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.

项目摘要 纳米级药物载体（即纳米载体）因运输潜水员的能力而引起了很多关注 治疗和诊断剂，并有选择地靶向特定的细胞和组织。这种提高的特异性 可以具有显着的临床意义，包括副作用降低和较低的剂量，较高 效力。 Schlemm的运河（SC）内皮细胞作为青光眼治疗的细胞靶标有望 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 - 解聚剂降低内皮细胞刚度，并在动物和人类中显着降低IOP 现在有几个批准用于临床使用。但是，这些药物与重大副作用有关， 包括结膜充血和角膜角膜菌。研究表明，在接受治疗的患者中，> 50％ 治疗表现出不良的副作用。有针对性的纳米载体输送系统可能会解决这些问题，但是 目前无法通过角膜上皮，因此必须通过 眼内注射。由于患者经常无法耐受眼睛的注射，因此眼内持续 需要输送系统来最大程度地减少药物给药的频率。基因治疗靶标 已经出现了眼部低血压的治疗 眼内注射，但需要一个靶向基因递送系统来增强SC细胞的选择性翻译。 因此，对持续的纳米载体输送系统和基因输送系统都存在很大的需求 针对SC的眼内策略。考虑到这些需求，该提案的目的是设计 可扩展的，可自定义的合成纳米载体平台，可以适应运输潜水员治疗 具有受控释放速率的出口通路细胞的代理。成功完成这项工作将导致 纳米载体的持续眼内释放的第一个输送系统，纳米载体是一种新型的非病毒基因输送平台 为了选择性转化SC细胞，并完成非人类灵长类动物研究以证明这些试验的合理性 人类的递送系统。 以下特定目标将完成： 目标1：优化针对Schlemm运河细胞的纳米载体的治疗效果的持续时间 小鼠眼睛的角膜和血管组织内的副作用和毒性。 AIM 2：使用靶向纳米载体在体内证明Schlemm的运河细胞的非病毒翻译 影响小鼠附近的眼组织 目标3：证明含有latrunculin-a的靶向纳米载体可显着增加常规 出口设施，降低非人类隐私的IOP，而不会产生不利影响。