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. Keywords BBB; CNS; drug delivery; HIV; nanoparticles; nanotechnologyTo maximize treatment of CNS diseases, drugs must cross the blood-brain barrier (BBB) and show limited systemic toxicities. This task is by no means simple. Owing to its structural and functional complexities, the BBB represents one of the greatest challenges impeding drug penetration for combating nervous system diseases [1]. For example, drugs, nucleic acids, proteins, imaging agents and other low-molecular-weight compounds and macromolecules are restricted in brain entry. Thus, the means to improve delivery of compounds across the BBB in an efficient, safe and site-specific manner remain a primary goal to achieve optimal therapeutics in the battle against neuroinflammatory and neurodegenerative diseases [2][3][4][5].The major bottleneck in the development of both diagnostic tools and therapies aimed at combating CNS disorders is in modulating BBB structure, function and biophysiology. With regards to structure, the ability of the barrier to effectively limit transport is attributed, in part, to brain microvessel endothelial cells (BMVECs) that form brain capillaries. Without question, BMVECs are a principal means for limiting transport and solute passage from blood to the CNS [1,[6][7][8][9]. The function and biophysiology of the barrier is also linked to its tight intercellular junctions, low pinocytic potentials and the presence of high levels of drug efflux transporters and metabolizing enzymes. †Author for correspondence: Department of Pharmacology & Experimental Neuroscience, Center for Neurovirology & Neurodegenerative Disorders, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA, Tel.: +1 402 559 8920, Fax: +1 402 559 3744, hegendel@unmc.edu. Financial & competing interests disclosure:The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.For r...

Comparative manufacture and cell-based delivery of antiretroviral nanoformulations

“…[1][2][3][4][5] However, the short half-life of the drugs necessitates multiple daily dosing schedules limiting both access and compliance. Moreover, failure of ART penetration into sanctuaries of persistent viral replication including the lymphoreticular and central nervous systems, and a range of secondary drug-induced toxicities further highlight the limitations of chronic drug treatment regimens.…”

Anti-HIV-1 nanotherapeutics: promises and challenges for the future

“…Another advantage of nanocarriers includes its ability to bypass the multidrug-resistant transporters, which may efflux drugs entering freely through the plasma membrane. [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] Inorganic solid lipid nanoparticles liposomes, polymeric micelles, dendrimers, cyclodextrins, and cell-based nanoformulations have been studied for delivery of drugs intended for HIV prevention or therapy. 43 For anti-HIV drugs to be effective, adequate distribution to specific sites in the body must be achieved, and effective drug concentrations must be maintained at those sites for the required period of time.…”

“…24,29 Nowacek and Gendelman have shown that a single intravenous dose of the nano-ART can elicit high-sustained tissue and plasma drug levels of antiretroviral drugs in the reticuloendothelial system and brain. 26 Nano-ART can be taken up within minutes by circulating monocytes and released in tissues over a period of 2 weeks. [56][57][58][59][60] Theoretically, cell-based nano-ART would travel to sites of inflammation and release drug(s) slowly with limited tissue toxicities.…”

“…Several additional nanotechnology systems for delivery of antiretroviral drugs have been outlined in recent reviews. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] We have made a comprehensive list of the antiretroviral used in HIV therapy in Table 3.…”

“…Nanoparticles offer great promise for neurotherapeutics. [25][26][27][28][29] Nanocarriers provide a means to overcome cellular and anatomical barrier such as the blood-brain barrier (BBB) to drug delivery. 54 The BBB inhibits the transport of antiretroviral drugs to the brain by the presence of tight endothelial cell junctions and efflux transporters such as P-glycoprotein (P-gp), a multidrug-resistant protein.…”