基于中空介孔硫化铜的多功能纳米递药系统的构建及初步研究

Construction and preliminary study of multifunctional drug delivery system based on hollow mesoporous copper sulfide nanoparticles

本文拟构建一种基于中空介孔硫化铜(hollow mesoporous copper sulfide nanoparticles, HMCuS)纳米粒的多功能纳米递药系统,以实现肿瘤靶向的光动力学治疗与化疗的协同治疗。本文采用置换法合成HMCuS纳米粒载体,负载多柔比星(doxorubicin, DOX)抗癌药物后由透明质酸(hyaluronic acid, HA)进行表面修饰,从而制备DOX/HMCuS-HA抗癌药物系统。结果表明:所制备的DOX/HMCuS-HA呈现均匀球状结构,载药量为33.6%,粒径和电位分别为113.8±6.9 nm和18.4±2.8 mV。100μg·mL^-1 HMCuS在808 nm激光(2W·cm^-2)下照射8 min可升温51℃,具有较好的产热效果。此外,电子自旋共振(electron spin resonance, ESR)及亚甲基蓝(methylene blue, MB)实验结果表明, HMCuS在近红外光(near infrared, NIR)照射下同时可以产生羟自由基(·OH)介导光动力学治疗。体外释药结果表明,制剂需经透明质酸酶降解后,在酸性pH值和NIR触发下促进DOX的释放,实现靶向多刺激响应型门控释药。以上结果为及时有效的抗肿瘤治疗提供了新的策略。

This study aims to develop multifunctional drug delivery system based on hollow mesoporous copper sulfide(HMCuS) nanoparticles. This type of nanoparticles is expected to achieve the synergistic treatment of tumor by targeted phototherapy and chemotherapy. The carrier was synthesized by a substitution method, and the anti-cancer drug doxorubicin(DOX) was loaded and then modified by hyaluronic acid(HA) to prepare the anticancer drug system DOX/HMCuS-HA. The results suggested that DOX/HMCuS-HA presented uniform spherical structure, with the drug loading efficiency of 33.6%, the particle size and zeta potential being 113.8±6.9 nm and 18.4±2.8 mV, respectively. When 100 μg · mL^-1 HMCuS was irradiated under 808 nm laser(2 W·cm^-2) for 8 min, the temperature can heat up 51 ℃, demonstrating high photothermal conversion efficacy. Electron spin resonance(ESR) tests and methylene blue degradation experiments showed that HMCuS nanoparticles could simultaneously produce hydroxyl radical(·OH) mediated photodynamic therapy. In addition, HA was responsible for minimizing premature drug release and increasing tumor targeting efficiency by acting as a smart gatekeeper with tumor specific targeting moiety. In vitro drug release experiments showed that the coated HA could be degraded by intracellular lysosomal enzyme hyaluronidase, which facilitated DOX release. The acidic microenvironment of tumor cell and external near infrared(NIR) stimulus could trigger further release of DOX from the nanoparticles. These results point to a new strategy for timely and effective anti-tumor treatment.