TY - JOUR
T1 - Transformation of tenofovir into stable ProTide nanocrystals with long-acting pharmacokinetic profiles
AU - Cobb, Denise A.
AU - Smith, Nathan
AU - Deodhar, Suyash
AU - Bade, Aditya N.
AU - Gautam, Nagsen
AU - Shetty, Bhagya Laxmi Dyavar
AU - McMillan, Jo Ellyn
AU - Alnouti, Yazen
AU - Cohen, Samuel M.
AU - Gendelman, Howard E.
AU - Edagwa, Benson
N1 - Funding Information:
We thank the University of Nebraska Medical Center (UNMC) cores for NMR (Ed Ezell), Elutriation and Cell Separation (Myhanh Che, Na Ly, and Li Wu), Electron Microscopy (Nicholas Conoan and Tom Bargar), Histology (Tissue Sciences Facility), MALDI/TOF Mass Spectrometry (Eric Troudt), compound purity by UPLC photodiode array detector (Brady Sillman), as well as Comparative Medicine for technical assistance and animal care. We also wish to thank Gilead Sciences Inc. for the supply of TAF. This research is 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, the Frances and Louie Blumkin Endowment, and the Harriet Singer Endowment; the Vice Chancellor’s Office of the University of Nebraska Medical Center for Core Facilities; Nickolus Badami Fellowship (to B.E.) and the National Institutes of Health grants 1R01AI145542-01A1, 1R56 AI138613-01A1, P01 DA028555, and P30 MH062261.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-25690-5
DO - 10.1038/s41467-021-25690-5
M3 - Article
C2 - 34531390
AN - SCOPUS:85115269360
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 5458
ER -