Creation of a long-acting nanoformulated dolutegravir

Brady Sillman, Aditya N. Bade, Prasanta K. Dash, Biju Bhargavan, Ted Kocher, Saumi Mathews, Hang Su, Georgette D. Kanmogne, Larisa Y. Poluektova, Santhi Gorantla, JoEllyn McMillan, Nagsen Gautam, Yazen Alnouti, Benson Edagwa () and Howard E. Gendelman ()
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Brady Sillman: University of Nebraska Medical Center
Aditya N. Bade: University of Nebraska Medical Center
Prasanta K. Dash: University of Nebraska Medical Center
Biju Bhargavan: University of Nebraska Medical Center
Ted Kocher: University of Nebraska Medical Center
Saumi Mathews: University of Nebraska Medical Center
Hang Su: University of Nebraska Medical Center
Georgette D. Kanmogne: University of Nebraska Medical Center
Larisa Y. Poluektova: University of Nebraska Medical Center
Santhi Gorantla: University of Nebraska Medical Center
JoEllyn McMillan: University of Nebraska Medical Center
Nagsen Gautam: University of Nebraska Medical Center
Yazen Alnouti: University of Nebraska Medical Center
Benson Edagwa: University of Nebraska Medical Center
Howard E. Gendelman: University of Nebraska Medical Center

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Potent antiretroviral activities and a barrier to viral resistance characterize the human immunodeficiency virus type one (HIV-1) integrase strand transfer inhibitor dolutegravir (DTG). Herein, a long-acting parenteral DTG was created through chemical modification to improve treatment outcomes. A hydrophobic and lipophilic modified DTG prodrug is encapsulated into poloxamer nanoformulations (NMDTG) and characterized by size, shape, polydispersity, and stability. Retained intracytoplasmic NMDTG particles release drug from macrophages and attenuate viral replication and spread of virus to CD4+ T cells. Pharmacokinetic tests in Balb/cJ mice show blood DTG levels at, or above, its inhibitory concentration90 of 64 ng/mL for 56 days, and tissue DTG levels for 28 days. NMDTG protects humanized mice from parenteral challenge of the HIV-1ADA strain for two weeks. These results are a first step towards producing a long-acting DTG for human use by affecting drug apparent half-life, cell and tissue drug penetration, and antiretroviral potency.

Date: 2018
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DOI: 10.1038/s41467-018-02885-x

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