R Max Petty, Rajiv S Rangan, Stacy Curry, Calvin D Brooks, Nirupama Sabnis, Abbot F Clark, Andras G Lacko, Raghu R Krishnamoorthy
{"title":"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。","authors":"R Max Petty, Rajiv S Rangan, Stacy Curry, Calvin D Brooks, Nirupama Sabnis, Abbot F Clark, Andras G Lacko, Raghu R Krishnamoorthy","doi":"10.1089/jop.2024.0191","DOIUrl":null,"url":null,"abstract":"<p><p><b><i>Purpose:</i></b> 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. <b><i>Methods:</i></b> 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 <i>in vitro</i>, whereas scavenger receptor class B1 (SR-B1) expression was confirmed by Western blot. Receptor-mediated uptake was examined by SR-B1 receptor blocking. <i>Ex vivo</i> biodistribution was evaluated by intravitreal injection of rHDL into postmortem human donor eyes. <b><i>Results:</i></b> 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 <i>ex vivo</i> 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. <b><i>Conclusions:</i></b> 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.</p>","PeriodicalId":16689,"journal":{"name":"Journal of Ocular Pharmacology and Therapeutics","volume":" ","pages":"281-289"},"PeriodicalIF":1.9000,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Biodistribution of Reconstituted High-Density Lipoprotein Nanoparticles for Targeted Delivery to Retinal Ganglion Cells.\",\"authors\":\"R Max Petty, Rajiv S Rangan, Stacy Curry, Calvin D Brooks, Nirupama Sabnis, Abbot F Clark, Andras G Lacko, Raghu R Krishnamoorthy\",\"doi\":\"10.1089/jop.2024.0191\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b><i>Purpose:</i></b> 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. <b><i>Methods:</i></b> 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 <i>in vitro</i>, whereas scavenger receptor class B1 (SR-B1) expression was confirmed by Western blot. Receptor-mediated uptake was examined by SR-B1 receptor blocking. <i>Ex vivo</i> biodistribution was evaluated by intravitreal injection of rHDL into postmortem human donor eyes. <b><i>Results:</i></b> 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 <i>ex vivo</i> 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. <b><i>Conclusions:</i></b> 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.</p>\",\"PeriodicalId\":16689,\"journal\":{\"name\":\"Journal of Ocular Pharmacology and Therapeutics\",\"volume\":\" \",\"pages\":\"281-289\"},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2025-06-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Ocular Pharmacology and Therapeutics\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1089/jop.2024.0191\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/4/18 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"OPHTHALMOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Ocular Pharmacology and Therapeutics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1089/jop.2024.0191","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/4/18 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"OPHTHALMOLOGY","Score":null,"Total":0}
Biodistribution of Reconstituted High-Density Lipoprotein Nanoparticles for Targeted Delivery to Retinal Ganglion Cells.
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.
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.