MOE Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry and Chemical Engineering, Sun Yat-sen University, Guangzhou 510275, China.
Nanoscale. 2017 Apr 20;9(16):5329-5341. doi: 10.1039/c7nr00377c.
Drug to carrier ratio is an important consideration in designing drug platforms, since a low loading capacity necessitates the use of high doses of carriers, which can result in side effects. Here, we have engineered a platform to co-deliver small molecule drugs and small interfering RNA (siRNA). This platform consists of cyclodextrin-grafted polyethylenimine (CP) functionalized mesoporous silica nanoparticles (MSNP). A unique multi-step encapsulation procedure was used to obtain a high loading capacity for doxorubicin (DOX) and siRNA oligos specific for the PKM2 gene that encodes pyruvate kinase M2, an enzyme catalyzing the final rate-limiting step in glycolysis. We systematically characterized this platform (CP-MSNP@DOX/PKM2) in vitro and evaluated its therapeutic efficacy in vivo with a mouse model of triple negative breast cancer (TNBC). Exposure of TNBC cells to CP-MSNP@DOX/PKM2 resulted in suppressed target gene expression, reduced cell proliferation, and enhanced apoptosis. Intravenous administration of the drug substantially decreased the tumor burden in comparison to DOX or siRNA monotherapy. In conclusion, we have developed a platform for efficient co-delivery of small molecule drugs and therapeutic siRNA.
药物载体比是设计药物平台时的一个重要考虑因素，因为载药量低需要使用高剂量的载体，这可能导致副作用。在这里，我们设计了一种用于共递小分子药物和小干扰 RNA（siRNA）的平台。该平台由环糊精接枝的聚乙烯亚胺（CP）功能化介孔硅纳米粒子（MSNP）组成。采用独特的多步包封程序，获得了阿霉素（DOX）和针对编码丙酮酸激酶 M2（PKM2）的 siRNA 寡核苷酸的高载药量，PKM2 是催化糖酵解中最后限速步骤的酶。我们系统地表征了该平台（CP-MSNP@DOX/PKM2）体外，并在三阴性乳腺癌（TNBC）小鼠模型中评估了其体内治疗效果。TNBC 细胞暴露于 CP-MSNP@DOX/PKM2 会导致靶基因表达受到抑制、细胞增殖减少和细胞凋亡增强。与 DOX 或 siRNA 单药治疗相比，静脉给药大大降低了肿瘤负担。总之，我们开发了一种用于高效共递小分子药物和治疗性 siRNA 的平台。
