构建新型高效低毒药物共载聚合物应用于胰腺癌化疗和靶向药物联合治疗的研究

At present, the most important drugs in the treatment of advanced pancreatic cancer are gemcitabine and epidermal growth factor receptor tyrosine kinase inhibitor erlotinib. The targets of the two types of drugs are different, but the clinical trials showed that with the simple combination therapy model no obviously increased effect could be acquired. Many research showed the pharmacological antagonism mechanism between the action of gemcitabine and erlotinib with the simple combination model. The project intends to explore the pharmacological antagonism phenomenon between erlotinib and gemcitabine in pancreatic cancer cells and construct a novel kind of drugs co-loading polymer based on β- cyclodextrin - polylactic acid - glycolic acid copolymer to link gemcitabine with loading erlotinib simultaneously. With series of physical and chemical characterization of copolymer to determine the structure and component, the project tries to verify whether the constructed copolymer could circumvent the mutual antagonism effect between erlotinib and gemcitabine in pancreatic cancer cells and improve the pharmacokinetic characteristics of gemcitabine, thereby enhancing the curative effect in combination therapy. The project abandons the simple drug combination model but employs organic polymer with low toxicity to modify the structure of gemcitabine and co-load erlotinib to make the treatment elements in organic integrity to achieve a novel treatment method. The constructed delivery system is expected to be beneficial platform for further research in the combination drugs treatment of pancreatic cancer and other types of cancer.

目前晚期胰腺癌治疗中最重要的两类药物是化疗药物吉西他滨及表皮生长因子受体酪氨酸激酶抑制剂类药物厄洛替尼，两药物作用靶点不一样，但存在简单联合治疗不增效的临床现象。目前认为主要原因在于两个药物的简单联用存在药理拮抗机制。本项目拟探索厄洛替尼和吉西他滨作用于胰腺癌细胞后的药理拮抗现象，提出构建β-环糊精-聚乳酸-羟基乙酸共聚物链接吉西他滨并负载厄洛替尼，形成新的药物共载聚合物，经过系列理化表征确定载体结构成分，验证该共载聚合物是否可规避厄洛替尼和吉西他滨作用于胰腺癌细胞后的相互拮抗作用，改善吉西他滨的药动学特点，从而提高两者联合使用的治疗疗效。本项目利用低毒性的有机聚合物对吉西他滨进行结构改造，同时荷载厄洛替尼，摒弃药物的简单联用方式，有机结合药物的抗肿瘤作用，有望得到高效低毒的胰腺癌治疗新方法，为进一步研究胰腺癌及其他瘤种联合用药及机制研究提供了良好的研究平台。

目前晚期胰腺癌治疗中最重要的两类药物是化疗药物吉西他滨及表皮生长因子受体酪氨酸激酶抑制剂类药物厄洛替尼，两药物作用靶点不一样，但存在简单联合治疗增效有限的临床现象。目前认为主要原因在于两个药物的简单联用存在药动学拮抗机制。本项目的出发点为提出构建β-环糊精-聚乳酸-羟基乙酸共聚物链接吉西他滨并负载厄洛替尼，形成新的药物共载聚合物，经过系列理化表征确定载体结构成分，验证该共载聚合物是否可规避厄洛替尼和吉西他滨作用于胰腺癌细胞后的相互拮抗作用，改善吉西他滨的药动学特点，从而提高两者联合使用的治疗疗效。在项目支持下，本研究首先成功合成了药物共载聚合物Erlotinib/β-CD-PLGA-Gemcitabine，并采用各种理化表征手段证明聚合物的成功合成，通过毒性实验证明厄洛替尼预处理可以抑制胰腺癌细胞MIAPaCa-2细胞膜药物转运体hENT1的表达，拮抗吉西他滨的药理学作用，随后的生物学实验证明采用药物共载聚合物形式后降低MIAPaCa-2细胞膜药物转运体hENT1的表达效应下降，且其对其体外内对胰腺癌细胞及荷瘤小鼠具有增强的抗瘤作用，提示药物共载聚合物形式递药可以规避厄洛替尼和吉西他滨的跨膜递送拮抗作用，从而提高抗肿瘤效应。该项目为胰腺癌的联合用药的治疗指数最大化提供了新的研究思路，取得了有意义的进展。该项目按照计划较好地完成了研究任务。本研究团队今后将继续报送与本项目相关的研究成果。