Active Drug Loading to Nanovesicles for Targeted Drug Delivery

摘要： 炎症是免疫反应，以消除入侵的病原体，以防止组织损伤，但过度 血管炎症是大多数疾病的发病机制。靶向血管系统中的炎症通路 可能是控制宿主免疫应答以预防疾病发展的有吸引力的手段。在 因此，我们选择小鼠肺部疾病作为模型来检验我们的假设。细菌感染 引起急性肺部炎症/损伤（ALI），其迅速促成急性呼吸窘迫综合征（ARDS）。 目前的治疗方法是肺保护通气和液体保守管理。没有正式的 推荐的药物治疗ALI/ARDS。尽管在护理设备和努力开发方面取得了进展， 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， 炎症促进嗜中性粒细胞粘附和迁移到肺中。中性粒细胞，一种血型 循环白细胞通过几种结合分子结合并粘附到活化的肺内皮细胞上， 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，我们创造了纳米囊泡 由中性粒细胞膜构成。我们认为中性粒细胞纳米囊泡是一种新的药物载体 将药物输送到发炎的小鼠肺部以控制ALI发展的平台。基于我们 中性粒细胞纳米囊泡产生、活体显微镜检查和LPS或细菌诱导的 急性肺损伤小鼠模型，我们已经证明了这一建议的可行性，新颖的概念和一个 对纳米医学的巨大影响。我们提出三个目标来检验我们的假设： 目的1：确定人中性粒细胞膜形成的纳米囊泡的性质， 内皮靶向。 目的2：在纳米囊泡内主动装载NF-κB抑制剂以改善小鼠ALI的治疗 LPS诱导的。 目的3：通过纳米囊泡共递送抗生素和抗炎药物增强细菌粘附。 在细菌诱导的ALI小鼠模型中杀死并解决宿主炎症。 完成这一提案不仅可能导致开发新的交付系统，而且还可能改变 当前纳米医学的范例到纳米治疗的生物学启发设计。

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.