TY - JOUR
T1 - Synthesis and characterization of a long-acting emtricitabine prodrug nanoformulation
AU - Ibrahim, Ibrahim M.
AU - Bade, Aditya N.
AU - Lin, Zhiyi
AU - Soni, Dhruvkumar
AU - Wojtkiewicz, Melinda
AU - Shetty, Bhagya Laxmi Dyavar
AU - Gautam, Nagsen
AU - McMillan, Joellyn M.
AU - Alnouti, Yazen
AU - Edagwa, Benson J.
AU - Gendelman, Howard E.
N1 - Funding Information:
This research was supported by the University of Nebraska Foundation, which includes donations from the Carol Swarts, M.D. Emerging Neuroscience Research Laboratory, the Margaret R. Larson Professorship, and the Frances, and Louie Blumkin, and Harriet Singer Endowment, the Vice Chancellor’s Office of the University of Nebraska Medical Center for Core Facility Developments, and National Institutes of Health grants R01 MH104147, P01 DA028555, R01 NS36126, P01 NS31492, 2R01 NS034239, P01 MH64570, P30 MH062261, P30 AI078498, R01 AG043540 and 1 R56 AI138613-01A1.
Publisher Copyright:
© 2019 Ibrahim et al.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - Human immunodeficiency virus type 1
KW - Long-acting antiretrovirals
KW - Monocyte-derived macrophage
KW - Palmitoyl chloride
KW - Viral reservoirs
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U2 - 10.2147/IJN.S215447
DO - 10.2147/IJN.S215447
M3 - Article
C2 - 31496683
AN - SCOPUS:85071184831
VL - 14
SP - 6231
EP - 6247
JO - International Journal of Nanomedicine
JF - International Journal of Nanomedicine
SN - 1176-9114
ER -