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: 10539739
• 负责人: MARK JOHNSON
• 金额: $ 55.7万
• 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/10539739
• 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; Mind; Modeling; Monkeys; Mus; Ocular Hypotension; Ophthalmoscopes; Optical Coherence Tomography; Pathway interactions; Patients; Perfusion; Pharmaceutical Preparations; Phenotype; Physiologic Intraocular Pressure; Plasmids; Population; Primary Open Angle Glaucoma; Reducing Agents; Reporter; Resistance; Resolution; 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; depolymerization; 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; 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.

项目概要 纳米级药物载体（即纳米载体）因其运输多种药物的能力而备受关注。 治疗和诊断剂并选择性地针对特定细胞和组织。这增加了特异性 可以具有显着的临床意义，包括减少副作用和较低剂量 效力。施累姆氏管 (SC) 内皮细胞有望成为青光眼治疗的细胞靶标，因为它们 机械刚度与眼内压（IOP）的调节有关。 Rho 激酶抑制剂和肌动蛋白 解聚剂可降低动物和人类的内皮细胞硬度并显着降低眼压 一些现已批准用于临床。然而，这些药物具有显着的副作用， 包括结膜充血和角膜轮转。研究表明，超过 50% 的接受这些治疗的患者 疗法表现出不良副作用。靶向纳米载体递送系统可以解决这些问题，但是 目前无法穿过角膜上皮，因此必须通过 眼内注射。由于患者不能很好地耐受频繁的眼部注射，持续的眼内注射 需要输送系统来最大限度地减少给药频率。基因治疗目标 低眼压的治疗方法已经出现，为未来青光眼的治愈带来了希望。 眼内注射，但需要靶向基因递送系统来增强SC细胞的选择性转染。 因此，对于持续的纳米载体递送系统和基因递送系统存在着巨大的需求 针对 SC 的眼内策略。考虑到这些需求，本提案的目标是设计 一个可扩展、可定制的合成纳米载体平台，可适应运输多种治疗药物 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 第一个持续眼内释放纳米载体的递送系统，一种新型非病毒基因递送平台 用于选择性转染 SC 细胞，并完成非人类灵长类动物研究以证明这些临床试验的合理性 人类的输送系统。 将完成以下具体目标： 目标 1：优化纳米载体针对施累姆氏管细胞的治疗效果持续时间，同时避免 对小鼠眼睛角膜和血管组织的副作用和毒性。 目标 2：演示使用靶向纳米载体对施莱姆氏管细胞进行体内非病毒转染，无需 影响小鼠附近的眼组织 目标 3：证明含有 latrunculin-A 的靶向纳米载体显着提高了常规纳米载体的 在非人类灵长类动物中具有流出设施和较低的眼压，且无不良影响。