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Ibrahim M Ibrahim,1,2 Aditya N Bade,1 Zhiyi Lin,3 Dhruvkumar Soni,3 Melinda Wojtkiewicz,1 Bhagya Laxmi Dyavar Shetty,1 Nagsen Gautam,3 JoEllyn M McMillan,1 Yazen Alnouti,3 Benson J Edagwa,1 Howard E Gendelman1,31Department of Pharmacology and Experimental Neuroscience, College of Medicine, University of Nebraska Medical Center, Omaha, NE, USA; 2Department of Pharmacology, College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; 3Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USAPurpose: A palmitoylated prodrug of emtricitabine (FTC) was synthesized to extend the drug’s half-life, antiretroviral activities and biodistribution.Methods: A modified FTC prodrug (MFTC) was synthesized by palmitoyl chloride esterification. MFTC’s chemical structure was evaluated by nuclear magnetic resonance. The created hydrophobic prodrug nanocrystals were encased into a poloxamer surfactant and the pharmacokinetics (PK), biodistribution and antiretroviral activities of the nanoformulation (NMFTC) were assessed. The conversion of MFTC to FTC triphosphates was evaluated.Results: MFTC coated with poloxamer formed stable nanocrystals (NMFTC). NMFTC demonstrated an average particle size, polydispersity index and zeta potential of 350 nm, 0.24 and −20 mV, respectively. Drug encapsulation efficiency was 90%. NMFTC was readily taken up by human monocyte-derived macrophages yielding readily detected intracellular FTC triphosphates and an extended PK profile.Conclusion: NMFTC shows improved antiretroviral activities over native FTC. This is coordinate with its extended apparent half-life. The work represents an incremental advance in the development of a long-acting FTC formulation.Keywords: palmitoyl chloride, viral reservoirs, long-acting antiretrovirals, human immunodeficiency virus type 1, monocyte-derived macrophage