Nanoformulated Antiretrovirals for Penetration of the Central Nervous System: State of the Art

Abstract

The central nervous system is a very challenging HIV-1 sanctuary. But, despite complete suppression of plasmatic viral replication with current antiretroviral therapy, signs of HIV-1 replication can still be found in the cerebrospinal fluid in some patients. The main limitation to achieving HIV-1 eradication from the brain is related to the suboptimal concentrations of antiretrovirals within this site, due to their low permeation across the blood-brain barrier. In recent years, a number of reliable nanotechnological strategies have been developed with the aim of enhancing antiretroviral drug penetration across the blood-brain barrier. The aim of this review is to provide an overview of the different nanoformulated antiretrovirals, used in both clinical and preclinical studies, that are designed to improve their delivery into the brain by active or passive permeation mechanisms through the barrier. Different nanotechnological approaches have proven successful for optimizing antiretrovirals delivery to the central nervous system, with a likely benefit for HIV-associated neurocognitive disorders and a more debated contribution to the complete eradication of the HIV-1 infection.

Antimicrobial Essential Oil Formulation: Chitosan Coated Nanoemulsions for Nose to Brain Delivery

“…Data in the literature have been mainly focused on animal infection models of nose-to-brain delivery of ketoconazole in cryptococcal meningoencephalitis [ 7 ] or on adjunctive and long-acting nanoformulated antiretroviral therapies for HIV-associated neurocognitive disorders [ 9 , 45 , 46 ], whereas data regarding bacterial infections are scarce [ 7 ]. NEs described in this study appear suitable to be administered intranasally and indicated potential benefits over other types of delivery systems.…”

The Role of HIV Infection in Neurologic Injury

“…For example, while entry and integrase inhibitors are able to reach the CNS, the nucleoside/nucleotide reverse transcriptase inhibitors and non-nucleoside reverse-transcriptase inhibitors can only partially cross the BBB. Conversely, the majority of protease inhibitors (PI) are characterized by a medium/low permeability to the BBB [8,111,112,113]. Moreover, several cellular transporters (P-gp, MRP4, and MRP5) can reduce the optimal intracellular concentration of antiretroviral drugs, thus favoring both the emergence of drug-resistant viruses but also their productive infection to other cells [49,58,114,115].…”

“…In recent years, different types of nanoparticles have been identified. The most important are: (i) Lipid Nanoparticles (liposomes and solid lipid nanoparticles), that easily cross the barrier due to their lipidic nature [116,117]; (ii) Polymeric Nanoparticles, that exploit the interaction with low density lipoproteins (LDL) receptors on the surface of endothelial cells [111,118]; (iii) Inorganic Nanoparticles, such as small size silica with the addition of polyethylene glycol (PEG) [119], and Gold nanoparticles conjugated with cell-penetrating peptides (CPP) [120]. …”

“…When loaded with Ritonavir, for example, these nanoparticles significantly improved the trans-BBB delivery of the drug in mouse models, inhibiting viral replication in macrophages without inducing neuronal-toxicity [121]. Fiandra and his group reported that poly (dl-lactide-co-glycolide) nanoparticles also increase the peak concentrations of efavirenz [111]. In order to improve the PI penetration into the CNS, two novel non-peptidic PIs, GRL-04810 and GRL-05010, have been also developed.…”

CD4 + T Cell-Mimicking Nanoparticles Broadly Neutralize HIV-1 and Suppress Viral Replication through Autophagy

“…The development of nanoengineering has given rise to a new avenue of HIV treatment and prevention research. Nanoparticles are being assessed as vehicles for antiviral drugs to improve drug tolerability, circulation half‐life, and efficacy and as carriers for delivery to the central nervous system ( 14 – 19 ). They are also being evaluated for the delivery of small interfering RNAs (siRNAs) to silence gene expression in CD4 + T cells, macrophages, and dendritic cells, as well as HIV itself (reviewed in reference 20 ).…”