PROJECT SUMMARYTenofovir prodrugs tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide fumarate (TAF) arecornerstones of the first-line therapy in HIV/AIDS patients and there are at least 15 FDA-approved antiretroviralproducts that contain either TDF or TAF. However due to their hydrophilic nature low permeability andpremature hydrolysis or activation TDF and TAF both have a considerably low oral bioavailability of 25% and40% respectively. Given that these drugs need to be administered for the lifetime of HIV patients strategies toimprove oral bioavailability leading to optimal drug utilization and reduced therapeutic dose need to bedeveloped. Transformation of ionizable highly hydrophilic or hydrophobic drugs into ionic liquids (ILs) low-melting organic salts with a melting point < 100C has emerged as a novel and pharmaceutically viable approachto improving pharmaceutical processability solubility permeability and oral bioavailability of drugs. Ourpreliminary data show that it is possible to transform ionizable hydrophobic drugs such as anthelminticbenzimidazoles and hydrophilic ionizable drugs such as metformin hydrochloride into low-melting ILs usingpharmaceutically acceptable fatty anion such as sodium docusate. Our preliminary further show that thedeveloped ILs can be efficiently packaged into polymeric nanomicelles further leading to improved oral deliveryand in vivo efficacy. Hence we hypothesize that the transformation of TDF and TAF into amphiphilic ionicliquids (ILs) using generally regarded as safe (GRAS) fatty permeation enhancers and their subsequentincorporation into polymeric nanomicelles will improve oral bioavailability and in vivo antiviral efficacy. Ourpreliminary data show that TDF and TAF can be rapidly and efficiently converted to amphiphilic ILs using GRASfatty permeation enhancers such as decanoic acid undecylenic acid oleic acid and salcaprozic acid. Aim 1 willfocus on the development characterization and pharmacokinetic evaluation of polymeric nanomicellescontaining TDF-ILs or TAF ILs. Aim 2 will focus on the in vivo antiviral efficacy evaluation of oral polymericnanomicelles containing TDF IL in humanized BLT mouse model of HIV infection compared to pure TDF or TAFto establish the proof of concept. The successful completion of this proposal is expected to lead to thedevelopment of clinically viable pharmaceutical formulations containing ILs of tenofovir prodrugs to achieveeffective long-term management of HIV infection.