Nanotechnology for HIV/AIDS Treatment
Nanotechnology for Antiretroviral Drug Delivery
The use of nanotechnology platforms for delivery of drugs is revolutionizing medicine in many areas of disease treatment.[32] Cancer patients have been the biggest beneficiaries of this revolution so far, with significant advances in the last few decades. Many nanoscale systems for systemic cancer therapy are either FDA approved or in clinical trials.[19,33] This tremendous success has been due to the unique features that nanotechnology imparts on drug delivery systems. Using nanotechnology, it has become possible to achieve improved delivery of poorly water-soluble drugs, targeted delivery of drugs to specific cells or tissues and intracellular delivery of macromolecules.[18,32]
Nanotechnology-based platforms for systemic delivery of antiretroviral drugs could have similar advantages. Controlled-release delivery systems can enhance their half-lives, keeping them in circulation at therapeutic concentrations for longer periods of time. This could have major implications in improving adherence to the drugs. Nanoscale delivery systems also enhance and modulate the distribution of hydrophobic and hydrophilic drugs into and within different tissues due to their small size. This particular feature of nanoscale delivery systems appears to hold the most promise for their use in clinical treatment and prevention of HIV. Specifically, targeted delivery of antiretroviral drugs to CD4+ T cells and macrophages as well as delivery to the brain and other organ systems could ensure that drugs reach latent reservoirs.[29,34] Moreover, by controlling the release profiles of the delivery systems, drugs could be released over a longer time and at higher effective doses to the specific targets. Various nanoscale drug delivery systems shown in Figure 1 could be explored for these purposes. The use of nanotechnology systems for delivery of antiretroviral drugs has been extensively reviewed by Nowacek et al. and Amiji et al..[29,31,34] In this section, we only highlight a few of the most recent and significant examples of nanotechnology-based drug delivery.
Figure 1.
Schematic representation of various nanotechnology platforms that can be used in HIV/AIDS treatment and prevention.
In a recent study based on polymeric systems, nanosuspensions (200 nm) of the drug rilpivirine (TMC278) stabilized by polyethylene-polypropylene glycol (poloxamer 338) and PEGylated tocopheryl succinate ester (TPGS 1000) were studied in dogs and mice.[35] A single-dose administration of the drug in nanosuspensions resulted in sustained release over 3 months in dogs and 3 weeks in mice, compared with a half-life of 38 h for free drug. These results serve as a proof-of-concept that nanoscale drug delivery may potentially lower dosing frequency and improve adherence.
A series of experiments by Dou et al. showed that nanosuspension of the drug indinavir can be stabilized by a surfactant system comprised of Lipoid E80 for effective delivery to various tissues.[36–38] The indinavir nanosuspensions were loaded into macrophages and their uptake was investigated. Macrophages loaded with indinavir nanosuspensions were then injected intravenously into mice, resulting in a high distribution in the lungs, liver and spleen. More significantly, the intravenous administration of a single dose of the nanoparticle-loaded macrophages in a rodent mouse model of HIV brain infection resulted in significant antiviral activity in the brain and produced measureable drug levels in the blood up to 14 days post-treatment.[38]
These studies serve as a proof of concept for indinavir delivery to the brain and the sustained drug levels for up to 14 days, which is important when considering that the half-life of indinavir in its conventional dosage form is 2 h. The demonstration that macrophages could be used to target drugs to the brain could be utilized for in vivo nanoparticle-targeted delivery of other drugs to the brain in the future.
Active targeting strategies have also been employed for antiretroviral drug delivery. Macrophages, which are the major HIV reservoir cells, have various receptors on their surface such as formyl peptide, mannose, galactose and Fc receptors, which could be utilized for receptor-mediated internalization. The drug stavudine was encapsulated using various liposomes (120–200 nm) conjugated with mannose and galactose, resulting in increased cellular uptake compared with free drug or plain liposomes, and generating significant level of the drug in liver, spleen and lungs.[39–41] Stavudine is a water-soluble drug with a very short serum half-life (1 h). Hence, the increased cellular uptake and sustained release in the tissues afforded by targeted liposomes is a major improvement compared with free drug. The drug zidovudine, with half-life of 1 h and low solubility, was also encapsulated in a mannose-targeted liposome made from stearylamine, showing increased localization in lymph node and spleen.[42] An important factor to consider here is that although most of the nucleoside drugs such as stavudine and zidovudine have short serum half-lives, the clinically relevant half-life is that of the intracellular triphosphate form of the drug. For example, despite zidovudine's 1 h half-life in plasma, it is dosed twice daily based on intracellular pharmacokinetic and clinical efficacy data. Therefore, future nanotechnology-based delivery systems will have to focus in showing significant increase of the half-lives of the encapsulated drugs to achieve a less frequent dosing such as once weekly, once-monthly or even less.
In separate work, a mannose-targeted poly (propyleneimine) dendrimer nanocarrier was used to deliver the drug efavirenz to human monocytes/macrophages in vitro.[43] The targeted nanocarrier resulted in 12-fold increase in cellular uptake compared with free drug. A similar system was used to deliver the drug lamivudine in vitro, resulting in significantly higher anti-HIV activity for the targeted and nontargeted dendrimer systems compared with free drugs.[44] In a more recent study, the tetra-peptide tuftsin (Thr-Lys-Pro-Arg) was conjugated to the same dendrimer to target the drug efavirenz to macrophages in vitro.[45] The targeted dendrimer system resulted in sixfold prolonged release, 34-fold increased cellular uptake and sevenfold increase in anti-HIV activity compared with free drug.
In a new approach to target macrophage HIV reservoirs, a peptide nanocarrier was proposed as a model where a drug is conjugated to the backbone of peptide-PEG and N-formyl-methionyl-leucyl-phenylalanine (fMLF), a bacterial peptide sequence for which macrophages express a receptor, is attached to the PEG for targeting.[46] The study found that fMLF-targeted peptide-PEG nanocarriers show increased cellular uptake and increased accumulation in macrophages of liver, kidney and spleen compared with those which are nontargeted.[30,46]
All the aforementioned efforts are examples of the potential nanotechnology platforms hold for improving targeted delivery of antiretroviral drugs to the cellular and anatomical reservoirs of HIV. These early efforts provide evidence for the potential of nanotechnology to improve delivery of antiretroviral therapy and support ongoing efforts to initiate clinical trials. Although the early efforts have not reached clinical trials yet, the works so far provide encouraging evidence that a subset of these preclinical technologies may enter clinical evaluation in the future.
Nanomaterials as Therapeutic Agents
In addition to being used as delivery agents, nanomaterials have also been shown to have therapeutic effects of their own. Studies have shown that the capsid of HIV could be a target for structure-based drug design for inhibiting viral replication.[47,48] As a result, both computational and experimental studies have identified compounds that could inhibit the assembly of the HIV capsid. Various nanomaterials have been found to inhibit viral replication in vitro and it is suggested that these effects are based on structural interference with viral assembly.
Various fullerene (C-60)-based structures, dendrimers and inorganic nanoparticles, such as gold and silver, have been shown to have anti-HIV activity in vitro.[49–60] While these efforts have not yet progressed beyond in vitro studies, they illustrate the potential of therapeutic nanomaterials to inhibit HIV replication.
Nanomedicine. 2010;5(2):269-285. © 2010 Future Medicine Ltd.
Cite this: Emerging Nanotechnology Approaches for HIV/AIDS Treatment and Prevention - Medscape - Apr 02, 2010.
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