Mechanisms of micropore closure after microneedle application in diverse skin types

不同皮肤类型微针应用后微孔闭合的机制

• 批准号: 10677154
• 负责人: Valeria Cota
• 金额: $ 3.26万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677154
• 关键词: Acceleration; Affect; Agonist; Area; Biochemical; Biological Assay; Bypass; CREB1 gene; Catecholamines; Cells; Clinical; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Development; Diffusion; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor; Dopamine Receptor; Drug Delivery Systems; Drug Kinetics; Drug Modelings; Epidermis; Frequencies; G-Protein-Coupled Receptors; Gel; Genetic; Goals; Hepatic; Human; Impaired healing; In Vitro; Individual; Length; Lipids; Measurement; Measures; Mediating; Melanins; Metabolism; Methods; Metronidazole; Needles; Neurotransmitters; Optical Coherence Tomography; Painless; Pathway interactions; Permeability; Pharmaceutical Preparations; Pharmacologic Substance; Phosphorylation; Physiological Processes; Plasma; Population Heterogeneity; Process; Production; Proliferating; Property; Receptor Signaling; Recovery; Research; Role; Signal Transduction; Skin; Skin Physiology; Skin wound healing; Solid; Spectrum Analysis; Stimulus; Stratum corneum; Testing; Therapeutic; Thick; Time; Topical application; Transdermal substance administration; Tyrosine; Variant; Visualization; Water; Western Blotting; absorption; antagonist; clinical practice; drug efficacy; electric impedance; healing; hydrophilicity; improved; in vivo; insight; interest; keratinocyte; knock-down; micropore; pharmacologic; prevent; receptor binding; skin color; small hairpin RNA; therapy outcome; translational approach; wound; wound healing

PROJECT ABSTRACT Microneedles (MNs) are micron scale projections that allow for improved drug delivery through the skin via formation of transient micropores. For successful transdermal drug delivery, it is crucial that the micropores remain open (drug delivery ceases rapidly after micropore closure, usually within ~48 hrs). Delaying micropore closure would be advantageous by allowing a longer period of drug delivery from each MN treatment. Previous methods that have been explored for delaying micropore closure timeframes did not account for the biochemical differences seen in diverse skin types; further, previous studies did not address the physiological processes that impact micropore closure. We have shown that darker skin types have longer micropore closure timeframes. This could result in altered therapeutic outcomes from unexpected drug delivery windows in diverse skin types, which may be especially problematic for drugs with narrow therapeutic windows. Catecholamines such as dopamine play a role in cutaneous wound healing and may mediate micropore closure, but the direct role of dopamine in micropore closure has never been studied. Dopamine may alter wound healing through dopamine receptor binding and subsequent cAMP modulation. Interestingly, melanin production (responsible for skin color) also relies on the same dopaminergic precursors and alters intracellular cAMP production. Therefore, we hypothesize that drug delivery through micropores in diverse skin types will differ in a manner dependent upon micropore closure times, and variability in micropore closure among skin types is influenced by dopamine secretion and receptor signaling. To test this, we will establish a translational approach through two Aims. In Aim 1 we will assess the impact of differences in micropore closure times on model drug absorption using a pharmacokinetic study. In Aim 2 we will investigate how dopamine D1/D2 receptor signaling alters microwound recovery using a dual in-vitro knockdown approach. The overall goal is to identify a possible pharmaceutical target for delaying micropore closure, ultimately improving MN-assisted transdermal drug delivery and informing development of better MN products for diverse populations.

项目摘要 微针（MN）是微米量表的投影，可通过 瞬态微孔的形成。对于成功的经透皮药物，至关重要的是微孔 保持开放状态（微孔闭合后，通常在约48小时内迅速停止）。延迟微孔 通过从每种MN治疗中允许更长的药物递送，闭合将是有利的。以前的 已经探索了延迟微孔闭合时间范围的方法没有考虑到 在各种皮肤类型中看到的生化差异；此外，以前的研究没有针对生理 影响微孔封闭的过程。我们已经表明，较深的皮肤类型具有更长的微孔 闭合时间范围。这可能会导致意外药物输送窗口的治疗结果改变 在各种皮肤类型中，对于具有狭窄治疗窗户的药物而言，这可能是尤其有问题的。 多巴胺等儿茶酚胺在皮肤伤口愈合中起作用，并可能介导微孔 闭合，但是多巴胺在微孔闭合中的直接作用从未被研究过。多巴胺可能会改变 通过多巴胺受体结合和随后的cAMP调节，伤口愈合。有趣的是，黑色素 生产（负责肤色）也依赖于相同的多巴胺能前体并改变细胞内 营地生产。因此，我们假设通过微孔中的不同皮肤类型的药物输送药物将 取决于微孔闭合时间的方式不同，皮肤之间微孔闭合的可变性 类型受多巴胺分泌和受体信号传导的影响。为了测试这一点，我们将建立翻译 接近两个目标。在AIM 1中，我们将评估微孔关闭时间差异的影响 使用药代动力学研究模型吸收药物。在AIM 2中，我们将研究多巴胺D1/D2如何 受体信号传导使用双重视频敲低方法来改变微观恢复。总体目标是 确定延迟微孔闭合的可能的药物目标，最终改善了MN辅助 透皮药物输送并为各种种群的更好的MN产品开发。