title: Development of a macrophage-based nanoparticle platform for antiretroviral drug delivery.
abstract: Complex dosing regimens, costs, side effects, biodistribution limitations, and variable drug pharmacokinetic patterns have affected the long-term efficacy of antiretroviral medicines. To address these problems, a nanoparticle indinavir (NP-IDV) formulation packaged into carrier bone marrow-derived macrophages (BMMs) was developed. Drug distribution and disease outcomes were assessed in immune-competent and human immunodeficiency virus type 1 (HIV-1)-infected humanized immune-deficient mice, respectively. In the former, NP-IDV formulation contained within BMMs was adoptively transferred. After a single administration, single-photon emission computed tomography, histology, and reverse-phase-high-performance liquid chromatography (RP-HPLC) demonstrated robust lung, liver, and spleen BMMs and drug distribution. Tissue and sera IDV levels were greater than or equal to 50 microM for 2 weeks. NP-IDV-BMMs administered to HIV-1-challenged humanized mice revealed reduced numbers of virus-infected cells in plasma, lymph nodes, spleen, liver, and lung, as well as, CD4(+) T-cell protection. We conclude that a single dose of NP-IDV, using BMMs as a carrier, is effective and warrants consideration for human testing.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, Center for Neurovirology and Neurodegenerative Disorder, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: Huanyu
authors.initials: H
authors.lastname: Dou
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Destache
authors.forename: Justin R
authors.initials: JR
authors.lastname: Morehead
authors.forename: R Lee
authors.initials: RL
authors.lastname: Mosley
authors.forename: Michael D
authors.initials: MD
authors.lastname: Boska
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Kingsley
authors.forename: Santhi
authors.initials: S
authors.lastname: Gorantla
authors.forename: Larisa
authors.initials: L
authors.lastname: Poluektova
authors.forename: Jay A
authors.initials: JA
authors.lastname: Nelson
authors.forename: Mahesh
authors.initials: M
authors.lastname: Chaubal
authors.forename: Jane
authors.initials: J
authors.lastname: Werling
authors.forename: James
authors.initials: J
authors.lastname: Kipp
authors.forename: Barrett E
authors.initials: BE
authors.lastname: Rabinow
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D015497:HIV-1; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D008264:Macrophages / Q000378:metabolism* / Q000637:transplantation / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008855:Microscopy, Electron, Scanning; D049329:Nanostructures; D036103:Nanotechnology; D014018:Tissue Distribution
chemical_list: D017320:HIV Protease Inhibitors; D019469:Indinavir