by Andrew Owen

HIV/AIDS is described by the World Health Organisation as a global pandemic. Estimates show that over 25 million people have died since 1981 and over 33 million people including adults and children are currently living with the disease. In 2005, AIDS claimed an estimated 3.3 million lives globally, including more than 570,000 children. The prevalence of HIV/AIDS continues to increase and it is expected that over 90 million will ultimately be infected in Africa alone. Between 2001 and 2007, the UK had the highest growth in HIV/AIDS infection in Western Europe with a 64% increase.

HIV treatment suffers from many issues including the need for patient compliance with very strict drug regimens. HIV mutation leads to resistance to existing therapies but the ability of therapies to target HIV in the body is critical to the success of medication. HIV resides in various sites throughout the body but there are both cellular and tissue sites which are particularly difficult for drugs to reach. These so called ‘sanctuary sites’ have the potential to be targeted by particles of drug, rather than dissolved drug molecules.

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. A range of unmet clinical needs may benefit considerably from the research and application of new nanoparticle synthesis techniques and the development of appropriate nanomedicines and provision of scale-able, commercially viable technologies that can impact patient outcomes is a key goal of nanomedicine research. Validation of new technologies through optimisation of product performance, demonstration of pharmaceutically relevant manufacturing and in-man pharmacokinetic studies is critical for progression as is the study of nanotoxicology to establish a safety assessment that supports future investment.

Project 1: Solid drug nanoparticles for treatment of HIV/AIDS

To date, a series of candidate solid drug nanomedicines for HIV/AIDS treatment have been generated at the University of Liverpool in collaboration with IOTA NanoSolutions Ltd, a specialist start-up company in the UK, and supported by RCUK (EP/G062196/1) and EPSRC (EP/K002201/1) funding. IOTA is commercialising a novel nanoparticle synthesis technology (initially developed at UoL with EPSRC funding support) that rivals the most successful commercial top-down nanomedicine technology – nanomilling. The HIV/AIDS nanomedicine candidates have been the subject of 3 patent filings and optimisation of their production and their behaviour is currently underway using clinical research techniques. Additionally we are seeking to increase the understanding of nanomedicine behaviour through fundamental mechanistic studies, thereby producing new insight into the mode of action and the safety of future nanomedicines.

If successful, the programme will produce the first nanomedicine options for oral delivery in HIV/AIDS with benefits for patient care potentially including lower dosing, reduced side effects, better patient-to-patient consistency and a reduction of tablet size. Significant interest has been generated within Médecins Sans Frontière who are keen to utilise the outputs for charitable medicines in the developing world, treating children with HIV infection with better products and prevent HIV infection in newborns. Currently, to prevent transmission of HIV to children from infected mothers, the World Health Organisation has recommended dosing from 3 weeks after birth with antiretrovirals. The only children’s medicines available include high levels of alcohol to dissolve the poorly water-soluble drugs. The nanomedcines within this programme are dispersible in water and offer a step-forward in paediatric therapy.

It is hoped that the successful establishment of the fundamental research underpinning new nanomedicines will provide a clear advance in the UK’s global standing in this emerging area.

Project 2: Early evaluation of drug-loaded polydendrons for HIV/AIDS applications

The use of nanoscale polymer carriers which act as vehicles to transport and deliver poorly soluble drugs to the desired site of action, has been beneficial for tumour targeting as the particle nature of the nanomedicine drives the accumulation in tumour tissues. Cellular and tissue sanctuary sites in HIV infection have been widely speculated to also be ideal candidates for particle-based approaches but there has been limited work in this area.

Branched polymers may operate as particle-like drug delivery vehicles and many have been shown to have therapeutic advantages. The best materials are however very expensive to synthesise and would not be viable for treatments in populations such as the sub-Saharan regions (over 20 milllion HIV infections) where cost is a critical component of treatment choice. The University of Liverpool has developed a new class of materials, Polydendrons, which offer many of the benefits of the most sophisticated branched polymers, but can be produced relatively cheaply. In early work, prototype materials have been produced with particle sizes of >40nm and encapsulation capabilities. These materials are unique and still at a very early stage of development.

Through EPSRC funding (EP/I038721/1 ), simultaneously exploration of the synthesis of Polydendrons and their ability to intervene in HIV treatments is being conducted. Polydendrons are being studied as drug carriers of specific size, shape and surface functionality and their ability to target HIV in sanctuary sites is being established. It is hoped that our approach with integrated material synthesis and pharmacology will considerably accelerate the development of potential new therapies generating a leading position for the UK that will be applicable to other health issues such as cancer, tuberculosis and hepatitis C.

Project 3: Early evaluation of drug-loaded nanoemulsions for HIV/AIDS applications

We hypothesize that many of the issues with conventional antiretroviral therapy can be tackled using recent advances at Liverpool in Pickering stabilized nanoemulsion technology. In work funded by the British Society for Antimicrobial Chemotherapy we are developing Pickering emulsifiers to create novel formulations. Nanoemulsions are being evaluated in vitro against resistant and sensitive strains of HIV. Nanomedicines offer the opportunity to target HIV-infected macrophages via endocytosis or phagocytosis, which exhibit greater phagocytic activity than uninfected cells. Therefore, this research approach has the potential to combat resistance by improving bioavailability/targeting and reducing pill burden.