An Elvitegravir Nanoformulation Crosses the Blood–Brain Barrier and Suppresses HIV-1 Replication in Microglia

Abstract

Even with an efficient combination of antiretroviral therapy (ART), which significantly decreases viral load in human immunodeficiency virus type 1 (HIV-1)-positive individuals, the occurrence of HIV-1-associated neurocognitive disorders (HAND) still exists. Microglia have been shown to have a significant role in HIV-1 replication in the brain and in subsequent HAND pathogenesis. However, due to the limited ability of ART drugs to cross the blood–brain barrier (BBB) after systemic administration, in addition to efflux transporter expression on microglia, the efficacy of ART drugs for viral suppression in microglia is suboptimal. Previously, we developed novel poly (lactic-co-glycolic acid) (PLGA)-based elvitegravir nanoparticles (PLGA-EVG NPs), which showed improved BBB penetration in vitro and improved viral suppression in HIV-1-infected primary macrophages, after crossing an in vitro BBB model. Our objective in the current study was to evaluate the efficacy of our PLGA-EVG NPs in an important central nervous system (CNS) HIV-1 reservoir, i.e., microglia. In this study, we evaluated the cyto-compatibility of the PLGA-EVG NPs in microglia, using an XTT (2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) assay and cellular morphology observation. We also studied the endocytosis pathway and the subcellular localization of PLGA NPs in microglia, using various endocytosis inhibitors and subcellular localization markers. We determined the ability of PLGA-EVG NPs to suppress HIV-1 replication in microglia, after crossing an in vitro BBB model. We also studied the drug levels in mouse plasma and brain tissue, using immunodeficient NOD scid gamma (NSG) mice, and performed a pilot study, to evaluate the efficacy of PLGA-EVG NPs on viral suppression in the CNS, using an HIV-1 encephalitic (HIVE) mouse model. From our results, the PLGA-EVG NPs showed ~100% biocompatibility with microglia, as compared to control cells. The internalization of PLGA NPs in microglia occurred through caveolae-/clathrin-mediated endocytosis. PLGA NPs can also escape from endo-lysosomal compartments and deliver the therapeutics to cells efficiently. More importantly, the PLGA-EVG NPs were able to show ~25% more viral suppression in HIV-1-infected human-monocyte-derived microglia-like cells after crossing the in vitro BBB compared to the EVG native drug, without altering BBB integrity. PLGA-EVG NPs also showed a ~two-fold higher level in mouse brain and a trend of decreasing CNS HIV-1 viral load in HIV-1-infected mice. Overall, these results help us to create a safe and efficient drug delivery method to target HIV-1 reservoirs in the CNS, for potential clinical use.

HIV Infection and Related Mental Disorders

“…Unfortunately, this drug had to be excluded from the treatment regimen, as it caused depression and paranoid ideation in some patients [ 153 , 154 , 155 ]. Recently, promising results were obtained by Gong et al, with their new elvitegravir nanoformulation (poloxamer-PLGA nanoformulation loaded with elvitegravir (integrase inhibitor)) [ 156 , 157 ]. Using an in vitro BBB model (co-cultured endothelial cells with astrocytes), Gong et al showed that elvitegravir nanoformulation provided improved BBB penetration and increased the suppression of HIV replication in infected human-monocyte-derived macrophages and human-monocyte-derived microglia-like cells after crossing the BBB compared to the original elvitegravir [ 156 , 157 ].…”

“…Recently, promising results were obtained by Gong et al, with their new elvitegravir nanoformulation (poloxamer-PLGA nanoformulation loaded with elvitegravir (integrase inhibitor)) [ 156 , 157 ]. Using an in vitro BBB model (co-cultured endothelial cells with astrocytes), Gong et al showed that elvitegravir nanoformulation provided improved BBB penetration and increased the suppression of HIV replication in infected human-monocyte-derived macrophages and human-monocyte-derived microglia-like cells after crossing the BBB compared to the original elvitegravir [ 156 , 157 ]. Using NSG mouse (NOD scid gamma mouse) and HIV-1 encephalitic (HIVE) mouse models, Gong et al demonstrated nearly twofold higher levels of elvitegravir nanoformulation in vivo in the mouse brain and a trend of decreasing HIV-1 viral load in the CNS of the HIV-1-infected mice [ 157 ].…”

Challenges in Biomaterial-Based Drug Delivery Approach for the Treatment of Neurodegenerative Diseases: Opportunities for Extracellular Vesicles

“…AgNPs can also trigger the anti-inflammatory reaction inside microglia, which can be beneficial in neurodegenerative diseases [ 14 ]. This mechanism may also be used to treat HAND, since microglia are a targeting site for antiretroviral drug delivery [ 5 ]. Metal oxide nanoparticles, such as iron oxide, cerium oxide, and zinc oxide, are developed for imaging and decreasing oxidative stress.…”

“…The porous structure of polymeric nanoparticles provides a large space to encapsulate cargos. PLGA nanoparticle-based drug formulations have been shown to cross the BBB and deliver cargos into both macrophages [ 6 ] and microglia [ 5 ]. Similarly, paclitaxel-loaded PLGA-NPs were also reported to cross the BBB with the assistance of glutathione coating [ 38 ].…”

“…The human BBB is a highly selective, semipermeable brain barrier that offers a protective mechanism for the human brain. With the presence of multiple efflux transporters and tight junctions, certain drug molecules have difficulty crossing the BBB [ 5 , 6 ]. Therefore, it is critically important to design and develop biomaterial-based drug delivery systems to combat neuronal diseases.…”