title: Functional proteome of macrophage carried nanoformulated antiretroviral therapy demonstrates enhanced particle carrying capacity.
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.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198-5880, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Martinez-Skinner
authors.forename: Ram S
authors.initials: RS
authors.lastname: Veerubhotla
authors.forename: Han
authors.initials: H
authors.lastname: Liu
authors.forename: Huangui
authors.initials: H
authors.lastname: Xiong
authors.forename: Fang
authors.initials: F
authors.lastname: Yu
authors.forename: JoEllyn M
authors.initials: JM
authors.lastname: McMillan
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D000480:Alkynes; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D000069446:Atazanavir Sulfate; D048588:Benzoxazines / Q000737:chemistry / Q000494:pharmacology; D002465:Cell Movement; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D003521:Cyclopropanes; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000494:pharmacology*; D004339:Drug Compounding; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D053758:Nanoparticles / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010316:Particle Size; D010587:Phagocytosis / Q000187:drug effects; D015221:Potassium Channels / Q000378:metabolism; D020543:Proteome / Q000378:metabolism*; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D019438:Ritonavir / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D018925:Chemokines; D003521:Cyclopropanes; D003598:Cytoskeletal Proteins; D004337:Drug Carriers; D009842:Oligopeptides; D015221:Potassium Channels; D020543:Proteome; D011725:Pyridines; D000069446:Atazanavir Sulfate; C098320:efavirenz; D019438:Ritonavir
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