Nanoparticle Defense for Agrichemical Exposures

描述(申请人提供)：这个第一阶段的SBIR项目寻求开发专门的蛋白质-聚合物纳米颗粒，这些纳米颗粒被设计成一种治疗药物，以对抗暴露于有机磷(OP)杀虫剂后的不良影响。这些纳米颗粒的概念基于“定制、触发释放”，即聚合脂质体纳米颗粒(PLN)的膜显示功能性乙酰胆碱酯酶(OPS的主要靶点)，同时包裹治疗货物(例如，肟类)。在OP暴露期间，AChE被抑制(与外源性ChE相同)以引起蛋白质变化，随后聚合物纳米颗粒膜允许肟类物质(可能的各种机制)被释放并立即可用于恢复外源性ChE。由于PLN是针对OP定制的，因此PLN-AChE纳米颗粒不会在没有OP暴露的情况下在体内产生不需要的高浓度治疗剂。在这个应用中，我们将开发并随后证明AChE-PLN可以由功能酶产生，并被有机磷(OP)选择性地抑制。我们将进一步证明，小分子货物可以装载和储存在功能性AChE-PLN中，与OPs反应释放被捕获的货物。我们将生产三个功能完整的CHE-PLN中的每一个25毫克，为该研发项目的第二阶段做好准备。 公共卫生相关性：公民可通过家庭使用、空中喷洒、种植农作物、作为杀菌剂以及通过食物链接触到有机磷杀虫剂。意外接触含有OP的杀虫剂可能会导致多种级别的毒性、伤害或对人类造成致命伤害。几十年来，只有高水平接触有机磷农药的人才会得到医疗护理，因为低水平的慢性接触没有得到控制，很大程度上是因为他们可能没有症状，通常通过累积接触而表现出疾病。如果可以通过预防过程和高度特异性地针对OP暴露采取治疗措施，则可以预期减少短期和长期的健康不良影响。

DESCRIPTION (provided by applicant): This Phase I SBIR project seeks to develop specialized protein-polymer nanoparticles that are engineered to a therapeutic drug to counter the ill effects following exposure to organophosphate (OP) insecticides. The concept for these nanoparticles is based on 'customized, triggered-release' in which the membrane of a polymerized liposome nanoparticle (PLN) displays functional acetylcholinesterase, the primary target for OPs, while a therapeutic cargo is encapsulated (e.g., oxime). During an OP exposure, the AChE is inhibited (the same as exogenous ChE) to cause protein changes that later the polymeric nanoparticle membrane allowing the oxime cargo (various mechanisms possible) to be released and immediately available to restore exogenous ChE. Because the PLNs are customized and specific to OPs, PLN-AChE nanoparticles will not produce unwanted, high concentrations of the therapeutic agents in the body without OP exposure. In this application, we will develop and subsequently show that AChE-PLNs can be generated with functional enzyme and are selectively inhibited by organophosphates (OP). We will further demonstrate that small molecule cargo can be loaded and stored in functional AChE-PLNs that reaction with OPs releases the entrapped cargo. We will produce ¿ 25 mg each of three functional, intact ChE-PLNs in readiness for the Phase II portion of this R&D project. PUBLIC HEALTH RELEVANCE: Citizens can be exposed to organophosphate (OP) insecticides via domestic application, aerial spraying, crops, as a pediculicide, and through the food chain. Accidental exposure to OP- containing pesticides can cause many tiers of toxicity, injury or be fatal to humans. For decades, only high-level exposures to OPs receive medical attention because low, chronic exposures have gone unchecked largely because they can asymptomatic, usually manifesting illnesses through accumulated exposures. If therapeutic measures could be available through a preventative process and highly specific toward OP exposures, a reduction in short- and long- term ill health effects could be expected.