Functional Proteome of Macrophage Carried Nanoformulated
Antiretroviral Therapy Demonstrates Enhanced Particle Carrying Capacity
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Abstract
Our
laboratory developed long-acting nanoformulations of antiretroviral
therapy (nanoART) to improve drug compliance, reduce toxicities, and
facilitate access of drug to viral reservoirs. These all function
to inevitably improve treatment of human immunodeficiency virus (HIV)
infection. Formulations are designed to harness the carrying capacities
of mononuclear phagocytes (MP; monocytes and macrophages) and to use
these cells as Trojan horses for drug delivery. Such a drug distribution
system limits ART metabolism and excretion while facilitating access
to viral reservoirs. Our prior works demonstrated a high degree of
nanoART sequestration in macrophage recycling endosomes with broad
and sustained drug tissue biodistribution and depots with limited
untoward systemic toxicities. Despite such benefits, the effects of
particle carriage on the cells’ functional capacities remained
poorly understood. Thus, we employed pulsed stable isotope labeling
of amino acids in cell culture to elucidate the macrophage proteome
and assess any alterations in cellular functions that would affect
cell–drug carriage and release kinetics. NanoART-MP interactions
resulted in the induction of a broad range of activation-related proteins
that can enhance phagocytosis, secretory functions, and cell migration.
Notably, we now demonstrate that particle–cell interactions
serve to enhance drug loading while facilitating drug tissue depots
and transportation