Efficient, controlled delivery of synthetic anion carriers to epithelial cells for CFTR replacement therapy

遗传性疾病囊性纤维化是由囊性纤维化跨膜传导调节基因的致病变异引起的。大量的突变体及其对CFTR表达和作为上皮性阴离子通道功能的复杂影响，刺激了对CF的通道替代治疗策略的发展。在之前的工作中，英国布里斯托尔大学的AP Davis和Dn Seppard教授设计、合成并测试了人工脂膜和细胞中的人工阴离子转运体(阴离子载体)。这项工作确定了反式十氢萘阴离子载体具有良好的生物活性，包括效力和持久性，没有毒性影响。然而，许多在人工脂膜中具有高活性的阴离子载体对细胞的递送能力很差，认为它们需要特定的药物递送系统来实现其治疗潜力。这一博士项目研究了利用基于介孔二氧化硅颗粒的纳米结构药物输送平台将阴离子载体输送到上皮细胞，该纳米结构药物输送平台是由AE Garcia-Bennett博士(麦格理大学)开发的。这一创新的阴离子载体给药平台将有助于将阴离子载体转化为治疗CF的通道替代疗法。此外，该项目在对职业发展至关重要的跨学科研究方面提供了出色的培训。它属于EPSRC医疗保健技术主题和化学生物学和生物化学研究领域。

The genetic disease cystic fibrosis (CF) is caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The large number of variants and their complex effects on CFTR expression and function as an epithelial anion channel have stimulated the development of channel replacement therapeutic strategies for CF. In previous work, Professors AP Davis and DN Sheppard (University of Bristol) designed, synthesized and tested artificial anion transporters (anionophores) in artificial lipid membranes and cells. This work identified trans-decalin anionophores with promising biological activity, including potency and persistence without toxic effects. However, many anionophores with high activity in artificial lipid membranes are poorly deliverable to cells, arguing that they require specific drug delivery systems to achieve their therapeutic potential. This PhD project investigates the delivery of anionophores to epithelial cells using nanostructured drug-delivery platforms based on mesoporous silica particles developed by Dr AE Garcia-Bennett (Macquarie University). This innovative drug-delivery platform for anionophore delivery to CF epithelial cells will facilitate the translation of anionophores as a channel replacement therapy for CF. Moreover, the project provides excellent training in interdisciplinary research important for career development. It falls within the EPSRC Healthcare Technologies theme and Chemical biology and Biological Chemistry research area.