叶酸和可解离TPGS类似物修饰的pH敏感靶向脂质体同步传递阿霉素和伊马替尼协同治疗多药耐药肿瘤的研究

Currently, multi-drug resistance (MDR) to anticancer drugs is a major obstacle to successful treatment of cancer. Therefore, looking for a therapeutic strategy that can overcome MDR through multitarget treatment will be of great clinical importance. Among the numerous mechanisms, overexpression of drug efflux transporter proteins belonging to the ATP-binding cassette and disruption of apoptotic pathways were widely recognized as the two most important mechanisms underlying the MDR of cancer cells. Imatinib, a molecular target drug, can affect the two mechanisms to reverse the MDR and increase the sensitivity of cancer cells to chemotherapeautic drugs. Furthermore, in our previous study, we had found doxorubicin combined with imatinib could show a synergistic anti-tumor effect and folate receptor-targeted liposomes could enhance the anti-tumor activity of doxorubicin with reducing toxicity. Therefore, we will try to build a pH-sensitive targeted liposomes modified with folate and cleavable TPGS analogue to co-delivery imatinib and doxorubicin synchronously. We expect the designed drug delivery system can specifically target to tumor cells through the folate receptor-mediated actvie cell uptake, maintain the appropriate drug ratio from the site of administration until it reaches the tumor cells, and fully release the encapsulated drugs at the target cell with the help of pH sensitivity. All of these are aiming at providing an advantaged platform for the effective delivery of drug combination and ensuring the drugs can act on their specific target to pruduce a synergistic effect on overcoming MDR. We will further explore the relevant mechanisms of the multitarget treatment based on the co-delivery of imatinib and doxorubicin through the folate receptor-targeted pH sensitive liposomes.

肿瘤细胞产生的多药耐药（MDR）作用是导致化疗失败的主要原因，针对MDR的发生机制开发靶向药物、多靶点联合治疗是目前研究的重要方向。其中，ABC转运蛋白对抗肿瘤药物的外排以及肿瘤细胞的凋亡缺陷被认为是广泛存在且作用显著的两个机制。分子靶向药物伊马替尼能够针对这两个机制作用，逆转肿瘤细胞的MDR，提高肿瘤细胞对化疗的敏感性。我们在前期研究中也发现，伊马替尼能增加肿瘤细胞对阿霉素的敏感性，协同抑瘤；叶酸受体靶向脂质体能提高阿霉素的抗肿瘤效果，并降低毒性。据此，本课题试图构建一种由叶酸和可解离型TPGS类似物修饰的pH敏感靶向脂质体来同步传递阿霉素和伊马替尼，期望该载药系统能在叶酸受体介导的靶向作用下将药物按比例同步递送至肿瘤细胞，并通过pH敏感性能实现药物在靶细胞的定位充分释放，从而保证药物能作用于各自靶点，发挥伊马替尼逆转MDR的作用和阿霉素的细胞杀伤作用，多靶点联合治疗多药耐药肿瘤。

肿瘤细胞产生的多药耐药（MDR）作用是导致乳腺癌化疗失败的主要原因。本项目设计并制备了一种叶酸受体靶向pH敏感脂质体按比例同步传递阿霉素和伊马替尼两种药物（FPL-DOX/IM）用来对抗耐药肿瘤。本项目制备的脂质体粒径在150nm左右，表面覆盖有可解离的长循环材料，在血循环中能避免巨噬细胞吞噬并保持稳定。当脂质体通过被动靶向作用浓集在肿瘤组织周围后，在叶酸受体的介导下被主动摄入到肿瘤细胞内，并在细胞溶酶体的酸性环境中脱掉表面的长循环材料从而发生膜的融合迅速释放阿霉素和伊马替尼。伊马替尼通过阻断药物外排泵和增强肿瘤细胞对化疗药物的敏感性从而逆转肿瘤细胞的耐药性，阿霉素得以发挥细胞毒作用有效杀伤肿瘤。体内和体外研究结果显示本项目设计的FA-PSL-DOX/IM脂质体具有显著增强的对抗耐药肿瘤的作用，为多药耐药肿瘤的治疗提供极具潜力的治疗策略。