Abstract：
Pathological ocular neovascularization resulting from retinal ischemia constitutes a major cause of vision loss. Current anti-VEGF therapies rely on burdensome intravitreal injections of Bevacizumab (Beva). Herein ultrasmall polymeric micelles encapsulating Beva (P@Beva) are developed for noninvasive topical delivery to posterior eye tissues. Beva is efficiently loaded into 11 nm micelles fabricated via self-assembly of hyperbranched amphiphilic copolymers. The neutral, brush-like micelles demonstrate excellent drug encapsulation and colloidal stability. In vitro, P@Beva enhances intracellular delivery of Beva in ocular cells versus free drug. Ex vivo corneal and conjunctival-sclera-choroidal tissues transport after eye drops are improved 23-fold and 7.9-fold, respectively. Anti-angiogenic bioactivity is retained with P@Beva eliciting greater inhibition of endothelial tube formation and choroid sprouting over Beva alone. Remarkably, in an oxygen-induced retinopathy (OIR) model, topical P@Beva matching efficacy of intravitreal Beva injection, is the clinical standard. Comprehensive biocompatibility verifies safety. Overall, this pioneering protein delivery platform holds promise to shift paradigms from invasive intravitreal injections toward simplified, noninvasive administration of biotherapeutics targeting posterior eye diseases.
摘要：
由视网膜缺血引起的病理性眼部新生血管形成构成视力丧失的主要原因。当前的抗VEGF疗法依赖于贝伐单抗(Beva)的繁重的玻璃体内注射。本文开发了包封Beva(P@Beva)的超小聚合物胶束,用于非侵入性局部递送至眼后部组织。Beva通过超支化两亲共聚物的自组装有效地加载到11nm胶束中。中立的,刷状胶束表现出优异的药物包封和胶体稳定性。体外，与游离药物相比,P@Beva增强眼细胞中Beva的细胞内递送。眼药水后的离体角膜和结膜-巩膜-脉络膜组织运输改善了23倍和7.9倍，分别。与单独的Beva相比，P@Beva保留了抗血管生成生物活性，从而引起对内皮管形成和脉络膜发芽的更大抑制。值得注意的是,在氧诱导的视网膜病变（OIR）模型中，玻璃体内注射Beva的局部P@Beva匹配疗效，临床标准。全面的生物相容性验证了安全性。总的来说,这个开创性的蛋白质递送平台有望将范例从侵入性玻璃体内注射转向简化，针对后眼疾病的生物治疗的非侵入性给药。本文受版权保护。保留所有权利。
