A Nanocarrier Platform for Targeting Schlemm's Canal Cells

用于靶向施累姆氏管细胞的纳米载体平台

• 批准号: 10705690
• 负责人: MARK JOHNSON
• 金额: $ 54.37万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705690
• 关键词: Actins; Address; Adverse effects; Affect; Animal Model; Animals; Antihypertensive Agents; Aqueous Humor; Attention; Blood Vessels; Bolus Infusion; Cells; Clinical; Clinical Trials; Cornea; Corneal Endothelium; Cytoskeleton; Diagnostic; Drug Carriers; Drug Delivery Systems; Drug vehicle; Endothelial Cells; Engineering; Evaluation; Exhibits; Eye; Formulation; Frequencies; Future; Gene Delivery; Glaucoma; Histology; Hour; Human; Hydrogels; Hyperemia; In Vitro; Injectable; Injections; Measures; Mechanics; Micelles; Microscopy; Modeling; Monkeys; Mus; Ocular Hypotension; Optical Coherence Tomography; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Phenotype; Physiologic Intraocular Pressure; Plasmids; Population; Primary Open Angle Glaucoma; Reducing Agents; Reporter; Resistance; Retina; Rho-associated kinase; Specificity; Structure of sinus venosus of sclera; System; Therapeutic; Therapeutic Agents; Therapeutic Effect; Tissues; Topical application; Toxic effect; Transfection; Vascular Endothelial Cell; Visible Radiation; Work; anterior chamber; cellular targeting; corneal epithelium; dosage; efficacy evaluation; eye chamber; gene delivery system; gene therapy; in vivo; kinase inhibitor; latrunculin A; mouse model; nanocarrier; nanoscale; non-viral gene delivery; nonhuman primate; novel; ocular hypotensive; pressure; rhoA GTP-Binding Protein; side effect; superresolution microscopy; targeted delivery; targeted treatment; therapeutic target; tonometry; ultrasound; uptake

PROJECT SUMMARY Nanoscale drug carriers (i.e. nanocarriers) have attracted much attention for their ability to transport diverse therapeutic and diagnostic agents and to selectively target specific cells and tissues. This increased specificity can have significant clinical implications, including decreased side effects and lower dosages with higher potency. Schlemm's canal (SC) endothelial cells hold promise as a cellular target for glaucoma therapy, as their mechanical stiffness is associated with modulation of intraocular pressure (IOP). Rho kinase inhibitors and actin- depolymerizing agents reduce endothelial cell stiffness and significantly lower IOP in animals and humans with several now approved for clinical use. However, these agents are associated with significant side effects, including conjunctival hyperemia and corneal verticillata. Studies show that >50% of patients treated with these therapeutics exhibit adverse side effects. Targeted nanocarrier delivery systems may address these issues but are not currently capable of passing through the corneal epithelium and must therefore be administered via intraocular injection. As frequent eye injections would not be well tolerated by patients, sustained intraocular delivery systems are needed to minimize the frequency of drug administration. Gene therapy targets for treatment of ocular hypotension have emerged, holding promise for a future glaucoma cure following a single intraocular injection, but a targeted gene delivery system is needed to enhance selective transfection of SC cells. A significant need therefore exists for both sustained nanocarrier delivery systems and gene delivery systems for intraocular strategies targeting the SC. With these needs in mind, the objective of this proposal is to engineer a scalable, customizable, synthetic nanocarrier platform that can be adapted to transport diverse therapeutic agents to outflow pathway cells with controllable release rates. Successful completion of this work will result in the first delivery system for sustained intraocular release of nanocarriers, a novel nonviral gene delivery platform for selective transfection of SC cells, and completion of nonhuman primate studies to justify clinical trials of these delivery systems in humans. The following Specific Aims will be completed: Aim 1: Optimize the duration of therapeutic effect for nanocarriers targeting Schlemm’s canal cells while avoiding side effects and toxicity within the cornea and vascular tissues in mouse eyes. Aim 2: Demonstrate nonviral transfection of Schlemm's canal cells in vivo using targeted nanocarriers without affecting nearby ocular tissues in mice Aim 3: Demonstrate that targeted nanocarriers containing latrunculin-A significantly increase conventional outflow facility and lower IOP in nonhuman primates without adverse effects.

项目总结 纳米级药物载体(即纳米载体)因其能够输送不同种类的药物而备受关注 治疗和诊断药物，并选择性地靶向特定的细胞和组织。这增加了专一性 可以有显著的临床意义，包括减少副作用和较低的剂量与较高的 威力。Schlemm管(SC)内皮细胞有望成为青光眼治疗的细胞靶点，因为它们 机械僵硬与眼压的调节有关。Rho激酶抑制剂和肌动蛋白- 解聚剂降低内皮细胞硬度并显著降低动物和人类的眼压 其中几种现已获准临床使用。然而，这些药物与显著的副作用有关， 包括结膜充血和角膜轮状疱疹。研究表明，使用这些药物治疗的患者中有50% 治疗药物表现出不良副作用。靶向纳米载体递送系统可能会解决这些问题，但 目前不能通过角膜上皮，因此必须通过 眼内注射。由于频繁的眼部注射不会被患者很好地耐受，所以持续的眼内注射 需要有给药系统，以最大限度地减少给药的频率。基因治疗的靶点 眼压过低的治疗方法已经出现，有望在单次治疗后治愈青光眼。 眼内注射，但需要一个靶向的基因输送系统来加强对SC细胞的选择性转染。 因此，对持续纳米载体递送系统和基因递送系统都存在重大需求 以SC为目标的眼内策略。考虑到这些需求，本提案的目标是设计 可扩展、可定制的合成纳米载体平台，可用于运输不同的治疗药物 药物以可控的释放速率流出途径细胞。这项工作的成功完成将导致 新型非病毒基因递送平台--纳米载体眼内缓释系统的研制 用于选择性地转导SC细胞，以及完成非人类灵长类研究以证明这些临床试验的合理性 人体内的递送系统。 将完成以下具体目标： 目的1：优化靶向Schlemm管细胞的纳米载体的治疗持续时间，同时避免 小鼠眼部角膜和血管组织的副作用和毒性。 目的2：利用靶向纳米载体在体内验证非病毒转染性Schlemm管细胞 对小鼠邻近眼组织的影响 目的3：证明含有LATRUNC-A的靶向纳米载体显著增加了传统的 非人类灵长类动物的流出便利和较低的眼压，没有不良影响。