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Principal Investigator: Abhijit A Date
Organization: UNIVERSITY OF ARIZONA
Fiscal Year: 2024
Award: $206,452
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Tenofovir prodrugs, tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) are
cornerstones of the first-line therapy in HIV/AIDS patients and there are at least 15 FDA-approved antiretroviral
products that contain either TDF or TAF. However, due to their hydrophilic nature, low permeability, and
premature hydrolysis or activation, TDF and TAF both have a considerably low oral bioavailability of 25% and
40% respectively. Given that these drugs need to be administered for the lifetime of HIV patients, strategies to
improve oral bioavailability leading to optimal drug utilization and reduced therapeutic dose need to be
developed. Transformation of ionizable, highly hydrophilic or hydrophobic drugs into ionic liquids (ILs), low-
melting organic salts with a melting point < 100°C, has emerged as a novel and pharmaceutically viable approach
to improving pharmaceutical processability, solubility, permeability, and oral bioavailability of drugs. Our
preliminary data show that it is possible to transform ionizable hydrophobic drugs such as anthelmintic
benzimidazoles, and hydrophilic ionizable drugs such as metformin hydrochloride into low-melting ILs using
pharmaceutically acceptable fatty anion such as sodium docusate. Our preliminary further show that the
developed ILs can be efficiently packaged into polymeric nanomicelles further leading to improved oral delivery
and in vivo efficacy. Hence, we hypothesize that the transformation of TDF and TAF into amphiphilic ionic
liquids (ILs) using generally regarded as safe (GRAS) fatty permeation enhancers and their subsequent
incorporation into polymeric nanomicelles will improve oral bioavailability and in vivo antiviral efficacy. Our
preliminary data show that TDF and TAF can be rapidly and efficiently converted to amphiphilic ILs using GRAS
fatty permeation enhancers such as decanoic acid, undecylenic acid, oleic acid, and salcaprozic acid. Aim 1 will
focus on the development, characterization, and pharmacokinetic evaluation of polymeric nanomicelles
containing TDF-ILs or TAF ILs. Aim 2 will focus on the in vivo antiviral efficacy evaluation of oral polymeric
nanomicelles containing TDF IL in humanized BLT mouse model of HIV infection compared to pure TDF or TAF
to establish the proof of concept. The successful completion of this proposal is expected to lead to the
development of clinically viable pharmaceutical formulations containing ILs of tenofovir prodrugs to achieve
effective long-term management of HIV infection.
Terms: <9-Octadecenoic Acid><ABC20><ABCB1><ABCB1 gene><AIDS Virus><AIDS/HIV><Acids><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Alimentary Canal><Anions><Anthelmintics><Anti-Retroviral Agents><Antihelminthic Agent><Antihelminthic Drugs><BLT humanized mice><BLT humanized mouse><BLT mice><BLT mouse><Bioavailability><Biodistribution><Biological Availability><Body Tissues><Brain><Brain Nervous System><Cations><Chronic Hepatitis B><Clinical><Cost Savings><Cryptococcosis><Data><Developed Countries><Development><Digestive Tract><Dimethylbiguanidine><Dimethylguanylguanidine><Diphosphates><Dose><Drug Kinetics><Drug Precursors><Drug Utilization><Drugs><Electrostatics><Encapsulated><Encephalon><Enhancers><Evaluation><FDA approved><Formulation><Fumarates><GI Tract><GP170><Gastrointestinal Tract><Gastrointestinal tract structure><Goals><HBV therapy><HBV treatment><HIV><HIV Infections><HIV-1><HIV-I><HIV/AIDS><HIV1><HPLC><HTLV-III Infections><HTLV-III-LAV Infections><Hepatitis B Therapeutic><Hepatitis B Therapy><Hepatitis B Treatment><High Performance Liquid Chromatography><High Pressure Liquid Chromatography><High Speed Liquid Chromatography><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Human immunodeficiency virus 1><Hydrolysis><Hydrophobicity><In vivo analysis><Industrialized Countries><Industrialized Nations><Infection><LAV-HTLV-III><LMIC><Liquid substance><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic nodes><MDR-1><MDR1><MDR1 Protein><Mediating><Medication><Metabolic><Metformin><Methods><Mice><Mice Mammals><Modeling><Multidrug Resistance 1><Multidrug Resistance Gene-1><Multidrug Resistance Gene-1s><Multidrug Resistance Proteins><Multidrug Resistant Proteins><Murine><Mus><N,N-dimethyl-imidodicarbonimidic diamide><Na element><Nature><Oleic Acids><Oral><Oral Administration><Oral Drug Administration><P-GP><P-Glycoprotein><P-Glycoprotein 1 Gene><PGY-1 Protein><PGY1><Patients><Permeability><Persons><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Physiologic Availability><Play><Polymers><PrEP><Predisposition><Pro-Drugs><Prodrugs><Pyrophosphates><Research><Role><Salts><Sodium><Solubility><Spinal Column><Spine><Susceptibility><Temperature><Tenofovir><Testing><Therapeutic><Time><Tissues><Torulosis><Treatment Cost><Vagina><Vermifuges><Vertebral column><Viral Activity><Viral Function><Viral Physiology><Viread><Virus-HIV><alimentary tract><amphiphilicity><anti-retroviral><anti-viral efficacy><antihelminthic><antiretroviral therapy><antiretroviral treatment><aqueous><backbone><benzimidazole><biodegradable polymer><bioresorbable polymer><bone marrow liver and thymus mice><bone marrow liver and thymus mouse><bone marrow liver and thymus transplanted mice><bone marrow liver and thymus transplanted mouse><chemical stability><chronic HBV infection><chronic hepatitis B virus infection><cis-9-Octadecenoic Acid><clinical development><degradable polymer><determine efficacy><developed country><developed nation><developed nations><developmental><digestive canal><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy testing><evaluate efficacy><examine efficacy><fluid><hydrophilicity><improved><improved outcome><in vivo><in vivo evaluation><in vivo testing><inter-individual variability><inter-individual variation><interindividual variability><interindividual variation><intraoral drug delivery><liquid><low and middle-income countries><lymph gland><lymph nodes><lymphnodes><melting><mouse model><murine model><nano polymer><nanomicelles><nanopolymer><new approaches><novel><novel approaches><novel strategies><novel strategy><pharmaceutical><polymer><polymeric><pre-exposure prophylaxis><premature><prematurity><social role>