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Research Spotlight: Nanomedicines for HIV therapy
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Therapeutic Delivery (2013)
Marco Siccardi*1, Philip Martin1, Tom O McDonald2, Neill J Liptrott1, Marco Giardiello2, Steve Rannard2 & Andrew Owen1
Pharmacology, University of Liverpool, Liverpool, UK.
2Department of Chemistry, University of Liverpool, Liverpool, UK.
ABSTRACT
Heterogeneity in response to HIV treatments has been attributed to several causes including variability in pharmacokinetic exposure. Nanomedicine applications have a variety of advantages compared with traditional formulations, such as the potential to increase bioavailability and specifically target the site of action. Our group is focusing on the development of nanoformulations using a closed-loop design process in which nanoparticle optimization (disposition, activity and safety) is a continuous process based on experimental pharmacological data from in vitro and in vivo models. Solid drug nanoparticles, polymer-based drug-delivery carriers as well as nanoemulsions are nanomedicine options with potential application to improve antiretroviral deployment.
Disease Focus
The HIV/AIDS epidemic is one of the major public health threats and currently more than 34 million people worldwide are estimated to be infected. In 2010, AIDS claimed an estimated 1.8 million lives globally, including more than 250,000 children. The prevalence of HIV/AIDS continues to increase and it is expected that over 90 million people will ultimately be infected in Africa alone [1]. Between 2001 and 2007, the UK had the highest growth in HIV/AIDS infection in western Europe with a 64% increase. Worldwide, the total number of people accessing antiretroviral therapy at the end of 2009 was estimated to be more than 6 million. In low- and middle-income countries, approximately 5 million patients were receiving antiretroviral therapy, more than 1.2 million more people than at the end of 2008. This represents a 30% increase in 1 year and a tenfold increase in 5 years [1].
Highly active antiretroviral therapy is based on the co-administration of drugs from two or three different classes, aiming to inhibit multiple viral targets, maximizing the inhibition of viral replication and reducing the risk of developing drug resistance [2]. Several issues can jeopardize the efficacy of the HIV treatment, including the necessity of patient compliance with very strict drug regimens and side effects associated with acute and/or chronic exposure to antiretroviral drugs. Heterogeneity in the response to antiretroviral agents has been attributed to multiple factors, such as adherence to therapy, characteristics of the virus, immunological status and pharmacokinetic exposure to antiretrovirals. All of these factors exhibit large inter-patient variability. Therapeutic failure is due to several factors, such as a high rate of viral replication (with more than 109 virions produced daily) and the high error rate of reverse transcriptase, due to the lack of proof-reading capability, resulting in a high mutation rate. HIV can develop resistance to existing therapies but the ability of therapies to target HIV replication-competent cells is critical to the success of medication. The virus resides in various sites throughout the body but there are both cellular and tissue sites that are particularly difficult for drugs to reach. Numerous side effects result from exposure of different cells and tissues to antiretroviral drugs, which in some cases are concentration-depenent and in other cases are concentration-independent. As such, off-target toxicities are common for HIV drugs and are exacerbated by the need for a life-long commitment to medication.
The purpose of this Research Spotlight is to discuss ongoing progress at the University of Liverpool (Liverpool, UK) in the development of nanomedicine options for HIV therapy.
Nanomedicine applications
Nanomedicines have proven extremely valuable in recent years and many are used daily to treat patients with a range of conditions or needs - from the treatment of cancer and menopausal symptoms to the prevention of organ rejection or malnutrition/weight loss [3-5]. Nanomedicine applications can improve a variety of pharmacological issues, from increasing bioavailability to specific targeting to the site of action, often reducing the doses of drug needed for the therapeutic activity and, therefore, the overall exposure. A range of unmet clinical needs will benefit considerably from the research and application of new nanoparticle synthesis techniques, the development of appropriate nanomedicines, and the provision of scalable, commercially viable technologies that can impact patient outcomes. This is a key goal of nanomedicine research. Validation of new technologies through optimization of product performance, demonstration of pharmaceutically relevant manufacturing, and clarification of mechanisms regulating distribution, efficacy and toxicity is critical for progression as is the study of nano-specific toxicities to establish safety assessments that support future investment and translation.
