Opportunities for nanomedicine in the management of atherosclerosis will be considered this afternoon in a joint Symposium with the European Atherosclerosis Society. The prefix ‘nano’ derives from the Greek for ‘dwarf’, with nanoparticles defined as small objects behaving as whole units with respect to transport. Similar in scale to biological macromolecules, such as proteins and DNA, nanomolecules, typically in the range of 1-100 nanometres in size, can be engineered to deliver payloads of different drugs in atherosclerosis.
By attaching antibodies, proteins, peptides or other ligands to the surface, a nanoparticle can be targeted to single or multiple receptors on the surface of atherosclerotic plaques. Additionally, neovascularisation, arising from compensatory defence mechanism to restore nutrient supply to the vessel wall, can allow nonspecific targeting of atherosclerosis by nanoparticles.
‘The big advantage of packaging drugs into nanoparticles,’ explains Erik Stroes, from the Academic Medical Centre, Amsterdam, ‘is that you can deliver high concentrations to the area of interest, enabling efficacy to be increased and side effects reduced.’ Thus, using nanoparticles to deliver glucorticoids in atherosclerosis provides an example of how specific targeting of agents might help patients. Although widely used for anti-inflammatory effect in rheumatoid arthritis, glucocorticoids have not been used in CVD because of their pro-atherogenic effects. Experimental animal models have demonstrated their local administration via PEGylated liposomes has the ability to reduce neo-intimal formation and arterial wall inflammation.
Although 75% of macrophages isolated from the plaques contained liposomes, there was, however, no anti-inflammatory effect. ‘We are now in the position where we know we can deliver drugs directly to plaques using nanoparticles,’ says Stroes. ‘But it appears inflammation in atherosclerotic plaques may be distinct from classical inflammation. We need to go back to the drawing board and consider if other anti-inflammatory agents might prove a better choice and if we should change delivery systems.’
In mouse atherosclerotic models it has been shown that nanoparticles exploiting the inherent targeting properties of HDL can deliver statins. Near infra-red fluorescence images reveal nanoparticle accumulate in plaque-rich regions of the aorta, where they co-localised with macrophages. The investigators showed the arteries of mice given the nanoparticle were 16% more open than arteries in mice with no treatment, and 12% more open than mice given systemic statins.
Use of nanoparticles in cardiology undoubtedly lags behind oncology, where Doxil, a liposomal formulation of doxorubicin, was first approved in 1995 by the FDA. ‘The reason for this is that in patients with advanced cancer, high-risk nanoparticulate drugs may be approved as long as they prolong life by a few months,’ explains Iwona Cicha from University Hospital, Erlangen, Germany. ‘However, many CVD patients live with their conditions for years, which makes the potential toxicity risks posed by nanoparticles unacceptable.’ Nanotoxicology, she adds, is emerging as an important area in the field of nanomedicine.
Nanoparticles, says Cicha, can be enormously varied in composition and frequently have multicomponent formulations. In addition to the different types of drugs or contrast agents attached to their surface, antibodies or ligands can be used to achieve specific targeting. The size, shape, surface charge and colloidal stability of nanoparticles can all be modified. Size matters, says Cicha, with nanoparticles smaller than 5 nanometres being quickly cleared by the kidney and those above 100 nanometres rapidly cleared by the liver.
Every parameter you change, says Cicha, can influence circulation half-life, and the biological effects of nanoparticles. ‘Right now,’ she says, ‘nanoparticulate medicines are not treated any differently from other drugs, but regulators must soon realise that their characterisation needs to be standardised. For safety reasons, we all need the reassurance that nanoparticles intended for CV applications have been put through a whole range of defined analytical and toxicity tests.’
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