Active Drug Loading to Nanovesicles for Targeted Drug Delivery

摘要： 炎症是一种免疫反应，可以消除入侵的病原体，防止组织损伤，但过度 血管炎症是大多数疾病的发病机制。血管系统中的靶向炎症途径 可能是一种有吸引力的手段来管理宿主的免疫反应，以防止疾病的发展。在……里面 在这个建议中，我们选择了小鼠肺部疾病作为模型来检验我们的假设。细菌感染 引起急性肺炎症/损伤(ALI)，迅速引发急性呼吸窘迫综合征(ARDS)。 目前的治疗方法是肺保护、呼吸机和液体保守治疗。没有正式的 ALI/ARDS的推荐药物治疗。尽管护理设备取得了进步，并努力开发出 新的治疗方法，死亡率仍然高达40%，令人无法接受。在ALI/ARDS的发病机制中，血管 炎症促进了中性粒细胞的黏附和向肺部的迁移。中性粒细胞，一种血液 循环中的白细胞通过与活化的肺内皮细胞之间的几个结合分子结合和黏附 中性粒细胞和内皮细胞。受这种独特的细胞间相互作用的启发，我们创造了纳米胶囊 由中性粒细胞膜制成。我们认为中性粒细胞纳米囊泡是一种新的药物释放方式。 用于将药物输送到发炎的小鼠肺以控制ALI发展的平台。基于我们的 中性粒细胞纳米囊泡产生、活体显微镜和细菌或内毒素诱导的初步结果 通过建立小鼠急性肺损伤模型，论证了该方案的可行性，提出了新的概念和方法。 对纳米医学产生了巨大的影响。我们提出了三个目标来检验我们的假设： 目的1：测定人中性粒细胞膜形成的纳米微囊的性质 内皮细胞靶向。 目的2：纳米微囊内主动负载核因子-κB抑制物改善小鼠急性肺损伤的治疗 内毒素诱导。 目的3：纳米囊泡联合输送抗生素和抗炎药物可增强细菌 在细菌诱导的ALI小鼠模型中杀死和解决宿主炎症。 这一提议的完成不仅可能导致开发新的交付系统，而且还将使 从纳米医学的当前范式到以生物为灵感的纳米疗法设计。

Abstract: Inflammation is the immune response to eliminate invading pathogens to prevent tissue injury, but excessive vascular inflammation is the pathogenesis of most diseases. Targeting inflammation pathways in vasculature may be an attractive means to manage the host immune responses for prevention of disease developments. In this proposal, we choose the mouse lung disease as a model to examine our hypothesis. Bacterial infection causes acute lung inflammation/injury (ALI) that quickly precipitates acute respiratory distress syndrome (ARDS). Current therapies are lung-protection ventilation and fluid-conservative management. There is no formally recommended pharmacological therapy for ALI/ARDS. Despite advances in care devices and efforts to develop new therapeutics, the mortality is still unacceptably high at 40%. In pathogenesis of ALI/ARDS, vascular inflammation promotes neutrophil adhesion and transmigration into the lungs. Neutrophils, a type of blood circulating leukocytes, bind and adhere to activated lung endothelium via several binding molecules between a neutrophil and an endothelium. Inspired by this unique intercellular interaction we have created nanovesicles made from the neutrophil membrane. We propose that neutrophil nanovesicles are a new drug delivery platform for delivering drugs to inflamed mouse lungs to control ALI developments. Based on our preliminary results on neutrophil nanovesicle production, intravital microscopy and LPS- or bacterium-induced acute lung injury mouse models, we have demonstrated the feasibility of this proposal, novel concepts and a great impact in nanomedicine. We propose three aims to test our hypothesis: Aim 1: To determine the properties of human neutrophil membrane formed nanovesicles required for endothelial targeting. Aim 2: Active loading of NF-κB inhibitors inside nanovesicles for improved therapies of mouse ALI induced by LPS. Aim 3: Co-delivery of an antibiotic and an anti-inflammation drug by nanovesicles enhances bacterial killing and resolves host inflammation in a bacterium-induced ALI mouse model. Completion of this proposal may lead to not only the development of a new delivery system but also shift the current paradigm in nanomedicine to biology-inspired design of nanotherapeutics.