Several different nanomedicine strategies can be hypothesized to improve drug delivery and, in general, polymeric materials are used in three main approaches to enable the emerging science of nanomedicine. First, to overcome the inherent issues of bioavailability of orally dosed poorly water-soluble drugs, solid drug nanoparticles (SDNs) are often prepared using a variety of techniques such as nanomilling, homogenization or precipitation [6]. Second, polymers are used as containers for drug molecules either by forming solid polymer matrix nanoparticles to encapsulate drugs (e.g., bio-erodible poly(D,L-lactide-co-glycolide) [PLGA], microspheres), or through the self-assembled construction of vehicles such as block copolymer liposomes/vesicles or micelles [7]. Encapsulation is also a key component of implant technologies, including those that erode over time and those that are physically removed. Finally, direct non-covalent or covalent conjugation of drugs to polymers to form prodrugs has been successfully used to enhance circulatory times, reduce toxicity and deliver drugs through triggered/controlled release [8].
SDNs for treatment of HIV/AIDS
To date, a series of candidate SDNs for HIV/AIDS treatment have been generated at the University of Liverpool in collaboration with IOTA NanoSolutions Ltd (Liverpool, UK), a specialist start-up company in the UK, and supported by Research Councils UK and Engineering and Physical Sciences Research Council funding using an innovative new emulsion-templated freeze-drying technique. IOTA is commercializing a novel nanoparticle synthesis technology (initially developed at Liverpool with Engineering and Physical Sciences Research Council funding support) that rivals the most successful commercial top-down nanomedicine technology - nanomilling. It is noteworthy that there are other bottom-up approaches being applied, by other investigators, to antiretroviral SDN formation that continue to show opportunities for targeting HIV [9-12].
Three SDN candidates for the treatment of HIV infection have been subject to patent filings and currently a full investigation of their pharmacological and clinical potential is ongoing in Liverpool. We are seeking to increase the understanding of nanomedicine behavior through fundamental mechanistic studies, integrating in vitro and in vivo data to clarify the molecular mechanisms determining nanomedicine absorption, distribution and clearance, and producing new insights into the mode of action and the safety of future nanomedicines. Specifically, we are using multiple cell lines and primary cell systems for a complete assessment of nanomedicine pharmacology in comparison to dissolved molecules. First, we used transcellular permeability through Caco-2 cell monolayers (to model the intestinal epithelium) to identify nanoparticle candidates with potential for oral absorption. An intriguing question relates to whether or not SDNs are able to cross the intestinal epithelium as intact nanoparticles or whether the drug reaches the systemic circulation as a dissolved molecule. This has important implications for both the safety of SDNs and also for whether benefits conferred by intact SDNs entering the systemic circulation can be realized after oral dosing. Our studies with SDNs containing fluorescence resonance energy transfer dyes have indicated that at least a proportion of the nanoparticles can traverse epithelial monolayers as intact particles [13]. To probe putative differences in distribution of nanomedicines versus traditional formulations we are also assessing cellular accumulation across a range of cell lines, and because of functional abnormalities in cell lines, also in primary hepatocytes, CD4+ T lymphocytes, CD56+ natural killer cells, CD14+ monocytes and monocyte-derived macrophages. Previous studies with SDNs produced by a different approach have shown advantages for delivery of antiretrovirals to macrophages [12]. Our results will be included in physiologically based pharmacokinetic models to simulate nanoparticle pharmacokinetics and pharmacodynamics in virtual patients and to predict which SDNs are likely to have the best pharmacokinetics, allowing dose reduction, therapy simplification and/or optimization [14]. By modeling the impact of excipients, SDN size and surface charge, these data also provide insights into how particle properties influence biological interactions.
In parallel to the analysis of putative benefits, we are also conducting an evaluation of nano-specific safety using primary cells to assess cytotoxicity as well as potential immune interactions. Immune interactions have been reported for a number of nanoparticles (including environmental nanoparticles) [15] but less is known regarding SDNs. This information could have important implications if SDNs enter the systemic circulation after oral or parenteral dosing. It is worthy of note that antiretroviral SDNs of rilpivarine have been evaluated for their potential for intramuscular or subcutaneous administration with huge benefits for sustained release [16]. SDNs with the best pharmacokinetic and safety potential have been selected for preliminary evaluation of in vivo pharmacokinetics in animal models and compared with traditional formulations. This approach is giving insight into the potential pharmacokinetic improvements of SDNs, further reducing the number of nanoparticle candidates that will be tested in clinical trials in healthy human volunteers.
