梯度降解载药输尿管支架的构建及其预防上尿路上皮癌术后复发的研究

The tumor recurrence rate of upper tract urothelial carcinoma after conservative surgery is 20 to 30%, and there is no effective procedure for the drug instillation to prevent tumor relapse. In addition, a routine ureteral stent should be given to prevent scar formation and maintain the drainage of urine, which need a separate cystoscopic surgery for removal increasing the suffering of patients. In our previous study, the poly(ε-caprolactone)/poly(lactide-co-glycolide) (PCL/PLGA) stent with gradient degradation was fabricated using the technique of double nozzle electrospinning. The experiments revealed that the stent degraded from the distal to proximal end with no ureteral obstruction, and it was more biocompatible than the biostable stent. In this project, we will load the epirubicin into the uniform and “core-shell” nanofibers by electrospinning and emulsion electrospinning, respectively. The degradation mood, drug metabolism, drainage effect and tissue compatibility will be evaluated by inserting the stents to a porcine model. Moreover, the cell experiments and bladder cancer model in nude mice were used to confirm the anti-tumor effects of the drug-loaded stent. The successful implementation of the project will broaden the ideas and approaches for the exploitation of multifunctional degradable ureteral stents, and lay the experimental and theoretical bases for the acquisition of ideal functional ureteral stent with independent intellectual property rights.

上尿路上皮癌保留肾脏手术后有20 – 30%的复发率，目前缺乏有效的局部药物灌注方法预防肿瘤复发。此外，该术式术后需留置输尿管支架管起支撑及引流作用。该支架管需二次膀胱镜取出，增加了患者痛苦。在前期工作中，已采用双喷头电纺丝法制备出可梯度降解的聚（ε-己内酯）/聚乙丙交酯（PCL/PLGA）输尿管支架管，并证实了该支架的梯度降解模式及良好的组织相容性。在此基础上，本项目拟通过电纺丝和乳液电纺丝方法将表柔比星分别负载于均一和“芯-壳”结构的纳米纤维中，制备出两类具有支撑引流及预防上尿路上皮癌术后复发双重功能的支架管。拟将输尿管原位植入猪模型评价该支架管的降解模式、药物代谢、支撑引流及组织相容性，并通过体外细胞实验及裸鼠动物肿瘤模型评价该支架管的肿瘤抑制作用。本项目的成功实施将拓宽研发多功能可降解输尿管支架管的思路和方法，并为获得具有自主知识产权的理想的功能性输尿管支架管奠定实验和理论基础。

尿路上皮癌已成为人类第四大肿瘤，其中膀胱尿路上皮癌约占90%，上尿路（肾盂、输尿管）上皮癌约占10%。上尿路上皮癌保留肾脏手术后有20–30%的复发率，目前缺乏有效的局部药物灌注方法预防肿瘤复发。该术式术后需留置输尿管支架管起支撑及引流作用。该支架管需二次膀胱镜取出，增加了患者痛苦。此外，长期留置支架易引起感染及支架表面结石形成等问题。随着可降解材料在生物载药领域内的广泛应用，可降解载药输尿管支架的研制越来越受关注。本项目将表柔比星（EPI）分别通过直接电纺丝及乳液电纺丝法分别载入均一和“芯-壳”结构纳米纤维中，制备出两类具有支撑引流及预防肿瘤复发双重作用的输尿管支架管。选择15%及25%两种比例聚己内酯（PCL）/聚乳酸-羟基乙酸共聚物（PLGA）为基质材料，采用双喷头电纺丝工艺制备梯度输尿管支架管，利用高分子材料降解时间的差异，支架在完成支撑及引流任务后，由远端向近端降解，持续释放出表柔比星预防肿瘤局部复发。实验结果表明载药纤维支架具有良好的微观结构、力学性能、降解性能及高效药物释放模式。MTT体外肿瘤抑制实验证实该支架可诱导细胞凋亡，裸鼠膀胱癌模型实验证实该高分子载药支架管具有较好的抗肿瘤效果，并且安全性较高。通过以上研究，我们筛选出乳液电纺丝法制备的PCL25/PLGA+EPI10支架在降解时间、药物释放及体内外抗肿瘤方面明显优于其他支架，可满足上尿路肿瘤术后支撑引流及防止肿瘤复发的需求。本项目中可梯度降解载药抗肿瘤输尿管支架的设计与制备为功能性输尿管支架管的开发提供了新的思路，并将为获得具有自主知识产权的新一代高分子纳米药物奠定良好的研究基础。