基于Cu2S的多功能纳米复合材料的控制合成及其在癌症治疗中的应用

The toxic side effects and multidrug resistance (MDR) of cancer cells are the two main factors leading to the ineffectiveness of cancer chemotherapy. In order to overcome these difficulties, in this proposal, the multifunctional nanomedicine of PEI-coated Cu2S (Cu2S@PEI) will be designed, on which RGD molecules are linked for targeted tumor delivery. Simultaneously, doxorubicin (DOX)-intercalated double strands DNA and small interfering RNA (siRNA) for knocking-down the expression of the apoptosis-suppressing gene Bcl-2 are loaded on Cu2S@PEI. The DOX release can be triggered by NIR irradiation at the tumor site by the remote-controlled mode due to the photothermal effect of Cu2S nanoparticles, which can decrease the toxic side effects. Moreover, the gene interfering and photothermal ablation can be used to inhibit MDR or kill cancer cell directly. It is expected that the facile synthesis and low cost multifunctional nanomedicine can improve the anticancer effect in contrast to the single chemotherapy mode.

化疗所产生的毒副作用及多药耐药性是导致临床治疗癌症效率低的重要原因之一。本项目针对这一难题，拟设计和合成聚乙烯亚胺(PEI)包裹的Cu2S纳米粒子(Cu2S@PEI)，将肿瘤靶向分子RGD化学键合在纳米粒子的表面，利用癌细胞表面高表达的RGD受体实现靶向输送；同时携带阿霉素(DOX)插入的DNA复合物和靶向凋亡抑制基因Bcl-2的小干扰RNA(siRNA), 通过Cu2S的近红外光热效应在局部控制释放DOX, 从而降低系统毒副作用，而基因干扰和光热治疗可用于克服多药耐药性或直接杀死肿瘤细胞。这一制备方法简单、成本低廉、设计新颖的多功能联合治疗纳米药物能够大大改善单一化疗模式抑制肿瘤的效果。

基本按照计划执行并进行了一定的宽展。通过高温热分解和牺牲模板等方法成功制备了Cu9S5、CuS@Cu2S@Au等金属硫化物及复合半导体纳米颗粒，具有均一尺寸的形貌。在半导体纳米粒子表面成功修饰了PEI等功能性高分子和靶向分子及抗癌药物，体内和体外生物实验表明，纳米药物的光热和化疗联合治疗具有更加高效的抑癌效果，同时和小分子抗癌药物相比副作用更小。药物能够通过近红外光辐射引发快速在释放。另外，实验过程中我们也发现，Cu2S纳米粒子负载小干扰RNA的抑制癌细胞生长的效果较难实现，这可能是由于在纳米粒子表面修饰的PEI量不足，负载siRNA在量较小，基因转染效率低导致的。