Our research program aims to produce nanomedicines for oral or parenteral administration of antiretrovirals, with substantial benefit for patients. Such benefits include lower dosing, better patient-to-patient consistency and a reduction of tablet size. There is also excellent potential for pediatric antiretroviral formulations. Currently, to prevent transmission of HIV to children from infected mothers, the World Health Organization has recommended dosing with antiretrovirals from 3 weeks after birth [17]. Children are currently administered some antiretroviral drugs (e.g., protease inhibitors) in high concentrations of ethanol [18] or adult tablets are broken in poor clinical practice. SDN nanodispersions have the potential for administration in water, negating the need for alcohol to solubilize the drug. There are also potential benefits for the wider community such as a reduced cost of drug manufacture and potentially a lower frequency of adverse drug reactions.
Other Technologies
We are also working across a number of other polymer-based drug-delivery carriers as well as nanoemulsions. Nanoemulsions have attracted lots of recent attention for their potential in the food industry [19] but also for oral and parenteral administration of drugs [20]. Our work in this area is focusing on developing novel nanoemulsion technology as an approach to solve several issues that characterize conventional antiretroviral therapy. The approach provides flexibility for passive or active targeting nanocarriers. In a project funded by the British Society for Antimicrobial Chemotherapy we are developing innovative formulations of HIV drugs. A unique aspect of our work with polymer carriers and nanoemulsions is the integration of in vitro pharmacology and safety early in the development and validation process. This enables early clarification of the mechanisms regulating cellular uptake, gut transport and activity against resistant and sensitive strains of HIV, to aid selection of appropriate technologies that offer the opportunity to target HIV-infected macrophages via endocytosis or phagocytosis, which exhibit greater phagocytic activity than uninfected cells. Therefore, this research approach may result in strategies to combat resistance by improving bioavailability and targeting, thereby reducing pill burden while decreasing accumulation in tissues not infected by HIV.
Future perspective
HIV infection represents a disease area in which nanomedicine can find large application, with the potential to substantially improve the efficacy and reduce the toxicity of antiretroviral treatments. We envisage an integrated research approach in which material chemists, pharmacologists, virologists and clinicians collaborate to develop nanomedicines for HIV treatment. Our approach attempts to apply a closed-loop design process in which nanoparticle optimization is a continuous process based on experimental pharmacological data from in vitro and in vivo models. It is hoped that the successful establishment of the fundamental research underpinning the benefits and safety of new nanomedicines will provide a platform for development of effective future medicines for HIV and beyond. Effective dissemination to academics, industry, regulators and the public is essential if the true ambitions of nanomedicine are to be achieved - British Society for Nanomedicine was launched in Liverpool in October 2012 to facilitate this [101].
Solid drug nanoparticles
Nanosized drug particles with high drug dissolution rate for poorly soluble drug.
Nanoemulsions
Oil-in-water emulsions with mean droplet diameters ranging from 50 to 1000 nm that contain therapeutic agents.
Executive summary
· HIV infection represents a disease area in which nanomedicine can find successful application, improving the efficacy and reducing the toxicity of antiretroviral treatments.
· Nanomedicine applications can improve a variety of pharmacological issues, such as increasing bioavailability and specific targeting to the site of action.
· We are developing a closed-loop design process in which material chemists, pharmacologists, virologists and clinicians collaborate to develop nanomedicines for HIV treatment.
· Our research program aims to produce nanomedicines for oral or parenteral administration of antiretrovirals, with substantial benefit for patients.
Executive summary
· HIV infection represents a disease area in which nanomedicine can find successful application, improving the efficacy and reducing the toxicity of antiretroviral treatments.
· Nanomedicine applications can improve a variety of pharmacological issues, such as increasing bioavailability and specific targeting to the site of action.
· We are developing a closed-loop design process in which material chemists, pharmacologists, virologists and clinicians collaborate to develop nanomedicines for HIV treatment.
· Our research program aims to produce nanomedicines for oral or parenteral administration of antiretrovirals, with substantial benefit for patients.
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