Modulating cellular autophagy for controlled antiretroviral drug release

Area of Science:

• Pharmacology
• Nanotechnology
• Immunology

Background:

• Developing long-acting antiretroviral (ARV) drug delivery systems is crucial for improving patient adherence and treatment outcomes.
• Macrophage-based drug depots offer a promising strategy for sustained ARV release.
• Modulating cellular processes like autophagy may enhance the efficacy of nanoformulated ARVs.

Purpose of the Study:

• To investigate the potential of pharmacologic agents that modulate autophagy to enhance nanoformulated antiretroviral drug (ARV) depots.
• To evaluate the impact of these agents on ARV retention, antiretroviral activity, and autophagosomal formation within macrophages.

Main Methods:

• Human monocyte-derived macrophages were treated with nanoformulated atazanavir (ATV) nanoparticles.
• Several autophagy-affecting agents, including URMC-099, rapamycin, metformin, desmethylclomipramine, 2-hydroxy-β-cyclodextrin (HBC), and clonidine, were administered.
• ARV retention, antiretroviral activity, and autophagosomal formation were assessed.

Main Results:

• URMC-099, HBC, and clonidine demonstrated the ability to retain atazanavir (ATV).
• HBC, URMC-099, and rapamycin enhanced intracellular ATV retention.
• URMC-099 exhibited superior performance in improving antiretroviral activities.

Conclusions:

• Autophagy-inducing agents, particularly URMC-099, can facilitate the development of nanoformulated ARV depots.
• These agents promote sustained drug release and enhance antiretroviral responses.
• Autophagy modulators show potential for integration into long-acting antiretroviral therapy regimens.