CCR5 Decorated Rilpivirine Lipid Nanoparticles Build Myeloid Drug Depots Which Sustains Antiretroviral Activities.
Authors: Gendelman HE, Patel M, Panja S, Zaman LA, Yeapuri P, Bhattarai S, Gorantla S, Chang L, Heredia A, Walczak P, Cohen S, Kevadiya B
Antiretroviral therapy (ART) improves the quality of life for those living with the human immunodeficiency virus type one (HIV-1). However, poor compliance reduces ART effectiveness and leads to immune compromise, viral mutations, and disease co-morbidities. A novel drug formulation is made whereby a lipid nanoparticle (LNP) carrying rilpivirine (RPV) is decorated with the C-C chemokine receptor type 5 (CCR5). This facilitates myeloid drug depot deposition. Particle delivery to viral reservoirs is tracked by positron emission tomography. The CCR5-mediated RPV LNP cell uptake and retention reduce HIV-1 replication in human monocyte-derived macrophages and infected humanized mice. Focused ultrasound allows the decorated LNP to penetrate the blood-brain barrier and reach brain myeloid cells. These findings offer a role for CCR5-targeted therapeutics in antiretroviral delivery to optimize HIV suppression.
Introduction
Purpose
Drug delivery with BBB opening
Study Objective
To develop and test a CCR5-decorated rilpivirine lipid nanoparticle that targets myeloid HIV-1 reservoirs to improve antiretroviral delivery, retention, and viral suppression.
Animal model / Human subject
Mus musculus, NSG (humanized), not specified, not specified
Disease model
HIV-1 infection (HIV/AIDS)
MRI or image guidance method
MRI
Targeted brain region(s)
Brain Myeloid Cells
Cargo name and characteristics
rilpivirine-loaded lipid nanoparticle
Route of administration
intravenous
Outcomes and Safety
Summary of Outcomes
CCR5-targeted rilpivirine-loaded lipid nanoparticles (LNP-RPV-CCR5) increased macrophage uptake and intracellular drug depot formation, enhanced spleen (and, with focused ultrasound, brain) delivery and retention, and produced prolonged HIV-1 suppression in infected macrophages (up to 25 days) and reduced viremia in humanized mice.
Duration of biological effect
25 days
Safety-related matter
No significant toxicity reported.
Brain Region
Ultrasound Parameters
Ultrasound instrument
none.
FUS Pressure
Not reported
FUS Mode
not specified
Pulse duration
not reported
Focal Characteristics
Cellular
Treatment frequency
Not specified
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