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) 是微米级的突出物，可以通过皮肤改善药物输送 瞬时微孔的形成。对于成功的透皮药物递送，微孔至关重要 保持开放（微孔关闭后药物输送迅速停止，通常在约 48 小时内）。延迟微孔 封闭将是有利的，因为允许每次 MN 治疗的药物输送时间更长。以前的 已探索的延迟微孔闭合时间的方法并未考虑到 不同皮肤类型的生化差异；此外，之前的研究并未解决生理学问题 影响微孔闭合的过程。我们已经证明，深色皮肤类型的微孔更长 关闭时间表。这可能会导致意外的药物递送窗口改变治疗结果 在不同的皮肤类型中，这对于治疗窗口狭窄的药物来说可能尤其成问题。 多巴胺等儿茶酚胺在皮肤伤口愈合中发挥作用，并可能介导微孔 但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 调节来愈合伤口。有趣的是，黑色素 产生（负责肤色）也依赖于相同的多巴胺能前体并改变细胞内 cAMP 生产。因此，我们假设通过不同皮肤类型的微孔进行药物输送将 其差异取决于微孔闭合时间以及皮肤之间微孔闭合的变异性 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，我们将建立一个翻译 通过两个目标来实现。在目标 1 中，我们将评估微孔闭合时间差异对 使用药代动力学研究建立药物吸收模型。在目标 2 中，我们将研究多巴胺 D1/D2 如何 受体信号传导使用双重体外敲低方法改变微伤口恢复。总体目标是 确定延迟微孔闭合的可能药物靶标，最终改善 MN 辅助 透皮给药并为不同人群开发更好的 MN 产品提供信息。