基质金属蛋白酶响应的纳米粒子共输送顺铂吉西他滨用于非小细胞肺癌的协同治疗

Matrix metalloproteinases responsive nanoparticle co transfer cisplatin and gemcitabine for synergistic treatment of non-small cell lung cancer

目的合成两亲性基质金属蛋白酶（matrixmetalproteinase，MMPs）响应的mPEG-CPLGLAGG（PDDC）聚合物，将聚合物与疏水的化疗药物顺铂,吉西他滨共组装形成纳米粒子，并初步评价该纳米药物输送系统对非小细胞肺癌的治疗效果。方法以碳化二亚胺/N-羟基琥珀酰亚胺为缩合剂，将MMPs响应的多肽（CPLGLAGG）通过酰胺化反应接支到mPEG上，并且采用核磁共振和红外光谱对其结构进行确证，通过体外细胞抗增殖实验初步评价其活性。结果通过酰胺化反应成功得到了两亲性聚合物（PDDC），聚合物与药物共组装形成粒径200nm左右的均一的纳米粒子，体外细胞实验结果表明负载药物的纳米粒子表现出了很好的协同作用。药代动力学结果表明纳米粒子的血液循环时间明显长于游离的化疗药物。结论PDDC两亲性聚合物共输送化疗药物对非小细胞肺癌表现出了良好的协同作用，表明该聚合物可以作为一个潜在的药物输送材料用于肿瘤的治疗。

Objective To designand synthesize a matrix metalproteinases(MMPs)responsiveamphiphilic polymer mPEG-CPLGLAGG(PDDC)which can be self-assembled with hydrophobic chemotherapeautic drugs(gemcitabine and cisplatin)to form nanoparticles,in order to makethe nanoparticles respond to the MMP-2and release the payloads at the tumor site.Methods Use EDC as condensing agent to form amphiphilic polymer PDDC via amide bond of which the chemical structure was characterizedby1H-NMR and FT-IR.Then in vitro anti-proliferation assay was conducted to evaluate the activity of drug-loaded nanoparticles.Results The amphiphilic polymer(PDDC)and uniform drug-loaded nanoparticles was obtained,performing obvious synergistic effect on A549cells.In vivo pharmacokinetic study showed that drug-loaded nanoparticles exhibit longer retention time in contrast to free drug.Conclusion Our amphiphilic polymer(PDDC)could load hydrophobic chemotherapeutics effectively,andthe uniform drug-loaded nanoparticles exhibit good synergistic effect on non-small cell lung cancer(NSCLC),indicating PDDC could be used a potential drug carrier in the future.