title: Macrophage folate receptor-targeted antiretroviral therapy facilitates drug entry, retention, antiretroviral activities and biodistribution for reduction of human immunodeficiency virus infections.
abstract: Macrophages serve as vehicles for the carriage and delivery of polymer-coated nanoformulated antiretroviral therapy (nanoART). Although superior to native drug, high drug concentrations are required for viral inhibition. Herein, folate-modified ritonavir-boosted atazanavir (ATV/r)-encased polymers facilitated macrophage receptor targeting for optimizing drug dosing. Folate coating of nanoART ATV/r significantly enhanced cell uptake, retention and antiretroviral activities without altering cell viability. Enhanced retentions of folate-coated nanoART within recycling endosomes provided a stable subcellular drug depot. Importantly, up to a five-fold enhanced plasma and tissue drug levels followed folate-coated formulation injection in mice. Folate polymer encased ATV/r improves nanoART pharmacokinetics bringing the technology one step closer to human use.
  
  
  BACKGROUND
  This team of authors describes a novel method for macrophage folate receptor-targeted antiretroviral therapy. Atazanvir entry, retention, and antiretroviral activities were superior using the presented method, and so was its biodistribution, enabling a more efficient way to address human immunodeficiency virus infections, with a hoped for clinical application in the near future.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA. Electronic address: pavan.puligujja@unmc.edu.
authors.forename: Pavan
authors.initials: P
authors.lastname: Puligujja
authors.forename: Joellyn
authors.initials: J
authors.lastname: McMillan
authors.forename: Lindsey
authors.initials: L
authors.lastname: Kendrick
authors.forename: Tianyuzi
authors.initials: T
authors.lastname: Li
authors.forename: Shantanu
authors.initials: S
authors.lastname: Balkundi
authors.forename: Nathan
authors.initials: N
authors.lastname: Smith
authors.forename: Ram S
authors.initials: RS
authors.lastname: Veerubhotla
authors.forename: Benson J
authors.initials: BJ
authors.lastname: Edagwa
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Kabanov
authors.forename: Tatiana
authors.initials: T
authors.lastname: Bronich
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Liu
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000069446:Atazanavir Sulfate; D002478:Cells, Cultured; D016503:Drug Delivery Systems; D058973:Folate Receptors, GPI-Anchored / Q000378:metabolism*; D005492:Folic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015658:HIV Infections / Q000188:drug therapy* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution
chemical_list: D019380:Anti-HIV Agents; D058973:Folate Receptors, GPI-Anchored; D009842:Oligopeptides; D011725:Pyridines; D000069446:Atazanavir Sulfate; D005492:Folic Acid
keywords: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; ATV; ATV/r; BSA; CHO; Chinese hamster ovary; FA; FOLR; Folate; Human immunodeficiency virus; LAMP; MDM; MTT; Macrophages; NanoART; PBS; PDI; PFA; Poloxamer 407; RME; RT; RTV; Targeted drug delivery; atazanavir; bovine serum albumin; folate receptor; folic acid; lysosomal associated membrane protein; monocyte-derived macrophages; nanoART; nanoformulated antiretroviral therapeutics; paraformaldehyde; phosphate buffered saline; polydispersity index; receptor-mediated endocytosis; reverse transcriptase; ritonavir; ritonavir-boosted atazanavir