Targeted nanomedicine for ALI and I/R

 描述(申请人提供)：急性肺损伤(ALI)和肺缺血/再灌注是破坏性的、普遍的急性临床综合征，没有有效的药物治疗。肺血管内皮细胞单层排列紊乱是其发病的共同关键因素。尤其是，内皮细胞中产生的活性氧(ROS)介导了这些细胞中有害的促炎异常，释放了炎症、氧化应激和组织损伤相互传播的恶性循环。我们设计了靶向内皮递送抗氧化剂和抗炎药的纳米载体(NC)，在ALI和I/R动物模型中发挥了非靶向载体所无法比拟的保护作用。初步研究的结果表明：i)抗氧化剂在空泡内小体中的释放进一步增强了保护作用；ii)抗体靶向弹性纳米凝胶载体(Ab/NG)尽管比空泡入口大，但仍在肺小窝中积聚；以及iii)炎症促进了大而硬的抗体/NC的空泡靶向，否则不会在幼稚小鼠的肺中积聚。我们将使用针对空泡靶PV1和先前鉴定的非空泡靶PECAM的Ab/NG和Ab/NC来定义抗氧化剂对内皮靶向的机制，表征其益处-风险比，并通过追求以下特定目标使其能够在临床上翻译：1)在正常和病理改变的内皮细胞中针对小凹的对照靶向；2)使用临床相关读数在临床相关动物模型中表征Ab/NG和Ab/NC的益处/风险比；以及，3)以对人类患者有用的分子形式重新设计抗体/NG和Ab/NC的亲和力部分，并在灌流和换气的人肺中测试它们的内皮靶向性和活性。我们假设，靶向凹陷内体的载体在减轻ALI和I/R典型的炎性异常方面将是无与伦比的。然而，AIMS 2和3不依赖于AIM 1，因为它们将首次确定PECAM靶向载体的收益/风险比，这些载体已经确立了相对于非靶向载体的优势。这项研究将使ALI和I/R治疗的一种有前景的方法能够在临床上转化。

 DESCRIPTION (provided by applicant): Acute Lung Injury (ALI) and lung ischemia/reperfusion are devastating prevalent acute clinical syndromes that have no effective pharmacotherapy. The derangement of endothelial monolayer in the pulmonary vasculature is the common key component of their pathogenesis. In particular, reactive oxygen species (ROS) produced in endothelial caveolar endosomes mediate harmful pro- inflammatory abnormalities in these cells, unleashing the vicious cicle of mutual propagation of inflammation, oxidative stress and tissue injury. We have designed nanocarriers (NC) for targeted endothelial delivery of antioxidant and anti-inflammatory agents, which exerted protective effects in animal models of ALI and I/R unmatched by untargeted counterparts. Results of pilot studies indicate that: i) antioxidant delivery in caveolar endosomes further boosts the protective effect; ii) antibody- targeted elastic nanogel carriers (Ab/NG) accumulate in the pulmonary caveoli despite being larger than caveolar entrance; and, iii) inflammation boosts caveolar targeting of large rigid Ab/NC that otherwise do not accumulate in the lungs of naïve mice. We will use Ab/NG and Ab/NC targeted to caveolar target PV1 versus previously characterized non-caveolar target PECAM, to define mechanism of the endothelial targeting of antioxidants, characterize its benefit-risk ratio and enable its clinical translation by pursuing the following Specific Aims: 1) Control targeting to caveolae in normal and pathologically altered endothelial cells; 2) Characterize benefit/risk ratio of Ab/NG and Ab/NC in clinically relevant animal models using clinically relevant readouts; and, 3) Re-engineer affinity moieties of Ab/NG and Ab/NC in a molecular format useful in human patients and test their endothelial targeting and activity in perfused and ventilated isolated human lungs. We posit that carriers targeted to caveolar endosomes will be unrivaled in mitigating inflammatory abnormalities typical of ALI and I/R. Nevertheless, Aims 2 & 3 are not dependent on Aim 1, since they will for the first time determine benefit/risk ratio of PECAM-targeted carriers with already established superiority to untargeted counterparts. This study will enable clinical translation of a promising approach for ALI and I/R treatment.