TOPS-Ester: Pharmacokinetics and Imaging in Human Skin

描述（由申请人提供）：tops -酯是一种外用药物，因其在皮肤细胞内分区和表达抗氧化活性的独特能力而被选中用于开发，这种能力可以限制氧化介导的病理，包括牛皮癣、晒伤、皮肤老化和皮肤癌。本提案的目的是利用非侵入性电子顺磁共振（EPR）光谱和成像技术监测人体皮肤中的tops -酯（即2,2,6,6-四甲基-1-氧-4-胡椒丁琥珀酸二乙基，或DETOPS），以指导皮肤疾病的预防和治疗。DETOPS酯是一种顺磁性分子，因此可以方便地使用EPR光谱进行研究。根据我们的初步数据，我们提出DETOPS在穿透表皮和真皮细胞后，分子的琥珀酸酯部分被细胞内酯酶水解成琥珀酸阴离子；从而促进皮肤中带负电荷的DETOPS羧酸衍生物的细胞内潴留。具体目的是证明区分DETOPS和Tempol在人体皮肤中时间分布差异的可行性。EPR测量将使用约翰霍普金斯大学新开发的人类局部EPR成像仪器进行。利用空间分辨药代动力学成像数据研究DETOPS在人类志愿者前臂皮肤中的渗透、区隔和代谢。预计这项初步研究将导致对DETOPS配方在预防和治疗各种皮肤病理生理障碍方面的治疗潜力的评估。

DESCRIPTION (provided by applicant): TOPS-ester is a topical drug selected for development for it's unique ability to compartmentalize within skin cells and express antioxidant activity that limits oxidant mediated pathologies including psoriasis, sunburn, skin aging and skin cancer. The objective of this proposal is to use a non-invasive electron paramagnetic resonance (EPR) spectroscopy and imaging technique to monitor TOPS-ester (i.e. diethyl 2,2,6,6-tetramethyl-1-oxyl-4-piperidene succinate, or DETOPS) in human skin for the purpose of guiding the prophylactic and therapeutic treatment of skin disease. The DETOPS ester is a paramagnetic molecule and hence can be conveniently studied using EPR spectroscopy. Based on our preliminary data, we propose that after DETOPS penetrates cells of the epidermis and dermis, the succinate-ester moiety of the molecule is hydrolyzed by intracellular esterases to succinate anions; thereby facilitating intracellular retention of negatively charged carboxylate derivatives of DETOPS in the skin. The specific aims are to demonstrate the feasibility of distinguishing the difference between DETOPS and Tempol in their temporal distribution in human skin. The EPR measurements will be performed using the newly developed topical EPR imaging instrumentation for humans at the Johns Hopkins University. The skin penetration, compartmentalization and metabolism of the DETOPS in the forearm skin of human volunteers will be investigated using spatially resolved pharmacokinetic imaging data. It is expected that this preliminary study will lead to the evaluation of the therapeutic potential of the DETOPS formulation for the prevention and treatment of a variety of skin pathophysiological disorders.