Modulating cellular autophagy for controlled antiretroviral drug release

Aim: To evaluate pharmacologic modulators of autophagy for their ability to enhance the formation and sustained release of macrophage-based nanoformulated antiretroviral (ARV) drug depots.
Methods: Human monocyte-derived macrophages were treated with nanoformulated atazanavir (ATV) in combination with one of the following agents: URMC-099, rapamycin, metformin, desmethylclomipramine, 2-hydroxy-β-cyclodextrin (HBC), or clonidine. ARV retention, antiviral activity, and nanocrystal-associated autophagosome formation were assessed.
Results: URMC-099, HBC, and clonidine enhanced ATV retention, with URMC-099, HBC, and rapamycin showing the greatest improvement in intracellular ATV levels. URMC-099 demonstrated the most significant enhancement of antiretroviral efficacy.
Conclusion: Autophagy-inducing agents—particularly URMC-099—promote the formation of nanoformulated ARV depots and support sustained drug release, leading to improved antiretroviral responses. These agents hold promise for inclusion in long-acting ARV treatment strategies.