基有效地和选择性地标记癌细胞表面。在此，系统地研究了DCL-AAM在体外各种肿瘤细胞和体内SKOV 3异种移植肿瘤中的标记动力学和一般性。在此基础上，开发了二苯并环辛炔-顺铂（DBCO-Pt）前药，DCL-AAM介导的SKOV 3细胞代谢标记通过生物正交点击化学使DBCO-Pt的肿瘤蓄积增加了约2倍，增强了顺铂的抗肿瘤功效，同时减轻了全身毒性。因此，这项工作为未来设计基于糖代谢的靶向递送系统提供了实验和理论支持，并可能为缺乏适当生物标志物的癌症治疗提供有希望的候选药物。
The discrepancy of surface receptors on cancerous and non-cancerous cells has been regarded as the mainstay of cancer-targeted therapy. However, due to the heterogeneity of tumor cells and the insufficient levels of receptors on the tumor cell surface, the success of cancer cell-targeted therapies is largely limited. Histone deacetylase/cathepsin L-responsive acetylated azidomannose (DCL-AAM) was previously developed to effectively and selectively label cancer cell surfaces with reactive azido groups via sugar metabolism. Herein, the labeling kinetics and generality of DCL-AAM were systematically investigated in varieties of tumor cells in vitro and in SKOV3 xenograft tumors in vivo. Based on this, dibenzocyclooctyne-cisplatin (DBCO-Pt) prodrug was developed, and DCL-AAM-mediated metabolic labeling of SKOV3 cells enhanced the tumor accumulation of DBCO-Pt ∼2 fold via bioorthogonal click chemistry, potentiating the anti-tumor efficacy of cisplatin yet alleviating the systemic toxicity. This work, therefore, provides the experimental and theoretical support for the future design of sugar metabolism-based targeted delivery systems and may provide a promising candidate for the treatment of cancers lacking appropriate biomarkers.