Background Factors limiting the efficacy of conventional antiretroviral therapy for HIV-1 infection include treatment adherence, pharmacokinetics and penetration into viral sanctuaries. These affect the rate of viral mutation and drug resistance. In attempts to bypass such limitations, nanoparticles containing ritonavir, indinavir and efavirenz (described as nanoART) were manufactured to assess macrophage-based drug delivery. Methods NanoART were made by high-pressure homogenization of crystalline drug with various surfactants. Size, charge and shape of the nanoparticles were assessed. Monocyte-derived macrophage nanoART uptake, drug release, migration and cytotoxicity were determined. Drug levels were measured by reverse-phase high-performance liquid chromatography. Results Efficient monocyte-derived macrophage cytoplasmic vesicle uptake in less than 30 min based on size, charge and coating was observed. Antiretroviral drugs were released over 14 days and showed dose-dependent reduction in progeny virion production and HIV-1 p24 antigen. Cytotoxicities resulting from nanoART carriage were limited. Conclusion These results support the continued development of macrophage-mediated nanoART carriage for HIV-1 disease.
Long-term antiretroviral therapy (ART) for human immunodeficiency virus type one (HIV-1) infection shows limitations in pharmacokinetics and biodistribution while inducing metabolic and cytotoxic aberrations. In turn, ART commonly requires complex dosing schedules and leads to the emergence of viral resistance and treatment failures. We posit that the development of nanoformulated ART could preclude such limitations and affect improved clinical outcomes. To this end, we wet-milled 20 nanoparticle formulations of crystalline indinavir, ritonavir, atazanavir, and efavirenz, collectively referred to as “nanoART,” then assessed their performance using a range of physicochemical and biological tests. These tests were based on cell-nanoparticle interactions using monocyte-derived macrophages and their abilities to uptake and release nanoformulated drugs and effect viral replication. We demonstrate that physical characteristics such as particle size, surfactant coating, surface charge, and most importantly shape are predictors of cell uptake and antiretroviral efficacy. These studies bring this line of research a step closer to developing nanoART that can be used in the clinic to affect the course of HIV-1 infection.
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...
We posit that improvements in pharmacokinetics and biodistributions of antiretroviral therapies (ART) for human immunodeficiency virus-type one infected people can be achieved through developments in nanoformulations. To this end, we manufactured nanoparticles of atazanavir, efavirenz, and ritonavir (termed nanoART) and treated human monocyte-derived macrophages (MDM) in combination therapies. This resulted in improved drug uptake, release and antiretroviral efficacy over monotherapy. MDM rapidly, within minutes, ingested nanoART combinations, at equal or similar rates, as individual formulations. Combination nanoART ingested by MDM facilitated drug release from 15 to > 20 days. These findings are noteworthy as a nanoART cell-mediated drug delivery provides a means to deliver therapeutics to viral sanctuaries, such as the central nervous system during progressive human immunodeficiency virus-type one infection. The work brings us yet another step closer to realizing the utility of nanoART for virus-infected people.
Aim Nanoformulated antiretroviral therapy can improve drug compliance for people infected with HIV. Additional benefits would include specific drug deliveries to viral reservoirs and reduction in systemic toxicities. Methods In this article, we describe mechanisms of crystalline antiretroviral nanoparticle (NP) uptake, intracellular trafficking and release in human monocyte-derived macrophages. Results Following clathrin-dependent endocytosis NPs bypassed lysosomal degradation by sorting from early endosomes to recycling endosome pathways. Disruption of this pathway by siRNAs or brefeldin-A impaired particle release. Proteomic and biological analysis demonstrated that particle recycling was primarily Rab11 regulated. Particles were released intact and retained complete antiretroviral efficacy. Conclusion These results suggest possible pathways of subcellular transport of antiretroviral nanoformulations that preserve both particle integrity and antiretroviral activities demonstrating the potential utility of this approach for targeted drug delivery.
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