Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles

Tian Zhou, Hang Su, Prasanta Dash, Zhiyi Lin, Bhagya Laxmi Dyavar Shetty, Ted Kocher, Adam Szlachetka, Benjamin Lamberty, Howard S Fox, Larisa Y Poluektova, Santhi Gorantla, JoEllyn M McMillan, Nagsen Gautam, R Lee Mosley, Yazen Alnouti, Benson J Edagwa, Howard Eliot Gendelman

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)53-65
Number of pages13
JournalBiomaterials
Volume151
DOIs
StatePublished - Jan 2018

Fingerprint

Pharmacokinetics
Lymphocytes
Macrophages
Body fluids
Prodrugs
Drug delivery
Viruses
Nanoparticles
Crystals
Kinetics
HIV-1
Integrase Inhibitors
Pharmaceutical Preparations
Mononuclear Phagocyte System
SCID Mice
Intramuscular Injections
Body Fluids
Macaca mulatta
HIV Infections
Half-Life

Keywords

  • Cabotegravir
  • HIV-1
  • Long-acting
  • Nanoformulation
  • Prodrug

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials

Cite this

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 Y; Gorantla, Santhi; McMillan, JoEllyn M; Gautam, Nagsen; Mosley, R Lee; Alnouti, Yazen; Edagwa, Benson J; Gendelman, Howard Eliot.

In: Biomaterials, Vol. 151, 01.2018, p. 53-65.

Research output: Contribution to journalArticle

Zhou, Tian ; Su, Hang ; Dash, Prasanta ; Lin, Zhiyi ; Dyavar Shetty, Bhagya Laxmi ; Kocher, Ted ; Szlachetka, Adam ; Lamberty, Benjamin ; Fox, Howard S ; Poluektova, Larisa Y ; Gorantla, Santhi ; McMillan, JoEllyn M ; Gautam, Nagsen ; Mosley, R Lee ; Alnouti, Yazen ; Edagwa, Benson J ; Gendelman, Howard Eliot. / Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. In: Biomaterials. 2018 ; Vol. 151. pp. 53-65.
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