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, Howard E. Gendelman

Research output: Contribution to journalArticle

32 Scopus citations

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 concentration of 64 ng/mL for 56 days, and tissue DTG levels for 28 days. NMDTG protects humanized mice from parenteral challenge of the HIV-1 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.

Original languageEnglish (US)
Article number443
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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