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

Denise A. Cobb, Nathan Smith, Suyash Deodhar, Aditya N. Bade, Nagsen Gautam, Bhagya Laxmi Dyavar Shetty, JoEllyn McMillan, Yazen Alnouti, Samuel M. Cohen, Howard E. Gendelman and Benson Edagwa ()
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Denise A. Cobb: University of Nebraska Medical Center
Nathan Smith: University of Nebraska Medical Center
Suyash Deodhar: University of Nebraska Medical Center
Aditya N. Bade: University of Nebraska Medical Center
Nagsen Gautam: University of Nebraska Medical Center
Bhagya Laxmi Dyavar Shetty: University of Nebraska Medical Center
JoEllyn McMillan: University of Nebraska Medical Center
Yazen Alnouti: University of Nebraska Medical Center
Samuel M. Cohen: University of Nebraska Medical Center
Howard E. Gendelman: University of Nebraska Medical Center
Benson Edagwa: University of Nebraska Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25690-5

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