An ultra-selective drug delivery platform technology using modular viral fusogen-actuated liposomes

项目摘要/摘要 脂质体药物包裹体最近作为一种治疗递送方式获得了显著的吸引力， 特别是作为一种增强局部药物释放或在癌症组织中直接给药的手段 药物副作用。大多数“靶向”脂质体技术的特点是囊泡显示配体或 与靶细胞上特定细胞表面部分结合的结合蛋白，以实现选择性脂质体 依恋。如果这些系统没有任何进一步的机械调节，脂质体注定要释放。 内容物进入靶细胞附近的胞外空间或通过内体途径进入靶细胞，这 限制了可以输送的药物类型以及细胞质输送的效率。几种脂质体 存在以蛋白质或脂质体化学为特征的技术，使膜融合能够 药物有效载荷直接进入胞浆或内体逃逸。然而，这些方法是极大的 受限于它们无法同时靶向预定义的感兴趣的受体，而非 对异种组织或器官中的其他细胞类型的特异性递送，同时使胞浆能够直接进入 通过脂质体和靶细胞之间的膜融合。在这项工作中，我们建议开发一种 利用重定向病毒融合系统的模块化、超选择性脂质体递送平台技术 结合目标受体的蛋白质，直接触发细胞表面的膜融合，并使 胞质有效载荷传递，同时最大限度地减少偏离目标的传递。作为概念验证，我们将使用此系统 以表达依赖的方式将有效载荷传递给HER2阳性细胞，以展示超选择性 在异种培养中向乳腺癌细胞传递。

Project Summary/Abstract Liposomal drug encapsulation has recently gained significant traction as a therapeutic delivery modality, especially as a means of enhancing localized drug release or direct delivery in cancerous tissues with reduced drug side effects. The majority of “targeted” liposome technologies feature vesicles displaying ligands or binding proteins that bind to specific cell-surface moieties on target cells to enable selective liposome attachment. Absent any further mechanistic regulation of these systems, liposomes are fated to release contents to the extracellular space near the target cell or enter target cells via endosomal pathways, which limits the type of drug that can be delivered as well as the efficiency of cytoplasmic delivery. A few liposome technologies exist which feature proteins or liposomal chemistries that enable membrane fusion to allow either direct entry of drug payloads into the cytosol or endosomal escape. However, these approaches are greatly limited by their inability to simultaneously target predefined receptors of interest with minimal risk of non- specific delivery to other cell types in heterogeneous tissues or organs, while enabling direct cytosolic entry through membrane fusion between the liposome and the target cell. In this work, we propose to develop a modular, ultra-selective liposomal delivery platform technology which utilizes a system of retargeted viral fusion proteins that bind a target receptor of interest to directly trigger membrane fusion at the cell surface and enable cytosolic payload delivery, while minimizing off-target delivery. As proof-of-concept, we will employ this system to deliver payloads to HER2-positive cells in an expression-dependent manner, to demonstrate ultra-selective delivery to breast cancer cells in heterogeneous cultures.