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A year-long extended release nanoformulated cabotegravir prodrug
- Source :
- Nature materials. 19(8)
- Publication Year :
- 2019
-
Abstract
- Long-acting cabotegravir (CAB) extends antiretroviral drug administration from daily to monthly. However, dosing volumes, injection site reactions and health-care oversight are obstacles towards a broad usage. The creation of poloxamer-coated hydrophobic and lipophilic CAB prodrugs with controlled hydrolysis and tissue penetrance can overcome these obstacles. To such ends, fatty acid ester CAB nanocrystal prodrugs with 14, 18 and 22 added carbon chains were encased in biocompatible surfactants named NMCAB, NM2CAB and NM3CAB and tested for drug release, activation, cytotoxicity, antiretroviral activities, pharmacokinetics and biodistribution. Pharmacokinetics studies, performed in mice and rhesus macaques, with the lead 18-carbon ester chain NM2CAB, showed plasma CAB levels above the protein-adjusted 90% inhibitory concentration for up to a year. NM2CAB, compared with NMCAB and NM3CAB, demonstrated a prolonged drug release, plasma circulation time and tissue drug concentrations after a single 45 mg per kg body weight intramuscular injection. These prodrug modifications could substantially improve CAB’s effectiveness. Nanoformulated long-acting cabotegravir prodrugs are shown to be capable of extending the native drug’s antiretroviral activity, biodistribution and pharmacokinetics for up to 12 months in mice and rhesus macaques.
- Subjects :
- Drug
Biodistribution
Pyridones
media_common.quotation_subject
Drug Compounding
02 engineering and technology
Pharmacology
010402 general chemistry
01 natural sciences
chemistry.chemical_compound
Mice
Cabotegravir
Pharmacokinetics
Drug Stability
Animals
General Materials Science
Drug Interactions
Prodrugs
media_common
Mechanical Engineering
Biological Transport
General Chemistry
Prodrug
021001 nanoscience & nanotechnology
Condensed Matter Physics
0104 chemical sciences
Nanostructures
chemistry
Anti-Retroviral Agents
Mechanics of Materials
Delayed-Action Preparations
Drug delivery
Pharmaceutics
0210 nano-technology
Intramuscular injection
Subjects
Details
- ISSN :
- 14764660
- Volume :
- 19
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- Nature materials
- Accession number :
- edsair.doi.dedup.....edce3d8d71ee6472b6755874ca83dc4b