仿生血小板纳米靶向递药体系增效吡非尼酮的抗食管再狭窄研究

Esophageal benign stenosis is a common but refractory disease in clinics. Traditional, esophageal dilation could temporarily alleviate the obstruction symptoms, but it’s easy to reappear. Patients suffer a lot for the repeated dilation. In our previous study, anti-proliferative mitomycin was able to delay the occurrence of restenosis by local drug administration. There might be the high risk of esophageal perforation due to non-specific cell inhibition. There is no effective treatment strategy for esophageal anti-stenosis. This study draws on the innovation and explores the molecular targeted therapy of pirfenidone for esophageal benign stenosis, and achieves selective fibroblast proliferation inhibition, anti-fibrosis and inflammatory control. It has been proved to efficiently reverse the hyperfunction of organism injury repair mechanism for pulmonary, hepatic and renal fibrosis. It will be inspiring to explore its specific prevention of esophageal restenosis. Based on previous study of nano-drug delivery, novel nano-delivery system was designed for improving pirfenidone administration in vivo. Platelet membrane cloaked technology will be applied to modify nanoparticles’ surface. CD 47 on platelet membrane could indicate “don’t eat me” signal and reduce macrophage clearance for this novel system. It will be useful to improve pharmacokinetic properties, which is important for reducing the clinical dose of pirfenidone and extend its metabolism half-life. Meanwhile, esophageal dilation could create tissue injury and musical bleeding, which could promote coagulation cascade effect. During coagulation, bionic platelet nano-system will be recruited by the signal and actively target esophageal stenosis lesions, to achieve drug targeted accumulation, which could greatly improve treatment benefits and avoid off-target side effects. This active nano-delivery system might significantly prevent esophageal restenosis and provide more new ideas for further development.

食管良性狭窄为临床常见疑难病，常规扩张虽能暂时缓解症状，复发率高、患者痛苦大。前期研究中抗增殖丝裂霉素局部注射，可以延缓再狭窄发生，但存在穿孔风险。临床尚无有效的抗狭窄治疗策略。本课题借鉴创新，探索上市药物吡非尼酮对食管良性狭窄的分子靶向治疗，实现选择性的成纤维细胞增殖抑制、抗纤维化沉积、炎性控制等，逆转机体损伤修复的功能亢进，实现食管再狭窄的特异性防治。基于已有纳米递药研究，依托仿生血小板修饰技术，构建新型纳米封装的吡非尼酮输送体系，减少纳米粒的巨噬细胞清除，改善药代动力学特性，克服临床吡非尼酮给药剂量大、半衰期短等缺陷；同时联合狭窄扩张出血损伤，激发凝血级联效应，仿生血小板纳米体系主动靶向食管狭窄关键病灶，实现药物选择性传输和蓄积，实现精确靶向药物治疗、提高药物治疗效益、避免非必要副作用，从而为食管抗狭窄临床诊疗研究和长期疗效改善提供新思路。

在基金支持下，按照三年期研究计划系统开展研究，围绕食管狭窄的造模、靶向给药、创新治疗等相关领域开展了一系列研究探索，取得了部分研究成果。围绕食管狭窄模型，我们创新探索了烧碱腐蚀、电灼伤、粘膜切除等，针对国内外研究争议和技术差别开展针对改进研究，初步建立大鼠的食管狭窄模型。围绕吡非尼酮的抗纤维化研究，我们推动了相关药物在体疗效研究，初步验证其抗炎抗纤维化的药理作用，但因其存在显著的免疫抑制，诱发较严重机体感染等毒副作用，延误试验了预期开展；我们针对调整研究策略，正积极探索食管狭窄新型靶点药物，围绕CD26靶向抗纤维化研究取得初步研究成果。.结合课题执行困难，我们结合临床特点，创新提出开拓尝试了自体食管粘膜移植治疗食管狭窄的创新研究，利用生物自体修复理念成功实现6例患者的内镜扩张+自体粘膜移植治疗，患者食管狭窄明显减轻，食管组织结构和功能得以重塑修复，为我们课题靶向修复理念开拓了新的研究领域。同时针对新粘膜移植的技术创新，课题组针对临床技术难点，提出了温敏气化辅助粘膜切除创新策略，系统化研究了微量全氟戊烷（1%生理盐水剂量）作为新兴粘膜下注射剂的可行性和有效性，其促粘膜切除和创伤愈合优势也将推进后续临床诊疗技术革新。.在基金支持下，申请人获得2019年江苏省卫健委新技术引进二等奖1项、2020年江苏省医学科技奖三等奖1项，主导和协助团队发表SCI论著等7篇，国际会议交流2次。