Semi-solid prodrug nanoparticles for long-acting delivery of water-soluble antiretroviral drugs within combination HIV therapies

James J. Hobson, Amer Al-khouja, Paul Curley, David Meyers, Charles Flexner, Marco Siccardi, Andrew Owen (), Caren Freel Meyers () and Steve P. Rannard ()
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James J. Hobson: University of Liverpool
Amer Al-khouja: The Johns Hopkins University School of Medicine
Paul Curley: University of Liverpool
David Meyers: The Johns Hopkins University School of Medicine
Charles Flexner: The Johns Hopkins University School of Medicine
Marco Siccardi: University of Liverpool
Andrew Owen: University of Liverpool
Caren Freel Meyers: The Johns Hopkins University School of Medicine
Steve P. Rannard: University of Liverpool

Nature Communications, 2019, vol. 10, issue 1, 1-10

Abstract: Abstract The increasing global prevalence of human immunodeficiency virus (HIV) is estimated at 36.7 million people currently infected. Lifelong antiretroviral (ARV) drug combination dosing allows management as a chronic condition by suppressing circulating viral load to allow for a near-normal life; however, the daily burden of oral administration may lead to non-adherence and drug resistance development. Long-acting (LA) depot injections of nanomilled poorly water-soluble ARVs have shown highly promising clinical results with drug exposure largely maintained over months after a single injection. ARV oral combinations rely on water-soluble backbone drugs which are not compatible with nanomilling. Here, we evaluate a unique prodrug/nanoparticle formation strategy to facilitate semi-solid prodrug nanoparticles (SSPNs) of the highly water-soluble nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (FTC), and injectable aqueous nanodispersions; in vitro to in vivo extrapolation (IVIVE) modelling predicts sustained prodrug release, with activation in relevant biological environments, representing a first step towards complete injectable LA regimens containing NRTIs.

Date: 2019
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DOI: 10.1038/s41467-019-09354-z

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