A fundamental study to determine the difference in barrier properties of healthy and diseased nail in order to facilitate drug delivery

指甲疾病影响到多达10%的人口，范围从无害的甲板变色，常见于吸烟者，到慢性感染，这可能会给患者带来非常痛苦和毁容。对于免疫功能低下的患者和糖尿病患者来说，指甲感染尤其严重，它们可能导致严重的并发症，如截肢。有许多非常有效的化合物可用于治疗指甲感染，但是，足跖角蛋白在局部给药后是一个非常有效的吸收屏障，因此，将治疗药物输送到作用部位，即甲板和甲床内，是一个重大的挑战。目前，用于真菌感染或牛皮癣等指甲疾病的局部治疗需要长期应用，因此患者的依从性往往较差，复发很常见。指甲疾病的治疗分为三大类；第一种方法是通过手术或化学方法切除全部或部分受感染的指甲，暴露感染部位，然后进行局部治疗。第二种治疗方法是口服适当的药物，第三种是局部给药。虽然目前，拔甲和口服给药是最有效的，但拔甲带来的疼痛、副作用和口服药物治疗的潜在药物相互作用，导致直接将治疗药物应用于甲板最受临床医生和患者的欢迎。目前有两种局部治疗甲癣的药物获得许可，Penlac由Dermik在美国上市，于1999年底获得批准，2003年的销售额为1.42亿美元，Loceryl在欧洲上市，同年的销售额超过1亿美元)。局部治疗不会带来与全身抗真菌药物相关的严重副作用（如肝毒性）的风险，并且比完全或部分去除指甲的治疗更少痛苦。然而，目前市场上用于治疗甲真菌病的外用产品报道治愈率低至24%。研究表明，局部治疗甲真菌病的效率低下与治疗药物对指甲的渗透性低有关，因为一些配方仅将其应用剂量的0.2%传递到目标部位。为了有效，药物必须能够以足够的量穿透甲板，以达到甲床内的有效剂量——这一点目前市场上的产品仍有待实现。其中一个主要原因是，与皮肤相比，指甲是一种更有效的化学渗透屏障，而且对这种屏障的结构特性完全缺乏基本的了解，这阻碍了有效设计可用于该局部部位的药物/配方。因此，本研究的目的是研究健康和甲真菌甲板的特性，包括它们对药物的渗透性。这些知识对于确定增强策略的新靶点，以改善这种生物屏障的药物渗透性差，并进一步实现局部成功治疗甲真菌病的最终目标至关重要。

Nail disorders affect up to 10% of the population and range from innocuous discoloration of the nail plate, commonly seen in smokers, to chronic infections, which can be very painful and disfiguring for the sufferer. Nail infections are especially serious for immunocompromised patients and diabetics where they can cause major complications such as limb amputation. There are many highly effective compounds available to treat infections found in the nail but, the ungual keratin represents a highly effective barrier against absorption following topical drug administration, and therefore, the delivery of therapeutic agents to the site of action i.e. within the nail plate and the nail bed, represents a significant challenge. At present, topical treatments used for nail disorders such as fungal infections or psoriasis require long term application, hence patient compliance is often poor and relapse common. The treatments for nail disorders fall into three general categories; the first involves the surgical /chemical removal of all or part of the affected nail to expose the site of infection, which can then be treated topically. The second method of treatment is the oral administration of an appropriate drug and the third is topical drug administration. Although, at present, nail removal and oral administration are the most effective, the pain associated with nail removal and side-effects and potential drug interactions associated with oral drug therapy result in the direct application of a therapeutic agent to the nail plate being most popular with clinicians and patients. Two topical treatments are currently licensed for onychomycosis, Penlac marketed by Dermik in the USA, approved in late 1999 with reported sales of $142 million in 2003 and Loceryl available in Europe with sales of greater than $100 million in the same year). Topical treatments do not carry the risks of serious side effects (such as hepatotoxicity) associated with systemic antifungals and are less painful than treatments involving full or partial nail removal. However, the topical products currently marketed to treat onychomycosis have reported cure rates as low as 24% . Research has suggested the inefficiency of topical onychomycosis treatment is linked to the low penetration of the therapeutic into the nail, as some formulations only deliver 0.2% of their applied dose to the target site. To be effective, the drug must be able to penetrate the nail plate in sufficient quantities, to achieve an efficacious dose within the nail bed something that remains to be achieved with the current marketed products. One of the major reasons for this is that the nail is a more effective barrier to chemical permeation even compared to skin and the complete lack of fundamental understanding of structural properties of this barrier are preventing the effective design of drugs/formulations that can be used at this topical site. As such the aim of this study is to investigate the properties of healthy and onychomycotic nail plates, including their permeability to drugs. Such knowledge will be critical to identify new targets for enhancement strategies to improve the poor drug permeability of this biological barrier and further the ultimate goal of successfully treating onychomycosis topically.