Mei Ling, Liu Yayuan, Xia Chunyu, Zhou Yubei, Zhang Zhirong, He Qin
Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University , No. 17, Block 3, Southern Renmin Road, Chengdu 610041, China.
Mol Pharm. 2017 Feb 6;14(2):513-522. doi: 10.1021/acs.molpharmaceut.6b00979. Epub 2017 Jan 17.
Here, a biocompatible amphiphilic copolymer of low molecular weight heparin (LMWH) and doxorubicin (DOX) connected by an acid-sensitive hydrazone bond for enhanced tumor treatment efficacy and safety has been designed and tested. The conjugate combines DOX delivery with LMWH antimetastatic capabilities. After the nanoparticles reach the tumor site, the acidic tumor microenvironment triggers the breakage of the hydrazone bond releasing DOX from the nanoparticles, which results in an increase in the cellular uptake and enhanced in vivo antitumor efficacy. A 3.4-fold and 1.5-fold increase in tumor growth inhibition were observed compared to the saline-treated control group and free DOX treated group, respectively. The LMWH-based nanoparticles effectively inhibited interactions between tumor cells and platelets mediated by P-selectin reducing metastasis of cells in both in vitro and in vivo models. The improved safety and therapeutic effect of LMWW-DOX nanoparticles offers new potential for tumor therapy.
在此，设计并测试了一种由低分子量肝素（LMWH）和阿霉素（DOX）通过酸敏腙键连接而成的生物相容性两亲共聚物，以提高肿瘤治疗的疗效和安全性。该共轭物将阿霉素递送与低分子量肝素的抗转移能力相结合。纳米颗粒到达肿瘤部位后，酸性肿瘤微环境触发腙键断裂，使阿霉素从纳米颗粒中释放出来，这导致细胞摄取增加并增强体内抗肿瘤疗效。与生理盐水处理的对照组和游离阿霉素处理组相比，分别观察到肿瘤生长抑制增加了3.4倍和1.5倍。基于低分子量肝素的纳米颗粒在体外和体内模型中均有效抑制了由P-选择素介导的肿瘤细胞与血小板之间的相互作用，减少了细胞转移。低分子量肝素-阿霉素纳米颗粒安全性和治疗效果的改善为肿瘤治疗提供了新的潜力。
