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Synthesis and characterization of a long-acting emtricitabine prodrug nanoformulation

Authors Ibrahim IM, Bade AN, Lin Z, Soni D, Wojtkiewicz M, Dyavar Shetty BL, Gautam N, McMillan JM, Alnouti Y, Edagwa BJ, Gendelman HE

Received 12 May 2019

Accepted for publication 10 July 2019

Published 7 August 2019 Volume 2019:14 Pages 6231—6247


Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 2

Editor who approved publication: Dr Thomas J. Webster

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 Gendelman1,3

1Department 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, USA

Purpose: 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

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