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Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles.
Zhou, Tian; Su, Hang; Dash, Prasanta; Lin, Zhiyi; Dyavar Shetty, Bhagya Laxmi; Kocher, Ted; Szlachetka, Adam; Lamberty, Benjamin; Fox, Howard S; Poluektova, Larisa; Gorantla, Santhi; McMillan, JoEllyn; Gautam, Nagsen; Mosley, R Lee; Alnouti, Yazen; Edagwa, Benson; Gendelman, Howard E.
Afiliação
  • Zhou T; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Su H; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Dash P; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Lin Z; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Dyavar Shetty BL; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Kocher T; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Szlachetka A; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA; Nebraska Nanomedicine Production Plant, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Lamberty B; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Fox HS; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Poluektova L; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Gorantla S; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • McMillan J; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Gautam N; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Mosley RL; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Alnouti Y; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA.
  • Edagwa B; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: benson.edagwa@unmc.edu.
  • Gendelman HE; Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE 68198, USA; Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198, USA. Electronic address: hegendel@unmc.edu.
Biomaterials ; 151: 53-65, 2018 Jan.
Article em En | MEDLINE | ID: mdl-29059541
Long-acting parenteral (LAP) antiretroviral drugs have generated considerable interest for treatment and prevention of HIV-1 infection. One new LAP is cabotegravir (CAB), a highly potent integrase inhibitor, with a half-life of up to 54 days, allowing for every other month parenteral administrations. Despite this excellent profile, high volume dosing, injection site reactions and low body fluid drug concentrations affect broad use for virus infected and susceptible people. To improve the drug delivery profile, we created a myristoylated CAB prodrug (MCAB). MCAB formed crystals that were formulated into nanoparticles (NMCAB) of stable size and shape facilitating avid monocyte-macrophage entry, retention and reticuloendothelial system depot formulation. Drug release kinetics paralleled sustained protection against HIV-1 challenge. After a single 45 mg/kg intramuscular injection to BALB/cJ mice, the NMCAB pharmacokinetic profiles was 4-times greater than that recorded for CAB LAP. These observations paralleled replicate measurements in rhesus macaques. The results coupled with improved viral restriction in human adult lymphocyte reconstituted NOD/SCID/IL2Rγc-/- mice led us to conclude that NMCAB can improve biodistribution and viral clearance profiles upon current CAB LAP formulations.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridonas / Pró-Fármacos / HIV-1 / Fármacos Anti-HIV / Nanopartículas Limite: Adult / Animals / Humans / Male Idioma: En Revista: Biomaterials Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridonas / Pró-Fármacos / HIV-1 / Fármacos Anti-HIV / Nanopartículas Limite: Adult / Animals / Humans / Male Idioma: En Revista: Biomaterials Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos