Novel elvitegravir nanoformulation for drug delivery across the blood-brain barrier to achieve HIV-1 suppression in the CNS macrophages

Yuqing Gong,Mohammad A Rahman,Prashanth K B Nagesh,Pallabita Chowdhury,Murali M Yallapu,Kaining Zhi,Santosh Kumar

doi:10.1038/s41598-020-60684-1

Abstract

The use of antiretroviral therapy (ART) has remarkably decreased the morbidity associated with HIV-1 infection, however, the prevalence of HIV-1-associated neurocognitive disorders (HAND) is still increasing. The blood-brain barrier (BBB) is the major impediment for penetration of antiretroviral drugs, causing therapeutics to reach only suboptimal level to the brain. Conventional antiretroviral drug regimens are not sufficient to improve the treatment outcomes of HAND. In our recent report, we have developed a poloxamer-PLGA nanoformulation loaded with elvitegravir (EVG), a commonly used antiretroviral drug. The nanoformulated EVG is capable of elevating intracellular drug uptake and simultaneously enhance viral suppression in HIV-1-infected macrophages. In this work, we identified the clinical parameters including stability, biocompatibility, protein corona, cellular internalization pathway of EVG nanoformulation for its potential clinical translation. We further assessed the ability of this EVG nanoformulation to cross the in vitro BBB model and suppress the HIV-1 in macrophage cells. Compared with EVG native drug, our EVG nanoformulation demonstrated an improved BBB model penetration cross the in vitro BBB model and an enhanced HIV-1 suppression in HIV-1-infected human monocyte-derived macrophages after crossing the BBB model without altering the BBB model integrity. Overall, this is an innovative and optimized treatment strategy that has a potential for therapeutic interventions in reducing HAND.

Highlights

In the past two decades, the introduction of antiretroviral therapy (ART) has made significant advances in managing HIV-1/AIDS effectively[1]
Previous clinical studies demonstrate that the central nervous system (CNS) Penetration-Effectiveness (CPE) of ARVs is correlated with the inhibition of HIV-1 replication in the CNS and cognitive performance in HIV-1 positive patients[7,8]
PLGA was the main polymer core to hold EVG molecules, poly(vinyl alcohol) www.nature.com/scientificreports (PVA) was used to stabilize the emulsion; poloxamer 188 was used as a stabilizer and to provide a better brain penetration; PLL was used to provide slightly positive charge, which helps internalize into the cells

Summary

Introduction

In the past two decades, the introduction of antiretroviral therapy (ART) has made significant advances in managing HIV-1/AIDS effectively[1]. HIV1-infected macrophages serve as one of the major viral reservoirs in the CNS, provide active viral replication, even when systemic viral suppression has been achieved by ART5. Several approaches have been employed to improve the penetration of ARVs, including ATP-binding cassette (ABC) transporters blocking method, BBB opening strategy, prodrug therapy, and nanoparticle-based drug delivery[11]. We have successfully encapsulated EVG into poloxamer-PLGA NPs (PLGA-EVG NPs), which improved intracellular uptake of EVG in monocyte-derived macrophages and viral suppression in HIV-1-infected primary macrophages[23]. We performed the transmigration study of PLGA NPs in the in vitro BBB model, and subsequently assessed the efficacy of PLGA-EVG NPs on viral suppression of HIV-1-infected primary macrophages after crossing the BBB model.

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