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

Focal Characteristics Cellular

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