DESCRIPTION (provided by applicant): The blood-brain barrier (BBB) presents a formidable challenge in systemic delivery of therapeutic agents intended for central nervous system (CNS) diseases. In addition, lack of effective therapeutic delivery in infectious diseases, like HIV/AIDS, allows the virus to use the CNS as a sanctuary site. Since the BBB is both a physical (e.g., tight cellular junctions) and biological (e.g., membrane efflux transporters) obstacle to drug transport, a multi-modal strategy that addresses both of these issues is necessary for effective systemic delivery into the CNS. In this R21 proposal, the main objective is to develop and evaluate multifunctional oil-in-water nanoemulsions, made specifically with omega-3 polyunsaturated fatty acids (PUFA)-rich edible oils to enhance BBB permeability, and incorporate curcumin (CUR) for down-regulation of membrane efflux transporters. Using saquinavir (SQV), a model HIV protease inhibitor, which is also a P-glycoprotein substrate, we will examine systemic delivery efficiency in the brain. Our preliminary studies show that SQV- containing flax-seed oil nanoemulsions can promote oral absorption and BBB permeability. In addition, magnetic resonance imaging (MRI) studies with gadolinium ion (Gd3+)-incorporated nanoemulsions also show contrast enhancement. The specific aims of the application are to: (1) prepare, characterize, and optimize CUR-containing flax- seed and fish oil nanoemulsions with Gd3+ ions for MRI and SQV for enhanced drug delivery efficiency, (2) in vitro evaluations of efflux transporter down-regulation with CUR, MRI contrast enhancement, and SQV permeability enhancement in BBB co-culture model, and (3) in vivo evaluations of drug delivery efficacy upon systemic administration of CUR/SQV nanoemulsion formulations and MRI studies in Balb/c mice. The proposed multifunctional nanoemulsion systems, made with the use of omega-3 fatty acids-rich oils for enhancing permeability and CUR for down-regulation of efflux transporters, will provide a novel platform for non-invasive systemic administration of hydrophobic therapeutic agents with low CNS bioavailability. The multifunctional nanoemulsion strategy can be extended beyond HIV/AIDS therapy to other infectious diseases, cancer, and neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: More than 98% of small molecules therapeutics discovered for the treatment of brain diseases cannot cross the blood-brain barrier (BBB) upon systemic administration. Additionally, in HIV/AIDS and other infections, the brain also acts as an effective sanctuary site for the virus to survive despite chronic anti-viral therapy. Since the BBB is both a physical and biological obstacle to drug transport, our strategy is to develop a delivery vehicle that can address both of these issues. We will formulate oil-in-water nanoemulsions specifically with oils rich in omega-3 polyunsaturated fatty acids to increase BBB penetration and use curcumin to reduce drug efflux. Studies to evaluate improvement in delivery efficiency in the brain will be carried out with saquinavir, an anti-HIV protease inhibitor as a model drug. Additionally, we will formulate the nanoemulsion with gadolinium ions for magnetic resonance imaging studies.

PROJECT NARRATIVE More than 98% of small molecules therapeutics discovered for the treatment of brain diseases cannot cross the blood-brain barrier (BBB) upon systemic administration. Additionally, in HIV/AIDS and other infections, the brain also acts as an effective sanctuary site for the virus to survive despite chronic anti-viral therapy. Since the BBB is both a physical and biological obstacle to drug transport, our strategy is to develop a delivery vehicle that can address both of these issues. We will formulate oil-in-water nanoemulsions specifically with oils rich in omega-3 polyunsaturated fatty acids to increase BBB penetration and use curcumin to reduce drug efflux. Studies to evaluate improvement in delivery efficiency in the brain will be carried out with saquinavir, an anti-HIV protease inhibitor as a model drug. Additionally, we will formulate the nanoemulsion with gadolinium ions for magnetic resonance imaging studies.