NanoART, neuroAIDS and CNS drug delivery

Abstract

A broad range of nanomedicines is being developed to improve drug delivery for CNS disorders. The structure of the blood-brain barrier (BBB), the presence of efflux pumps and the expression of metabolic enzymes pose hurdles for drug-brain entry. Nanoformulations can circumvent the BBB to improve CNS-directed drug delivery by affecting such pumps and enzymes. Alternatively, they can be optimized to affect their size, shape, and protein and lipid coatings to facilitate drug uptake, release and ingress across the barrier. This is important as the brain is a sanctuary for a broad range of pathogens including HIV-1. Improved drug delivery to the CNS would affect pharmacokinetic and drug biodistribution properties. This article focuses on how nanotechnology can serve to improve the delivery of antiretroviral medicines, termed nanoART, across the BBB and affect the biodistribution and clinical benefit for HIV-1 disease.

Figure 1. Surface modification of nanoparticles greatly affects cellular utilization

(A) Schematic example of one method for modifying the surface of dextran-coated SPIO-nanoparticles (NPs) by enabling attachment to group -R: immunoglobulins, receptor ligands or other proteins. (B) Demonstration of how conjugation of IgG to SPIO-NPs greatly enhances their uptake by mononuclear phagocytes when compared with uncoated SPIO-NPs. SPIO: Superparamagnetic iron oxide.

Figure 2. Tissue distribution of drug nanoparticles after uptake by circulating monocytes

While in the blood (top), circulating immunocytes will specifically engulf nanoparticles by receptor-mediated endocytosis and store them within cytoplasmic vesicles (middle). The drug-laden cells will then respond to secreted chemokine messages and migrate from the circulation by diapedesis through vascular epithelial cells into target organs or travel through the reticuloendothelial system (bottom). The drugs are then released slowly ensuring that therapeutic concentrations are maintained for extended time periods.

Figure 3. Interdisciplinary development of nanomedicines for HIV-1 encephalitis and other human diseases

Modalities that are site specific hold considerable promise for human use and their development is illustrated herein. (A) Neuroprotective, anti-inflammatory, anti-apoptotic or antimicrobial agents are packaged into nanoparticles (NPs) with surfactant and protein coats that target circulating immunocytes or diseased regions within the CNS. (B) The NPs are developed in size, shape, charge and coating to facilitate their uptake into circulating monocytes. (C) The cells circulating in the body will scavenge the particles into cytoplasmic vesicles as a delivery vehicle. Laboratory tests can measure uptake and release of fluorescently tagged drug-laden NPs from monocytes and monocyte-derived macrophages (D). In the case of HIV-1 infections, for example, the drug-laden NPs not housed within monocyte-derived macrophages would release antiretroviral drugs leading to inhibition of viral replication, measured by the absence of multinucleated giant cells and HIV-1 p24 protein expression. (E) Such formulations can then be tested in animals demonstrating sustained drug levels for an extended period. (F) Final therapeutic use in humans will be dependent upon toxicity measures, pharmacokinetic responses and untoward side effects.