基于表面功能化碳纳米角的靶向纳米药物的构建和化疗-光热联合肿瘤治疗研究

Targeted delivery of therapeutic drugs to a cancer is key to successful cancer chemotherapy. To this purpose, we herein propose a cancer-targeted nanomedicine, CNHox-HPG-RGD-DOX, which is constructed by grafting hyperbranched polyglycerol (HPG) and RGD peptide on the surface of carbon nanohorns (CNHox), and then loading anticancer drug doxorubicin (DOX) through π–π interaction. The "stealth effect" of HPG can inhibit the uptake of the resulting nanomedicine by reticuloendothelial system, and meanwhile RGD peptide facilitates its accumulation in the cancer through specific binding with αVβ3 integrin overexpressed by the cancer cells. Moreover, the photothermal effect of CNHox enables enhanced drug release through photo-irradiation and causes damage to the cancer cells, generating synergistic effect of chemo-photothermal therapy. This research is to reveal the relationship between the composition of CNHox-HPG-RGD-DOX and its targeting effect, pharmacokinetics and anticancer effect through in vitro and in vivo experiments, providing experimental evidences for design of safe and highly efficient anticancer nanomedicine.

将药物靶向输送到肿瘤组织是肿瘤化疗成功的关键。本项目提出在碳纳米角（CNHox）表面共价接枝超支化聚缩水甘油（HPG）和RGD靶向肽并通过π–π作用负载抗肿瘤药物阿霉素（DOX）构建一种肿瘤靶向纳米药物（CNHox-HPG-RGD-DOX）。通过HPG的“隐身效应”抑制网状内皮系统对纳米药物的摄取，同时通过RGD肽与肿瘤细胞过表达的整合素αVβ3特异性结合使其在肿瘤部位聚集。基于CNHox的光热性质，光照产生的热量不仅可以促进药物的释放，还能够破坏肿瘤细胞，产生化疗－光热协同治疗效应。本研究将通过体内体外实验揭示CNHox-HPG-RGD-DOX的组成结构与靶向性、药代动力学以及抗肿瘤效应的内在关系，为设计安全高效的抗肿瘤纳米药物提供实验依据。

化疗是一种临床上常用的肿瘤治疗方式，但大多数化疗药物对肿瘤的选择性不强，导致治疗效果不佳以及副作用。利用多功能纳米载体将化疗药物选择性输运到肿瘤细胞内部，同时利用外界刺激控制装载药物的释放是解决上述问题的可能途径。碳纳米角是一种具有空腔结构的球状纳米颗粒，其比表面积非常大，而且在红外区域有强烈的吸收，能够将光能转化为热量。因此，碳纳米角是一种潜在的多功能纳米载体材料。在本研究中，我们设计并制备了两种基于碳纳米角的纳米药物载体CHN-PG和CHN-PG-RGD，通过表面接枝聚缩水甘油赋予纳米载体良好的分散性，然后通过进一步表面化学修饰赋予其肿瘤细胞靶向功能。碳纳米角纳米载体可以高效装载抗癌药物DOX，并在近红外光的照射下加速释放。体外细胞实验表明CHN-PG和CHN-PG-RGD没有明显的细胞毒性；CHN-PG-RGD能够被B16F10肿瘤细胞选择性內吞。同时，纳米药物DOX@CHN-PG-RGD在近红外光照下能够更高效杀死B16F10肿瘤细胞。体内实验显示DOX@CHN-PG-RGD结合光热和化疗产生协同效应，不仅能有效缩小肿瘤体积，还能抑制肿瘤复发。本研究开发了一种新型碳纳米角表面修饰方法，探索了碳纳米角作为抗肿瘤药物载体的应用，为深入研究碳纳米角在其他生物医学领域的应用打下了良好基础。