Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu 610041, People's Republic of China.
ACS Appl Mater Interfaces. 2015 Apr 1;7(12):6661-73. doi: 10.1021/am509204u. Epub 2015 Mar 23.
To improve the therapeutic efficacy of anticancer combination therapy, we designed a nanoplatform based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers that allows covalent bonding of two chemotherapeutics acting via different anticancer mechanisms and that can enter target cells by receptor-mediated endocytosis. Doxorubicin (DOX) was covalently conjugated to a nanosized HPMA copolymer using a pH-sensitive hydrazone bond and 5-fluorouracil (5-Fu) was conjugated to the same backbone using an enzymatically degradable oligopeptide Gly-Phe-Leu-Gly sequence. Then, the conjugate was decorated with galectin-3 targeting peptide G3-C12 [P-(G3-C12)-DOX-Fu]. The two drugs showed similar in vitro release profiles, suggesting that they may be able to work synergistically in the codelivery system. In galectin-3 overexpressed PC-3 human prostate carcinoma cells, P-(G3-C12)-DOX-Fu surprisingly exhibited comparable cytotoxicity to free DOX at high concentration by increasing cell internalization and exerting synergistic genotoxic effects of cell cycle arrest, caspase-3 activation, and DNA damage. In mice bearing PC-3 tumor xenografts, the use of tumor-targeting ligand substantially enhanced the intracellular delivery of P-(G3-C12)-DOX-Fu in tumors. The targeted dual drug-loaded conjugate inhibited tumor growth to a greater extent (tumor inhibition of 81.6%) than did nontargeted P-DOX-Fu (71.2%), P-DOX (63%), DOX·HCl (40.5%), P-Fu (32.0%), or 5-Fu (14.6%), without inducing any obvious side effects. These results demonstrate the potential of synergistic combination therapy using targeted nanocarriers for efficient treatment of prostate cancer.
为了提高抗癌联合治疗的疗效，我们设计了一种基于 N-(2-羟丙基)甲基丙烯酰胺（HPMA）共聚物的纳米平台，该平台允许通过两种不同抗癌机制作用的两种化疗药物通过受体介导的内吞作用进入靶细胞。阿霉素（DOX）通过 pH 敏感腙键共价连接到纳米级 HPMA 共聚物上，而 5-氟尿嘧啶（5-Fu）通过可酶降解的寡肽 Gly-Phe-Leu-Gly 序列连接到同一主链上。然后，将半乳糖凝集素-3 靶向肽 G3-C12 [P-(G3-C12)-DOX-Fu] 修饰到该缀合物上。两种药物表现出相似的体外释放曲线，表明它们可能在共递送系统中协同作用。在半乳糖凝集素-3 过表达的 PC-3 人前列腺癌细胞中，P-(G3-C12)-DOX-Fu 通过增加细胞内化并发挥细胞周期阻滞、半胱天冬酶-3 激活和 DNA 损伤的协同遗传毒性作用，在高浓度时出人意料地表现出与游离 DOX 相当的细胞毒性。在携带 PC-3 肿瘤异种移植物的小鼠中，使用肿瘤靶向配体可大大增强 P-(G3-C12)-DOX-Fu 在肿瘤中的细胞内递送。靶向双载药缀合物比非靶向 P-DOX-Fu（71.2%）、P-DOX（63%）、DOX·HCl（40.5%）、P-Fu（32.0%）或 5-Fu（14.6%）更能抑制肿瘤生长，而不会引起任何明显的副作用。这些结果表明，使用靶向纳米载体进行协同联合治疗具有治疗前列腺癌的潜力。
