载药微球用于前列腺动脉栓塞术治疗良性前列腺增生的基础研究

Background：Benign prostate hyperplasia (BPH) has high prevalence in men older than 60 years and produces symptoms in more than 40% of men in this age group. Multiple medical and surgical treatments are in use, but each has limitations. Prostatic arterial embolization (PAE) gained special attention in the past years as a potential minimally invasive technique for BPH. However, PAE with the commercial particles is currently limited with only 30% reduction in prostate volume, and up to 20% of patients fail to show clinical improvement. The embolic agents may be a key factor role in the clinical success. Objectives: To develop a new microsphere which is loaded with 5α-reductase inhibitors, and to evaluate pathophysiologic responses to PAE with the new drug eluting microsphere in a canine BPH model. Study Design:-Among the medical treatments, 5α-reductase inhibitor has demonstrated both efficacy and safety reducing the size of the prostate and BPH symptoms. Microspheres loaded with anti-cancer drug have been recently investigated in vitro and in vivo, provided a sustained release of the anticancer drug into the regional tumor area, and shown to provide a combined ischemia and cytotoxic effect locally with lower systemic toxic exposure. Thus, the same mechanism could be used for PAE with 5α-reductase inhibitor-eluting microsphere. -Development of 5-α-reductase inhibitor-eluting microsphere. The new microsphere is consisted of biological protein glue and a high molecular polymer. Unlike the commercially drug-eluting microspheres, which was loaded with special chemical or ionic bonds, the new microsphere is loaded the drug with adhesion and embdding. -Established BPH model. The dogs are surgically castrated and given hormonal therapy for 12 weeks to induce prostatic hyperplasia. MRI is performed to evaluate the prostatic volume before and after the hormonal therapy. -PAE of the canine BPH model. We test if the better result could be achived using the 5-α-reductase inhibitor-eluting microsphere for PAE. The dogs were randomly assigned to group A (n=7)PAE with 5-α-reductase inhibitor-eluting microsphere, group B (n=5) with bland microsphere (without the drug), and group C (n=4)without any treatment.To detect the drug-release characteristic, the peripheral blood sample are obtained from group A at 1,2,4,8 weeks, respectively, after PAE with 5-α-reductase inhibitor-eluting microsphere. To evaluate pathophysiologic reaction, the levels of testosterone/dihydro testosterone in the peripheral blood are tested from all 3 group at 1,2,4,8 weeks, respectively, after PAE.MRI is performed to evaluate pathologic responses before and after PAE. Eight weeks after the study is begun, all dogs are sacrificed for pathologic study. Predicting results: (i)Developing a new drug-eluting embolic microsphere, which could carry 5α-reductase inhibitor. (ii)Testing the safety and efficacy of the new type of drug-eluting embolic microsphere in canine BPH model.

良性前列腺增生(BPH)是中老年男性的常见病，目前各种治疗方法尚存在一定限度。超选择性前列腺动脉栓塞术(PAE)是一治疗BPH的新兴技术，具有安全性高、疗效良好、并发症很低、术后生活质量高等优点，有很好的应用前景。但目前尚存在术后前列腺的缩小程度有限(约30%)、临床有效率有待提高等问题，而改进栓塞材料是可能提高疗效的关键因素。[本课题拟]：研发新型的载药微球-生物蛋白胶-高分子聚合物微球、其具有携载并缓慢释放抑制前列腺增生的药物+长期机械性栓塞血管的双重特点、不依赖于特定化学键结合药物；通过建立犬BPH模型后用载药微球做PAE、与不携载药物微球对照，论证载药微球的安全性和有效性；通过实验解决微球携载药物的稳定性、缓释时相、精确导入靶部位及局部药理效应等问题，为提高PAE治疗BPH疗效提供一新的技术选择。[目标]：研发具有自主知识产权的载药微球；建立提高PAE疗效的新技术。

良性前列腺增生（BPH）是中老年男性的常见病，目前各种治疗方法尚存在一定限度。超选择性前列腺动脉栓塞术（PAE）是一治疗 BPH 的新兴技术，具有安全性高、疗效良好等优点，有很好的应用前景。但目前尚存在PAE后前列腺的坏死率不高、体积缩小程度有限等问题，而改进栓塞材料是可能提高疗效的关键因素。.实验研究结果及主要结论：.①研发了两种空白微球：即聚乳酸-羟基乙酸共聚物（Poly L-lactic-co-glycolic acid，PLGA）微球和以PVA-1788、丙烯酸、氯化钡为主要原料的不可降解的X线下可显影载药微球（PVA-AA-BaCl2微球），目的是为了携载药物；实验证实这两种空白微球栓塞内脏血管可靠、无明确毒副作用。.②研制了两种载药缓释性微球：即非那雄安缓释微球（PLGA）、博来霉缓释性微球（PVA-AA-BaCl2），均为“离子交换式”携载过程，体外检测证实这两种微球载药效能可靠、缓释作用明确、理化性质稳定。.③在建立实验动物犬的BPH模型后，用两种载药微球做PAE（与空白微球做对照），技术成功率100%，无并发症和药物相关的毒副反应。非那雄安缓释性微球的安全性与空白微球无异，栓塞效应与空白微球无统计学差异，分析探讨了导致阴性结果的相关原因，为后续拓展研究提供了借鉴；证实携载博来霉素的缓释性微球可破坏血管内皮结构、促进微小血管闭塞、避免侧枝建立且无毒副反应，栓塞效率显著高于空白微球组、也显著高于非那雄安缓释性微球组。.④建立犬BPH模型的方法有显著改进：通过调整性激素的剂量和用药间隔时间，使造模时间由经典方法的10-12周，缩短至4周，显著降低了耗费。作为基础研究工作的部分内容，对实验动物犬BPH模型的血供来源、走行、分部及与邻近器官的交通支等做了比较细致的观察，有独特独到发现；所用的方法有常规DSA、旋转DSA及最新型的血管成像技术—CB-CT。.⑤作为延伸拓展性研究，系统分析总结了国人前列腺动脉影像解剖特点、澄清了人类是否存在独立前列腺动脉的争议；通过改进技术，显著提高了PAE治疗BPH的疗效；证实PAE术前行盆腔增强MRA对指导PAE具有重要参考价值。