Nanocarriers for delivery of antioxidants to endothelium

用于将抗氧化剂递送至内皮的纳米载体

• 批准号: 6816060
• 负责人: Vladimir R Muzykantov
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-11 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6816060
• 关键词: acidity /alkalinity; antioxidants; binding sites; bioengineering /biomedical engineering; biotechnology; catalase; chemical structure function; disease /disorder model; drug administration rate /duration; drug design /synthesis /production; drug metabolism; drug screening /evaluation; drug vehicle; hydrogen peroxide; intermolecular interaction; intracellular transport; laboratory mouse; laboratory rat; lung ischemia /hypoxia; nanomedicine; nonhuman therapy evaluation; oxidative stress; polymers; protein localization; protein metabolism; proteolysis; respiratory disorder chemotherapy; vascular endothelium

DESCRIPTION (provided by applicant): Vascular oxidant stress plays a key role in many pathologic states including hyperoxia, inflammation, ischemia, pulmonary and cardiovascular diseases. However, current antioxidant therapies are not effective, in part due to sub-optimal delivery to endothelial cells (EC). Previous studies have shown that the antioxidant enzyme (AOE) catalase (that detoxifies freely diffusing H2O2) conjugated with antibodies to endothelial Cell Adhesion Molecules (CAM) accumulates in EC after intravenous injection and protects animals against acute oxidant lung injury. Unfortunately, anti-CAM/AOE conjugates are eliminated from the blood and degraded in the EC within a few hours, affording only transient effects. In order to solve this problem and to achieve higher therapeutic duration and utility, we propose to load catalase into H2O2-permeable, anti-CAM targeted di-block PEG-PLGA Polymer Nano-Carriers (PNC) that would prolong the AOE circulation and protect from lysosomal proteolysis. Pilot data show that catalase loaded inside stealth anti-CAM/PNC degrades H2O2, binds to and protects EC from oxidant injury, circulates in animals for a prolonged time, and accumulates in the lung vasculature. The goal of this grant is to explore, test and optimize this strategy, pursuing the following Specific Aims: 1. Optimize the design of PNC for AOE delivery to EC. PEG-PLA PNC formulation, composition, size, AOE loading, activity and protease resistance, rate of pH-dependent degradation, coupling of anti-CAM, binding, uptake and metabolism by EC, and protection of EC will be studied and optimized in vitro. 2. Characterize the behavior and targeting of anti-CAM/PNC/AOE in vivo. Their blood clearance, systemic effects, biodistribution, EC binding, pulmonary targeting, optimal administration routes and persistence in lungs will be tested in naive animals and animals with oxidant vascular stress. 3. Evaluate the effects of anti-CAM/PNC/AOE in animals. Mouse models of acute H2O2 generation in the pulmonary vasculature and sub-acute oxidant stress in the lungs (hyperoxia) will be employed to evaluate the degree and duration of protection, and refine regimens of AOE targeting and mechanisms of protection. Completion of these Aims will be a major step towards the long-term goal of our research, which is translation of this promising new technology platform into the clinical domain.

描述(由申请人提供)： 血管氧化应激在许多病理状态中起关键作用，包括高氧、炎症、缺血、肺和心血管疾病。然而，目前的抗氧化剂疗法并不有效，部分原因是对内皮细胞(EC)的输送不够理想。先前的研究表明，抗氧化酶(AOE)过氧化氢酶(能解毒，能自由扩散的过氧化氢)与抗内皮细胞黏附分子(CAM)抗体结合后，在静脉注射后聚集在EC中，保护动物免受急性氧化性肺损伤。不幸的是，抗CAM/AOE结合物在几个小时内从血液中清除并在EC中降解，仅提供短暂的效果。为了解决这一问题，并获得更高的治疗时间和实用性，我们建议将过氧化氢酶负载到过氧化氢透过性的、抗CAM靶向的双嵌段聚乙二醇聚乳酸聚合物纳米载体(PNC)中，以延长AOE循环并防止溶酶体蛋白降解。中试数据显示，装载在隐形抗CAM/PNC中的过氧化氢酶降解过氧化氢，结合并保护EC免受氧化损伤，在动物体内循环较长时间，并在肺血管系统中积累。这笔赠款的目标是探索、测试和优化这一战略，追求以下具体目标：1.优化面向EC的AOE交付的PNC设计。聚乙二醇聚乳酸PNC的处方、组成、大小、AOE负载量、活性和对蛋白酶的抗性、pH依赖的降解率、抗CAM的偶联、EC的结合、摄取和代谢以及EC的保护等方面将在体外进行研究和优化。2.研究抗CAM/PNC/AOE抗体在体内的行为和靶向性。它们的血液清除、全身效应、生物分布、EC结合、肺靶向、最佳给药途径和肺内持久性将在幼稚动物和氧化血管应激动物身上进行测试。3.评价抗CAM/PNC/AOE的动物实验效果。将采用小鼠肺血管产生急性过氧化氢和肺内亚急性氧化应激(高氧)的模型来评估保护的程度和持续时间，并改进AOE的靶向方案和保护机制。完成这些目标将是朝着我们研究的长期目标迈出的重要一步，也就是将这一前景看好的新技术平台转化为临床领域。

项目成果

Targeted endothelial delivery of nanosized catalase immunoconjugates protects lung grafts donated after cardiac death.

• DOI: 10.1097/tp.0b013e318226bc6b
• 发表时间: 2011-08-27
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Preissler G;Loehe F;Huff IV;Ebersberger U;Shuvaev VV;Bittmann I;Hermanns I;Kirkpatrick JC;Fischer K;Eichhorn ME;Winter H;Jauch KW;Albelda SM;Muzykantov VR;Wiewrodt R
• 通讯作者: Wiewrodt R

Modulation of endothelial targeting by size of antibody-antioxidant enzyme conjugates.

根据抗体 - 抗氧化剂酶结合的大小对内皮靶向的调节。

• DOI: 10.1016/j.jconrel.2010.10.026
• 发表时间: 2011-02-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Shuvaev VV;Tliba S;Pick J;Arguiri E;Christofidou-Solomidou M;Albelda SM;Muzykantov VR
• 通讯作者: Muzykantov VR

NO gets a test ride on high-tech transporting nanodevices: A commentary on "Sustained-release nitric oxide from long-lived circulating nanoparticles".

• DOI: 10.1016/j.freeradbiomed.2010.05.022
• 发表时间: 2010-08
• 期刊: Free radical biology & medicine
• 影响因子: 7.4
• 作者: V. Muzykantov