TY - JOUR
T1 - Creation of a long-acting nanoformulated dolutegravir
AU - Sillman, Brady
AU - Bade, Aditya N.
AU - Dash, Prasanta K.
AU - Bhargavan, Biju
AU - Kocher, Ted
AU - Mathews, Saumi
AU - Su, Hang
AU - Kanmogne, Georgette D.
AU - Poluektova, Larisa Y.
AU - Gorantla, Santhi
AU - McMillan, Joellyn
AU - Gautam, Nagsen
AU - Alnouti, Yazen
AU - Edagwa, Benson
AU - Gendelman, Howard E.
N1 - Funding Information:
We wish to thank the University of Nebraska Medical Center Cores: Electron Microscopy (Tom Bargar and Nicholas Conoan), Elutriation and Cell Separation (Myhanh Che and Na Ly), Flow Cytometry (Victoria Smith), and Comparative Medicine for technical assistance. We thank Dr. Shah Valloppilly of the University of Nebraska-Lincoln Nebraska Center for Materials and Nanoscience X-Ray Structural Characterization Facility for support in characterizing the modified antiretroviral drug(s) used in this study. Finally, we thank Bhagya Laxmi Dyavar Shetty, Celina Prince, and Sruthi Sra-vanam for technical assistance in drug level analysis, tissue sectioning, and immuno-histopathology. The research was supported by ViiV Healthcare; the University of Nebraska Foundation (donations from the Carol Swarts, M.D. Emerging Neuroscience Research Laboratory, the Margaret R. Larson Professorship, and the Frances and Louie Blumkin, and Harriet Singer Endowment); the Vice Chancellor for Research Office, University of Nebraska Medical Center, for core facility developments; and National Institutes of Health grants, P01 DA028555, R01 NS36126, P01 NS31492, 2R01 NS034239, P01 MH64570, 3P30 MH062261, P30 AI078498, 1R24 OD018546, and R01 AG043540.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-018-02885-x
DO - 10.1038/s41467-018-02885-x
M3 - Article
C2 - 29402886
AN - SCOPUS:85041667492
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 443
ER -