Transformation of tenofovir into stable ProTide nanocrystals with long-acting pharmacokinetic profiles.

Autor: Cobb DA; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA., Smith N; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA., Deodhar S; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA., Bade AN; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA., Gautam N; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA., Shetty BLD; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA., McMillan J; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA., Alnouti Y; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA., Cohen SM; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA., Gendelman HE; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA., Edagwa B; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA. benson.edagwa@unmc.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Sep 16; Vol. 12 (1), pp. 5458. Date of Electronic Publication: 2021 Sep 16.
DOI: 10.1038/s41467-021-25690-5
Abstrakt: Treatment and prevention of human immunodeficiency virus type one (HIV-1) infection was transformed through widespread use of antiretroviral therapy (ART). However, ART has limitations in requiring life-long daily adherence. Such limitations have led to the creation of long-acting (LA) ART. While nucleoside reverse transcriptase inhibitors (NRTI) remain the ART backbone, to the best of our knowledge, none have been converted into LA agents. To these ends, we transformed tenofovir (TFV) into LA surfactant stabilized aqueous prodrug nanocrystals (referred to as NM1TFV and NM2TFV), enhancing intracellular drug uptake and retention. A single intramuscular injection of NM1TFV, NM2TFV, or a nanoformulated tenofovir alafenamide (NTAF) at 75 mg/kg TFV equivalents to Sprague Dawley rats sustains active TFV-diphosphate (TFV-DP) levels ≥ four times the 90% effective dose for two months. NM1TFV, NM2TFV and NTAF elicit TFV-DP levels of 11,276, 1,651, and 397 fmol/g in rectal tissue, respectively. These results are a significant step towards a LA TFV ProTide.
(© 2021. The Author(s).)
Databáze: MEDLINE
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