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.
Public Health Relevance Statement: 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.
NIH Spending Category: Bioengineering; Gene Therapy; Genetics; Nanotechnology
Project Terms: Acetylcholinesterase; Ache; Adverse effects; Artificial nanoparticles; base; cholinergic; Cholinesterases; Chronic; Data; Drug Delivery Systems; emergency service/first responder; Encapsulated; Engineering; Enzymes; Event; Excretory function; Exposure to; Extravasation; Food Chain; Health; Human; Injury; innovation; Insecticides; Ligands; Liposomes; Measures; Medical; medical attention; Membrane; Morbidity - disease rate; Mortality Vital Statistics; nanoparticle; Neurologic; novel; novel therapeutics; Organophosphates; Oximes; Pediculicide; Pesticides; Pharmaceutical Preparations; Phase; Polymers; Process; prophylactic; Proteins; Reaction; Readiness; Reliance; Research; research and development; Research Project Grants; response; Scheme; Small Business Innovation Research Grant; small molecule; Structure; Testing; Therapeutic; Therapeutic Agents; Toxic effect; toxic organophosphate insecticide exposure; Validation
