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 Poluektova; Santhi Gorantla; Jo Ellyn McMillan; Nagsen Gautam; R. Lee Mosley; Yazen Alnouti; Benson Edagwa; Howard E. Gendelman

doi:10.1016/j.biomaterials.2017.10.023

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 Poluektova, Santhi Gorantla, Jo Ellyn McMillan, Nagsen Gautam, R. Lee Mosley, Yazen Alnouti, Benson Edagwa, Howard E. Gendelman

Research output: Contribution to journal › Article › peer-review

74 Scopus citations

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 language	English (US)
Pages (from-to)	53-65
Number of pages	13
Journal	Biomaterials
Volume	151
DOIs	https://doi.org/10.1016/j.biomaterials.2017.10.023
State	Published - Jan 2018

Keywords

Cabotegravir
HIV-1
Long-acting
Nanoformulation
Prodrug

ASJC Scopus subject areas

Mechanics of Materials
Ceramics and Composites
Bioengineering
Biophysics
Biomaterials

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10.1016/j.biomaterials.2017.10.023

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Zhou, T., Su, H., Dash, P., Lin, Z., Dyavar Shetty, B. L., Kocher, T., Szlachetka, A., Lamberty, B., Fox, H. S., Poluektova, L., Gorantla, S., McMillan, J. E., Gautam, N., Mosley, R. L., Alnouti, Y., Edagwa, B., & Gendelman, H. E. (2018). Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles. Biomaterials, 151, 53-65. https://doi.org/10.1016/j.biomaterials.2017.10.023

Zhou, T, Su, H, Dash, P, Lin, Z, Dyavar Shetty, BL, Kocher, T, Szlachetka, A, Lamberty, B, Fox, HS , Poluektova, L , Gorantla, S , McMillan, JE, Gautam, N, Mosley, RL , Alnouti, Y , Edagwa, B & Gendelman, HE 2018, 'Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles', Biomaterials, vol. 151, pp. 53-65. https://doi.org/10.1016/j.biomaterials.2017.10.023

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title = "Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles",

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.",

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doi = "10.1016/j.biomaterials.2017.10.023",

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AU - Zhou, Tian

AU - Su, Hang

AU - Dash, Prasanta

AU - Lin, Zhiyi

AU - Dyavar Shetty, Bhagya Laxmi

AU - Kocher, Ted

AU - Szlachetka, Adam

AU - Lamberty, Benjamin

AU - Fox, Howard S.

AU - Poluektova, Larisa

AU - Gorantla, Santhi

AU - McMillan, Jo Ellyn

AU - Gautam, Nagsen

AU - Mosley, R. Lee

AU - Alnouti, Yazen

AU - Edagwa, Benson

AU - Gendelman, Howard E.

PY - 2018/1

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AB - 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.

KW - Cabotegravir

KW - HIV-1

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KW - Nanoformulation

KW - Prodrug

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JO - Biomaterials

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ER -

Creation of a nanoformulated cabotegravir prodrug with improved antiretroviral profiles

Abstract

Keywords

ASJC Scopus subject areas

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