title: Pharmacodynamics of long-acting folic acid-receptor targeted ritonavir-boosted atazanavir nanoformulations.
abstract: Long-acting nanoformulated antiretroviral therapy (nanoART) that targets monocyte-macrophages could improve the drug's half-life and protein-binding capacities while facilitating cell and tissue depots. To this end, ART nanoparticles that target the folic acid (FA) receptor and permit cell-based drug depots were examined using pharmacokinetic and pharmacodynamic (PD) tests. FA receptor-targeted poloxamer 407 nanocrystals, containing ritonavir-boosted atazanavir (ATV/r), significantly increased drug bioavailability and PD by five and 100 times, respectively. Drug particles administered to human peripheral blood lymphocyte reconstituted NOD.Cg-Prkdc(scid)Il2rg(tm1Wjl)/SzJ mice and infected with HIV-1ADA led to ATV/r drug concentrations that paralleled FA receptor beta staining in both the macrophage-rich parafollicular areas of spleen and lymph nodes. Drug levels were higher in these tissues than what could be achieved by either native drug or untargeted nanoART particles. The data also mirrored potent reductions in viral loads, tissue viral RNA and numbers of HIV-1p24+ cells in infected and treated animals. We conclude that FA-P407 coating of ART nanoparticles readily facilitates drug carriage and antiretroviral responses.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: Pavan
authors.initials: P
authors.lastname: Puligujja
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA; Kansas University Innovation and Collaboration, Lawrence, KS 66045, USA.
authors.forename: Shantanu S
authors.initials: SS
authors.lastname: Balkundi
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: Lindsey M
authors.initials: LM
authors.lastname: Kendrick
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: Hannah M
authors.initials: HM
authors.lastname: Baldridge
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Hilaire
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: Aditya N
authors.initials: AN
authors.lastname: Bade
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: Prasanta K
authors.initials: PK
authors.lastname: Dash
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: Larisa Y
authors.initials: LY
authors.lastname: Poluektova
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: Santhi
authors.initials: S
authors.lastname: Gorantla
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: Xin-Ming
authors.initials: XM
authors.lastname: Liu
authors.affiliation: Protein Interactions Group, Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA; Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, Shanghai Medical College and Institute of Medical Microbiology, Fudan University, Shanghai 200032, China.
authors.forename: Tianlei
authors.initials: T
authors.lastname: Ying
authors.affiliation: Protein Interactions Group, Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Protein Interactions Group, Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Protein Interactions Group, Laboratory of Experimental Immunology, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Dimiter S
authors.initials: DS
authors.lastname: Dimitrov
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA.
authors.forename: JoEllyn M
authors.initials: JM
authors.lastname: McMillan
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA. Electronic address: hegendel@unmc.edu.
authors.forename: Howard E
authors.initials: HE
authors.lastname: Gendelman
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism; D000069446:Atazanavir Sulfate; D002626:Chemistry, Pharmaceutical; D005434:Flow Cytometry; D058975:Folate Receptor 1 / Q000378:metabolism*; D016655:HIV Core Protein p24 / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D053758:Nanoparticles / Q000737:chemistry*; D009842:Oligopeptides / Q000493:pharmacokinetics / Q000494:pharmacology*; D020442:Poloxamer / Q000737:chemistry; D011725:Pyridines / Q000493:pharmacokinetics / Q000494:pharmacology*; D019438:Ritonavir / Q000493:pharmacokinetics / Q000494:pharmacology*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D044966:Anti-Retroviral Agents; D015703:Antigens, CD; D058975:Folate Receptor 1; D016655:HIV Core Protein p24; D009842:Oligopeptides; D011725:Pyridines; C514799:p24 protein, Human Immunodeficiency Virus Type 1; D020442:Poloxamer; D000069446:Atazanavir Sulfate; D019438:Ritonavir
keywords: Folic acid receptor; Human immunodeficiency virus type one; Long-acting nanoformulated antiretroviral therapy; Non-obese diabetic severe combined immunodeficient mice; Pharmacodynamics; Pharmacokinetics