Brain-Accumulating Nanoparticles for Assisting Astrocytes to Reduce Human Immunodeficiency Virus and Drug Abuse-Induced Neuroinflammation and Oxidative Stress

Abstract

Human neurotropic immunodeficiency virus (HIV) ingress into the brain and its subsequent replication after infection results in viral reservoirs in the brain. The infected cells include microglia, perivascular macrophages, and astrocytes. HIV-associated neurocognitive disorders (HAND) affect glial cells by activating microglia and macrophages through neuroinflammation, as well as astrocytes through mitochondrial dysfunctions and the onset of oxidative stress, impairing the ability of these cells to engage in neuroprotection. Furthermore, the risk of neuroinflammation associated with HAND is magnified by recreational drug use in HIV-positive individuals. Most of the therapeutic options for HIV cannot be used to tackle the virus in the brain and treat HAND due to the inability of currently available combination antiretroviral therapies (ARTs) and neuroprotectants to cross the blood−brain barrier, even if the barrier is partially compromised by infection. Here, we report a strategy to deliver an optimized antiretroviral therapy combined with antioxidant and anti-inflammatory neuroprotectants using biodegradable brain-targeted polymeric nanoparticles to reduce the burden caused by viral reservoirs in the brain and tackle the oxidative stress and inflammation in astrocytes and microglia. Through in vitro coculture studies in human microglia and astrocytes as well as an in vivo efficacy study in an EcoHIV-infected, methamphetamine-exposed animal model, we established a nanoparticle-based therapeutic strategy with the ability to treat HIV infection in the central nervous system in conditions simulating drug use while providing enhanced protection to astrocytes, microglia, and neurons.

In-vivo time course of organ uptake and blood-brain-barrier permeation of poly(L-lactide) and poly(perfluorodecyl acrylate) nanoparticles with different surface properties in unharmed and brain-traumatized rats

“…Internalization of NPs by astrocytes is relevant in the context of the main role played by these cells in protective and deleterious pathophysiological mechanisms, such as during secondary lesion development in TBI or neurodegenerative disorders ( 99 – 103 ). Consistent with our findings, some polymeric NPs have been proven to be useful as carriers for antiretroviral therapy in combination with antioxidant and anti-inflammatory neuroprotectants into astrocytes, reducing the oxidative stress and neuroinflammation caused by human neurotropic immunodeficiency virus ( 104 ). Also, biodegradable PLGA NPs have even been used for gene delivery into astrocytes aiming to compensate for astrocytic dysfunction linked to neurodegeneration ( 103 ).…”

Progress in Treatment and Diagnostics of Infectious Disease with Polymers

“…BBB-penetrating polymeric nanoparticles containing ARVs, antioxidant CoQ10 and a pro-drug of aspirin. Reproduced with permission from reference . Copyright 2021 American Chemical Society.…”

“…The in vitro coculture (human astrocytes and microglia cells) and in vivo EcoHIVinfected methamphetamine-exposed animal model show improved protection of microglia, neurons and astrocytes (Figure 8). 93 In 2021 a solid dispersed material was developed with dispersed DTG and poloxamer 407 and was checked in vitro and in vivo; it showed an increased rate of dissolution with enhanced bioavailability. 94 The polymeric material Eudragit-100 was used as a taste masking agent for the orally disintegrating tablet cotrimoxazole (CTX).…”

Role of aging in Blood–Brain Barrier dysfunction and susceptibility to SARS-CoV-2 infection: impacts on neurological symptoms of COVID-19

“…Endogenous antioxidants such as coenzyme Q10, glutathione and melatonin are, therefore, potential and promising targets for anti-aging therapy and could prevent brain inflammaging effects [ 181 ]. In that direction, we have shown that a targeted delivery of COQ 10 prevented cellular senescence and oxidative stress in neural progenitor cells and astrocytes treated with antiretroviral drugs, exposed to drugs of abuse or infected with HIV-1 [ 182 , 183 ]. Moreover, exogenous melatonin treatment prevented neuroinvasion and cerebrovascular abnormalities in K18-hACE2 mice [ 184 ], thus corroborating a protective role of antioxidant therapy in Neuro-COVID-19.…”