In Vitro Human Tissue Model for Intravaginal Drug Delivery

描述（由申请方提供）：由于避免了首过肝脏代谢和胃肠道刺激，阴道内给药是全身给药的一种有吸引力的选择。目前的阴道给药研究主要使用FDA认可的兔模型进行。然而，这样的研究是昂贵和耗时的。此外，动物实验往往是高度可变的。为了避免这些问题，我们建议使用高度分化和可重复的体外重建的人阴道宫颈外（VEC）组织模型，如MatTek EpiVaginalTM模型。然而，需要优化EpiVaginal模型的屏障特性，以便它们准确地匹配天然体内组织的屏障特性。. 第一阶段的研究将产生各种不同的阴道上皮细胞培养物，其中组织表型已被修改。这些组织将在组织学、屏障特性（通过跨上皮电阻测量）和决定粘膜屏障特性的重要细胞器（如桥粒和紧密连接）的存在方面进行表征。此外，将定量屏障脂质的水平。将选择最有希望的组织进行药物渗透性研究，使用一组模型药物，其历史药代动力学阴道内家兔数据可用。将比较体外和体内数据，以选择具有最佳屏障性能的组织。最后，将比较临床前阴道内药物递送研究与兔研究使用体外组织模型的经济性。 公共卫生相关性：阴道途径由于其大的表面积、高血管化、对包括肽和蛋白质的广泛化合物的渗透性以及避免肝脏首过代谢和胃肠道刺激而具有用于全身药物递送的巨大潜力。由于药物吸收潜力已成为药物发现过程早期决策的重要标准，因此非常需要开发一种可靠的药物通过阴道途径吸附的筛选方法。该提案将优化高度分化的人类阴道组织模型，以促进此类研究。

DESCRIPTION (provided by applicant): Due to the avoidance of first-pass hepatic metabolism and gastrointestinal irritation, intravaginal administration is an attractive option for systemic delivery of drugs. Current vaginal drug delivery studies are primarily performed using the FDA-accepted rabbit model. However, such studies are costly and time consuming. In addition, animal experiments are often highly variable. To avoid these problems, we propose use of a highly differentiated and reproducible, in vitro reconstructed human vaginal ectocervical (VEC) tissue model such as MatTek EpiVaginalTM model. However, the barrier properties of the EpiVaginal model need to be optimized so that they accurately match those of native in vivo tissue. . Phase Iresearch will produce various EpiVaginal cultures in which the tissue phenotype has been modified. These tissues will be characterized in terms of histology, barrier properties (measured by transepithelial electrical resistance), and the presence of organelles important in determining mucosal barrier properties such as desmosomes and tight junctions. In addition, the levels of barrier lipids will be quantified. The most promising tissues will be selected for drug permeability studies using a set of model drugs for which historical pharmacokinetic intravaginal rabbit data are available. The in vitro and in vivo data will be compared to choose the tissue with optimized barrier properties. Finally, the economics of utilizing the in vitro tissue model for pre-clinical intravaginal drug delivery studies versus rabbit studies will be compared. PUBLIC HEALTH RELEVANCE: The vaginal route has a great potential for systemic drug delivery due to its large surface area, high vascularization, permeability to a wide range of compounds including peptides and proteins, and avoidance of the hepatic first-pass metabolism and gastrointestinal irritation. Since drug absorption potential has become important criterion for decisions early in the drug discovery process, there is a great need to develop a reliable screening method for drug adsorption through the vaginal route. This proposal will optimize a highly differentiated, human vaginal tissue model to facilitate such studies.