Enhanced Drug Access to Eye Tissues

增强药物进入眼组织的机会

• 批准号: 6787485
• 负责人: John M Tomich
• 金额: $ 23.29万
• 依托单位: NACELLE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6787485
• 关键词: MDCK cell; antibiotics; combination chemotherapy; confocal scanning microscopy; conjunctiva; cornea; corneal epithelium; dosage; drug design /synthesis /production; drug screening /evaluation; epithelium; eye; eye disorder chemotherapy; eye infections; eye pharmacology; fluorescence; laboratory rabbit; membrane permeability; peptides; pharmacokinetics; sclera; tissue /cell culture; tissue /cell preparation; topical drug application; vancomycin

DESCRIPTION (provided by applicant) The innovative use of a synthetic peptide to modulate epithelial cell-cell interactions is proposed for the augmentation of drug- or gene-based therapeutic interventions. Cell monolayers are a major obstacle to delivering drugs to selected locations throughout the body. Transient access to these compartments would provide an additional means to treat debilitating and life-threatening disorders. Recently Nacelle Therapeutics, Inc. identified a small group of ion channel-forming peptides that transiently reduces electrical resistance (a measure of barrier integrity) across a variety of transformed epithelial cell monolayers. This observation was outside of the targeted outcome, but its therapeutic potential was immediately recognized. Preliminary experiments indicated that peptide exposure increased the permeability of the paracellular pathway to small (<20 kDa) but not large dextrans for a short period of time. We now propose to explore the potential applications of these peptides as short-acting modulators of epithelial barriers in the eye. It has long been recognized that delivery of instilled hydrophilic or larger molecular weight drugs into the corneal stroma as well as interior portions of the eye is difficult due in part to the highly-resistive outer epithelial layer(s). For example, the drug vancomycin is extremely hydrophilic and must be administered to the eye by injection. We hypothesize that inclusion of NC-1059 with this or other hydrophilic antibiotics should greatly enhance ophthalmic drug delivery. Over the next year, we will measure transport of fluorescently-labeled antibiotics across isolated cornea and sclera-conjuntiva in the presence and absence of our highest potency peptide, NC-1059, as well as several control sequences. The outcomes of these studies will identify specific target tissues in the eye that can be therapeutically modulated by this peptide as well as the areas of the eye that can be accessed using this approach. Both sequential and combined administration schedules will be assessed. Solution formulations with different molar ratio formulations will be investigated for both increased efficacy as well as stability during storage. These proof-of-concept studies are directed toward the treatment of acute infections of the eye through the instillation of drugs in drops rather than the current approach using injections.

描述（由申请人提供） 提出了使用合成肽来调节上皮细胞-细胞相互作用的创新用途，以增强基于药物或基因的治疗干预。细胞单层是将药物输送到全身选定位置的主要障碍。短暂进入这些隔间将为治疗衰弱和危及生命的疾病提供额外的手段。最近，Nacelle Therapeutics, Inc. 发现了一小群离子通道形成肽，可暂时降低各种转化上皮细胞单层的电阻（屏障完整性的衡量标准）。这一观察结果超出了目标结果，但其治疗潜力立即得到认可。初步实验表明，肽暴露在短时间内增加了细胞旁途径对小（<20 kDa）但不是大葡聚糖的通透性。我们现在建议探索这些肽作为眼睛上皮屏障的短效调节剂的潜在应用。人们早就认识到，将滴注的亲水性或较大分子量的药物递送到角膜基质以及眼睛的内部部分是困难的，部分原因在于高电阻的外上皮层。例如，药物万古霉素具有极强的亲水性，必须通过注射给药于眼睛。我们假设将 NC-1059 与该亲水性抗生素或其他亲水性抗生素一起使用应该会大大增强眼科药物输送。明年，我们将在存在和不存在我们最高效力肽 NC-1059 以及几个控制序列的情况下，测量荧光标记抗生素在分离的角膜和巩膜-结膜上的转运。这些研究的结果将确定眼睛中可以通过这种肽进行治疗调节的特定靶组织，以及可以使用这种方法进入的眼睛区域。将评估顺序和联合给药方案。将研究具有不同摩尔比配方的溶液配方，以提高储存期间的功效和稳定性。这些概念验证研究旨在通过滴注药物来治疗眼睛的急性感染，而不是目前使用注射的方法。