Biodistribution of Reconstituted High-Density Lipoprotein Nanoparticles for Targeted Delivery to Retinal Ganglion Cells.

IF 1.9 4区 医学 Q2 OPHTHALMOLOGY
R Max Petty, Rajiv S Rangan, Stacy Curry, Calvin D Brooks, Nirupama Sabnis, Abbot F Clark, Andras G Lacko, Raghu R Krishnamoorthy
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引用次数: 0

Abstract

Purpose: Nanoparticle-based drug delivery systems offer a promising approach for overcoming the challenges of ocular drug delivery. Our study evaluated the biodistribution and potential targeting of reconstituted high-density lipoprotein nanoparticles (rHDL NPs) loaded with near-infrared dye IR780 to retinal ganglion cells (RGCs) and optic nerve head astrocytes (ONHAs) as a model for neuroprotective drug delivery in glaucoma. Methods: A stable rHDL-payload complex was formulated using IR780, phosphatidylcholine, and apolipoprotein A-I (Apo A-I) by using a novel preparation method. Fluorescent rHDL (rHDL-IR780) was assessed for cellular uptake in primary human ONHAs in vitro, whereas scavenger receptor class B1 (SR-B1) expression was confirmed by Western blot. Receptor-mediated uptake was examined by SR-B1 receptor blocking. Ex vivo biodistribution was evaluated by intravitreal injection of rHDL into postmortem human donor eyes. Results: Spectroscopic analysis confirmed IR780 encapsulation in rHDL NPs. Blocking SR-B1 receptors significantly reduced IR780 uptake by ONHAs, supporting an SR-B1-mediated delivery mechanism, in addition to confirming SR-B1 expression in human retinal lysates. In ex vivo experiments, 4 h postinjection, IR780 localized in the retinal nerve fiber and ganglion cell layers. By 24 h, IR780 penetrated deeper retinal layers, achieving RGC uptake. Conclusions: Our findings demonstrate that rHDL NPs facilitate targeted delivery to retinal tissues through an Apo A-I/SR-B1 pathway, overcoming ocular barriers to reach RGCs. This study supports the potential of rHDL NPs as a platform for neuroprotective drug delivery to treat glaucoma, enhancing both pharmacokinetics and targeted cellular uptake.

用于视网膜神经节细胞靶向递送的高密度脂蛋白纳米颗粒的生物分布。
目的:纳米颗粒给药系统为克服眼部给药的挑战提供了一种很有前途的方法。我们的研究评估了负载近红外染料IR780的重构高密度脂蛋白纳米颗粒(rHDL NPs)在视网膜神经节细胞(RGCs)和视神经头星形胶质细胞(ONHAs)中的生物分布和潜在靶向性,作为青光眼神经保护药物递送的模型。方法:以IR780、磷脂酰胆碱和载脂蛋白A- i (Apo A- i)为原料,采用新的制备方法制备稳定的rHDL-payload复合物。荧光rHDL (rHDL- ir780)在体外原代人ONHAs中的细胞摄取情况进行了评估,而清除受体B1类(SR-B1)的表达则通过Western blot证实。受体介导的摄取通过SR-B1受体阻断检测。通过在人死后供体眼玻璃体内注射rHDL来评估体外生物分布。结果:光谱分析证实IR780包封在rHDL NPs中。阻断SR-B1受体可显著降低ONHAs对IR780的摄取,支持SR-B1介导的递送机制,并证实SR-B1在人视网膜裂解物中的表达。在离体实验中,注射后4 h, IR780定位于视网膜神经纤维和神经节细胞层。24小时后,IR780穿透更深的视网膜层,实现RGC摄取。结论:我们的研究结果表明,rHDL NPs通过载脂蛋白A-I/SR-B1途径促进靶向递送到视网膜组织,克服眼屏障到达RGCs。这项研究支持rHDL NPs作为治疗青光眼的神经保护药物递送平台的潜力,增强了药代动力学和靶向细胞摄取。
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来源期刊
CiteScore
4.60
自引率
4.30%
发文量
72
审稿时长
1 months
期刊介绍: Journal of Ocular Pharmacology and Therapeutics is the only peer-reviewed journal that combines the fields of ophthalmology and pharmacology to enable optimal treatment and prevention of ocular diseases and disorders. The Journal delivers the latest discoveries in the pharmacokinetics and pharmacodynamics of therapeutics for the treatment of ophthalmic disorders. Journal of Ocular Pharmacology and Therapeutics coverage includes: Glaucoma Cataracts Retinal degeneration Ocular infection, trauma, and toxicology Ocular drug delivery and biotransformation Ocular pharmacotherapy/clinical trials Ocular inflammatory and immune disorders Gene and cell-based therapies Ocular metabolic disorders Ocular ischemia and blood flow Proliferative disorders of the eye Eyes on Drug Discovery - written by Gary D. Novack, PhD, featuring the latest updates on drug and device pipeline developments as well as policy/regulatory changes by the FDA.
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