title: Quantitative magnetic resonance and SPECT imaging for macrophage tissue migration and nanoformulated drug delivery.
abstract: We posit that the same mononuclear phagocytes (MP) [bone marrow (BM) and blood monocytes, tissue macrophages, microglia, and dendritic cells] which serve as targets, reservoirs, and vehicles for HIV dissemination, can be used as vehicles for antiretroviral therapy (ART). Toward this end, BM macrophages (BMM) were used as carriers for nanoparticle-formulated indinavir (NP-IDV), and the cell distribution was monitored by single photon emission computed tomography (SPECT), transverse relation time (T2)* weighted magnetic resonance imaging (MRI), histology, and gamma-scintillation spectrometry. BMM labeled with super paramagnetic iron oxide and/or 111indium oxine were infused i.v. into naïve mice. During the first 7 h, greater than 86% of cell label was recorded within the lungs. On Days 1, 3, 5, and 7, less than 10% of BMM were in lungs, and 74-81% and 13-18% were in liver and spleen, respectively. On a tissue volume basis, as determined by SPECT and MRI, BMM densities in spleen and liver were significantly greater than other tissues. Migration into the lymph nodes on Days 1 and 7 accounted for 1.5-2% of the total BMM. Adoptive transfer of BMM loaded with NP-IDV produced drug levels in lymphoid and nonlymphoid tissues that exceeded reported therapeutic concentrations by 200- to 350-fold on Day 1 and remained in excess of 100- to 300-fold on Day 14. These data show real-time kinetics and destinations of macrophage trafficking and demonstrate the feasibility of monitoring macrophage-based, nanoformulated ART.
authors.affiliation: Center for Neurovirology and Neurodegenerative Disorders, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: Santhi
authors.initials: S
authors.lastname: Gorantla
authors.forename: Huanyu
authors.initials: H
authors.lastname: Dou
authors.forename: Michael
authors.initials: M
authors.lastname: Boska
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Destache
authors.forename: Jay
authors.initials: J
authors.lastname: Nelson
authors.forename: Larisa
authors.initials: L
authors.lastname: Poluektova
authors.forename: Barett E
authors.initials: BE
authors.lastname: Rabinow
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
authors.forename: R Lee
authors.initials: RL
authors.lastname: Mosley
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001853:Bone Marrow / Q000737:chemistry; D002465:Cell Movement / Q000502:physiology; D003911:Dextrans; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005240:Feasibility Studies; D052203:Ferrosoferric Oxide; D019469:Indinavir / Q000737:chemistry* / Q000493:pharmacokinetics; D007205:Indium Radioisotopes; D007501:Iron / Q000493:pharmacokinetics; D008264:Macrophages / Q000187:drug effects / Q000502:physiology* / Q000637:transplantation; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000737:chemistry*; D009942:Organometallic Compounds / Q000493:pharmacokinetics; D010087:Oxides / Q000493:pharmacokinetics; D015125:Oxyquinoline / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D003911:Dextrans; D004337:Drug Carriers; D007205:Indium Radioisotopes; D058185:Magnetite Nanoparticles; D009942:Organometallic Compounds; D010087:Oxides; C032950:indium oxine; D015125:Oxyquinoline; D019469:Indinavir; D007501:Iron; C065507:ferumoxides; D052203:Ferrosoferric Oxide