Creation of a long-acting nanoformulated dolutegravir
Open accessAbstract
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.
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In rhesus macaques, prodrug nanoparticles maintained therapeutic concentrations of dolutegravir for ~40 days and extended the half-life of dolutegravir to ~19.5 days.
“In rhesus macaques, prodrug nanoparticles maintained therapeutic concentrations of dolutegravir for ~40 days and extended the half-life of dolutegravir to ~19.5 days.”
From Nanotechnology approaches for global infectious diseases (2021) · cites this paper as [94]
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References 68 · Cited by 125
Research works printed but not linked: 2
- [53]Grobler, J. et al. Long-acting oral and parenteral dosing of MK-8591 for HIV treatment or prophylaxis. in Conference on Retroviruses and Opportunistic Infections (Boston, Massachusetts, 2016).
- [54]Chua, C. X. et al. Transcutaneous refillable nanofluidic implant for constant delivery of HIV PrEP. in Conference on Retroviruses and Opportunistic Infections (Seattle, Washington, 2017).
- Authors
- Sillman, B., Bade, A. N., Dash, P. K., Bhargavan, B., Kocher, T., Mathews, S., Su, H., Kanmogne, G. D., Poluektova, L. Y., Gorantla, S., McMillan, J., Gautam, N., Alnouti, Y., Edagwa, B., & Gendelman, H. E.
- Affiliations
- University of Nebraska Medical Center (US)
- Corresponding author
- Edagwa, Benson
- Gendelman, Howard E.
- ORCID
- Venue
- Nature Communications
- Published
- 2018-02-06
- Volume
- 9
- Issue
- 1
- Pages
- 443-443
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5799307
- OpenAlex
- W2802170264
- Cited by
- 125
- References
- 68
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 18 · 2023: 12 · 2022: 15 · 2021: 23 · 2020: 15 · 2019: 17 · 2018: 13
- FWCI
- 12.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- University of Nebraska Medical Center
- University of Nebraska-Lincoln
- ViiV Healthcare
- National Institutes of Health (R24OD018546, AI078498, MH062261, DA028555)
- National Institute on Aging (R01AG043540)
- National Institute of Mental Health (P30MH062261, P01MH064570)
- National Institute on Drug Abuse (P01DA028555)
- National Institute of Allergy and Infectious Diseases (P30AI078498)
- National Institute of Neurological Disorders and Stroke (R01NS036126, P01NS031492, R01NS034239)
- Topics
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
- Keywords
- dolutegravir, long-acting antiretroviral therapy, HIV-1 integrase inhibitors, parenteral drug delivery, humanized mice, HIV-1 replication, pharmacokinetics, elimination half-life
- MeSH terms
- Dolutegravir, Animals, Drug Evaluation, Preclinical, Heterocyclic Compounds, 3-Ring, Humans, Male, Mice, Inbred BALB C, Oxazines, Piperazines, Pyridones, HIV Infections, Drug Delivery Systems, HIV Integrase Inhibitors, Myristic Acid, Nanoparticles
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