Synthesis and Characterization of a Long-Acting Tenofovir ProTide Nanoformulation

Antiretroviral therapy (ART) has significantly improved the quality of life of Human Immunodeficiency Virus (HIV) patients; but adverse side effects and poor patient compliance to lifelong daily pills remain major challenges. To this end, the need for long acting (LA) therapies that can improve treatment adherence, positively affect drug resistance patterns in addition to limiting drug toxicities cannot be overstated. Tenofovir alafenamide (TAF), a nucleotide reverse transcriptase inhibitor of HIV infection and prodrug of tenofovir (TFV), is characterized by potent antiretroviral activities and high genetic barrier to viral resistance making it a suitable candidate for long-acting antiretroviral therapy. However, the inherent physicochemical features of TAF that includes high water solubility and susceptibility to degradation in aqueous buffers has limited its transformation into long-acting sustained release formulations. With these limitations in mind, this work sought to produce a stable TFV prodrug that would facilitate development of a long-acting formulation without compromising on TAF’s antiretroviral activity and safety profile. A lipophilic and hydrophobic prodrug of TFV (M1TFV) was therefore developed through chemical synthesis making it possible to formulate the drug as a stable aqueous nanosuspension to improve upon drug dissolution. The aqueous poloxamer stabilized TFV prodrug nanosuspension (NM1TFV) was characterized for physicochemical properties, chemical stability, cellular drug uptake and retention. The average particle size of the nanoparticles was 220-270 nm with a polydispersity index of