非感染性葡萄膜炎是视力损害的主要原因,皮质类固醇药物治疗是导致严重副作用的主要临床策略。雷帕霉素(RAPA),一种有效的免疫调节剂,是非感染性葡萄膜炎的有希望的治疗方法。然而,因为需要高剂量和频繁剂量,由于其严重的毒性,将其临床转化为非感染性葡萄膜炎治疗是一个巨大的挑战。在本研究中,我们设计了一种基于可生物降解嵌段聚合物的可注射微粒药物递送系统(即,聚己内酯-聚(乙二醇)-聚己内酯,PCEC)通过结膜下注射途径有效地眼部递送RAPA,并在实验性自身免疫性葡萄膜炎(EAU)大鼠模型中研究了其治疗功效。使用乳液蒸发法制备RAPA-PCEC微粒,并使用扫描电子显微镜彻底表征,傅里叶变换红外光谱,X射线衍射,和差示扫描量热法。形成的微粒在28天内表现出缓慢的体外降解,并在4周内提供了RAPA的体外和体内缓释。此外,一次结膜下注射PCEC微粒可产生较高的眼部耐受性.更重要的是,结膜下注射RAPA-PCEC微粒通过减少炎性细胞浸润,以剂量依赖性方式显着减弱了EAU的临床体征(即,CD45+细胞和Th17细胞)并抑制小胶质细胞活化。总的来说,这些可注射微粒系统可能是用于眼内递送RAPA治疗非感染性葡萄膜炎的有前景的载体.
Noninfective uveitis is a major cause of vision impairment, and corticosteroid medication is a mainstay clinical strategy that causes severe side effects. Rapamycin (RAPA), a potent immunomodulator, is a promising treatment for noninfective uveitis. However, because high and frequent dosages are required, it is a great challenge to implement its clinical translation for noninfective uveitis therapy owing to its serious toxicity. In the present study, we engineered an injectable microparticulate drug delivery system based on biodegradable block polymers (i.e., polycaprolactone-poly (ethylene glycol)-polycaprolactone, PCEC) for efficient ocular delivery of RAPA via a subconjunctival injection route and investigated its therapeutic efficacy in an experimental autoimmune uveitis (EAU) rat model. RAPA-PCEC microparticles were fabricated using the emulsion-evaporation method and thoroughly characterized using scanning electron microscopy, fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry. The formed microparticles exhibited slow in vitro degradation over 28 days, and provided both in vitro and in vivo sustained release of RAPA over 4 weeks. Additionally, a single subconjunctival injection of PCEC microparticles resulted in high ocular tolerance. More importantly, subconjunctival injection of RAPA-PCEC microparticles significantly attenuated the clinical signs of EAU in a dose-dependent manner by reducing inflammatory cell infiltration (i.e., CD45+ cells and Th17 cells) and inhibiting microglial activation. Overall, this injectable microparticulate system may be promising vehicle for intraocular delivery of RAPA for the treatment of noninfective uveitis.