Developing nanocapsules for the targeted drug delivery to the neuroretina

遗传性视网膜变性（RD）是一组罕见的视网膜病变，导致视力进行性丧失。RD型疾病中光感受器的变性和丧失通常与cGMP信号传导的过度激活有关。此前，我们强调了使用环鸟苷酸抑制类似物来减少体外和体内感光细胞死亡的可能性。该项目的目的是使用脂质体药物递送系统将cGMP类似物递送至RD动物模型的视网膜，以减少副作用和给药频率。脂质体将需要促进类似物通过局部玻璃体内注射的运输，同时提供保护以防止类似物在玻璃体中降解并限制在视网膜中诱导积极作用所需的类似物浓度。同时，与游离化合物相比，脂质体还应通过提供低的药物释放和从玻璃体的较少清除来限制给药频率。脂质体将自下而上构建，考虑到可能有助于满足这些要求的设计选择（例如大小，表面变化，蛋白质缀合）。该项目将解决不同类型的脂质体在玻璃体中的生物分布，通过脂质体表面上的化学附着分子归巢装置来提高其对感光细胞的靶向，并从毒性、感光细胞保护和视网膜功能保护方面筛选雾状合适的脂质体递送系统。

Hereditary retinal degeneration (RD) is a group of rare retinopathies that cause progressive loss of vision. The degeneration and loss of photoreceptors in RD-type diseases is often associated with an excessive activation of cGMP-signalling. Previously, we highlighted the possibility to use inhibitory analogues of cGMP to reduce photoreceptor cell death in vitro and in vivo. The aim of the project is to deliver analogues of cGMP to the retina of RD animal models using a liposomal drug delivery system to reduce side effects and dosing frequency. The liposomes will need to facilitate the transport of the analogues through local, intravitreal injection, while offering protection from degradation of the analogues in the vitreous body and limiting the concentration of analogues needed to induce a positive effect in the retina. Simultaneously, the liposomes should also limit the dose frequency by providing a low drug release and less clearance from the vitreous body compared with free compound. The liposomes will be built from the bottom-up with design choices in mind (e.g. size, surface change, protein conjugation) that can potentially help meet these requirements. The project will address the biodistribution of different types of liposomes in the vitreous body, improve their targeting to photoreceptor cells by means of chemically attached molecular homing devices on the liposome surface, and screen for the mist suitable liposomal delivery system in terms of toxicity, photoreceptor protection, and preservation of retinal function.