抗肿瘤药物多功能纳米自组装载体逆转肿瘤多药耐药性及其机制研究

In this study, novel multifunctional nanoassemble carriers (MNACs) were designed using cationic antitumor agents as model drugs to enhance the antitumor activity via overcoming the multidrug resistance (MDR). The Bcl-2 inhibitor (sodium glycocholate, GcNa) was selected as an anionic molecule to enhance the encapsulation efficiency and sustain the drug release of cationic drug by electrostatic interaction. Serious of investigations would be conducted to evaluate in-vitro and in-vivo characteristics of the prepared MNACs including pharmaceutical properties, pharmacokinetics, tissue distribution, and antitumor activity. To investigate the MDR reversal effect and clarify the possible mechanism of MNACs, the studies on cytotoxicity, cellular uptake and uptake mechanism would be conducted in MCF-7, MCF-7/Adr and MCF-7/MX cells, respectively. The MNACs are anticipated to be uptaken into the resistant cancer cells by endocytosis pathway which can escape the efflux induced by transporters and thereby overcome the MDR, while the simultaneous encapsulation of the anticancer drug and Bcl-2 inhibitor into MNACs would obtain synergetic antitumor activity and reversion of MDR.

针对肿瘤化疗中普遍存在的多药耐药现象，本课题拟设计一种阳离子型抗肿瘤药物多功能纳米自组装载体(MNACs)，将抗肿瘤药物和Bcl-2蛋白抑制剂甘氨胆酸钠共同载入自组装纳米载体中用于注射给药，利用纳米载体在抗肿瘤药物传递中的优势，结合甘氨胆酸钠能够促进肿瘤细胞凋亡的特点，产生协同抗肿瘤作用，使抗肿瘤药物充分发挥疗效，克服并逆转肿瘤多药耐药性。制备过程拟采用自组装和纳米沉淀结合的方法，将甘氨胆酸钠（作为反离子化合物）与阳离子型抗肿瘤药物形成的静电复合物载入PLGA中，制备具有较高包封率和载药量的自组装纳米载体。对所制备的MNACs的制剂学特征、体内药物动力学、生物分配行为、细胞毒性以及药效学进行考察。通过比较IC50值、耐药指数RI和逆转耐药因子RF，综合评价多功能纳米自组装载体克服肿瘤多药耐药性的作用；通过细胞摄取及摄取机制的研究，进一步阐明其克服肿瘤多药耐药性的作用机制。

为了逆转肿瘤化疗中普遍存在的多药耐药性，本课题选择阳离子型抗肿瘤药物硫酸长春新碱（VCR）和盐酸米托蒽醌（MTO）为模型药，与阴离子化合物甘氨胆酸钠(GcNa)形成疏水性静电复合物，制备新型多功能纳米载体。对所制备的纳米载体的制剂学特征、体内药物动力学、生物分配行为、细胞毒性以及药效学进行考察。通过比较IC50值、耐药指数RI和逆转耐药因子RF，综合评价多功能纳米自组装载体克服肿瘤多药耐药性的作用；通过细胞摄取及摄取机制的研究，进一步阐明其克服肿瘤多药耐药性的作用机制。该纳米载体提高了阳离子药物的载药量和包封率，发挥纳米载体本身具有的抑制转运蛋白外排的特性，提高药物在肿瘤细胞的摄取；而且共载入的Bcl-2蛋白抑制剂GcNa具有促进肿瘤细胞凋亡的功能。以上多种功能起到协同抗肿瘤作用，可以逆转肿瘤细胞的多药耐药性。