Creation of a long-acting nanoformulated dolutegravir

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 hy...

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Vydáno v:	Nature communications Ročník 9; číslo 1; s. 443 - 14
Hlavní autoři:	Sillman, Brady, Bade, Aditya N., Dash, Prasanta K., Bhargavan, Biju, Kocher, Ted, Mathews, Saumi, Su, Hang, Kanmogne, Georgette D., Poluektova, Larisa Y., Gorantla, Santhi, McMillan, JoEllyn, Gautam, Nagsen, Alnouti, Yazen, Edagwa, Benson, Gendelman, Howard E.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 06.02.2018 Nature Publishing Group Nature Portfolio
Témata:	13/106 140/131 147/135 147/143 45/77 631/154/152 631/154/436/1729 631/154/436/2388 631/250/255/1901 631/92/2783 64/60 Animals Antiretroviral agents Antiretroviral drugs CD4 antigen Chemical modification Disease resistance Drug Delivery Systems Drug Evaluation, Preclinical Heterocyclic Compounds, 3-Ring - administration & dosage Heterocyclic Compounds, 3-Ring - pharmacokinetics HIV HIV Infections - drug therapy HIV Integrase Inhibitors - administration & dosage HIV Integrase Inhibitors - pharmacokinetics Human immunodeficiency virus Humanities and Social Sciences Humans Hydrophobicity Integrase Lipophilic Lymphocytes Lymphocytes T Macrophages Male Mice Mice, Inbred BALB C multidisciplinary Myristic Acid - chemistry Nanoparticles - chemistry Oxazines Pharmacokinetics Pharmacology Piperazines Polydispersity Pyridones Science Science (multidisciplinary) Viruses
ISSN:	2041-1723, 2041-1723
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Popis
Shrnutí:	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 90 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 ADA 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. Current ART for treatment of HIV-1 infection requires a strict daily regimen adherence. Herein, the authors report the manufacture and characterization of a nanoformulated dolutegravir prodrug with improved cell and tissue penetration, a remarkable apparent half-life and the potential for bimonthly drug administration.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-018-02885-x