mp9b00871_si_001.pdf (2.01 MB)
Synthesis and Characterization of Long-Acting Darunavir Prodrugs
journal contribution
posted on 2019-12-02, 23:44 authored by Mary G. Banoub, Aditya N. Bade, Zhiyi Lin, Denise Cobb, Nagsen Gautam, Bhagya Laxmi Dyavar Shetty, Melinda Wojtkiewicz, Yazen Alnouti, JoEllyn McMillan, Howard E. Gendelman, Benson EdagwaAntiretroviral therapy (ART) has improved the quality
of life in
patients infected with HIV-1. However, complete viral suppression
within anatomical compartments remains unattainable. This is complicated
by adverse side effects and poor adherence to lifelong therapy leading
to the emergence of viral drug resistance. Thus, there is an immediate
need for cellular and tissue-targeted long-acting (LA) ART formulations.
Herein, we describe two LA prodrug formulations of darunavir (DRV),
a potent antiretroviral protease inhibitor. Two classes of DRV prodrugs,
M1DRV and M2DRV, were synthesized as lipophilic and hydrophobic prodrugs
and stabilized into aqueous suspensions designated NM1DRV and NM2DRV.
The formulations demonstrated enhanced intracellular prodrug levels
with sustained drug retention and antiretroviral activities for 15
and 30 days compared to native DRV formulation in human monocyte-derived
macrophages. Pharmacokinetics tests of NM1DRV and NM2DRV administered
to mice demonstrated sustained drug levels in blood and tissues for
30 days. These data, taken together, support the idea that LA DRV
with sustained antiretroviral responses through prodrug nanoformulations
is achievable.