BBB seminar: Gillian Barratt
The use of colloidal drug delivery systems to improve the therapeutic index of drugs
National Center for Scientific Research (UMR CNRS), University Paris-Sud 11, France
The role of a drug carrier is to control the fate of a drug after administration, which depends mainly on the physicochemical properties of the drug and therefore on its chemical structure. Drug carriers are designed to modify drug distribution within the organism, but they may also affect absorption, metabolism and elimination.
Colloidal drug carriers, which include liposomes and nanoparticles, are small enough to be administered by a general route and to carry an active product to its site of action. It should be noted, however, that after intravenous administration most colloidal carriers are rapidly removed from the circulation by phagocytic cells in the liver and spleen. This limits their potential to deliver their contents to specific sites. Therefore, systems whose surface properties have been modified to reduce the deposition of plasma proteins and subsequent recognition by phagocytes have been developed. These are known as sterically stabilized carriers a nd remain in the blood compartment for a considerable time. Although such colloidal particles cannot cross normal continuous capillary endothelium, they have been shown to extravasate into sites where the endothelium is more permeable, such as solid tumours or regions of inflammation and infection.
The most effective method of steric stabilization is to graft polyethylene glycol (PEG) chains onto the surface of the carrier. This strategy has been applied to nanocapsules (NC), a reservoir form in which a polymeric shell encloses an oily core capable of carrying a high payload of lipophilic drug, as well as liposomes and nanospheres (NS). The polymeric wall of the NC was composed of blends of poly(D,L-lactide) (PLA) and diblock copolymers PLA-PEG. NC bearing PEG indeed showed complement-rejecting properties in vitro, as well as decreased association with a macrophage-like cell line, as a function of PEG chain length and density. The same tendency was shown in vivo when the NC were injected intravenously to mice: NC with a dense covering of 20-kDa PEG exhibited the longest time in the circulation.
The therapeutic potential of these long-circulating NC would be to provide circulating reservoirs of a drug in the blood and to convey a drug to accessible sites outside the vasculature, in particular when the endothelial barrier is leaky as in the case of infection, inflammation and vasculature supplying solid tumours. As an example of the use of NC as circulating reservoirs of drugs, the results of encapsulating an extremely lipophilic antimalarial drug, halofantrine, are described. The delivery of anti-cancer drugs by long-circulating NC has also been studied with two different drug classes. Meta-tetra (hydroxyphenyl) chlorin, a photosensitizer used in photodynamic therapy, was incorporated into the oily core of NC. PLA-PEG NS and NC have also been loaded with the pure antiestrogen RU 58668.
A second research interest in our group is the development of lipid-based colloids for the administration of Amphotericin B (AMB), a broad-spectrum antifungal agent. For over two decades, research has been directed towards incorporating AmB into lipid-based drug delivery systems in order to reduce its toxicity and three such systems are now commercially available. The aim of the research carried out in our laboratory was to develop a lipid formulation which could be manufactured by a simple and reproducible procedure. Thus, stable dispersions of AMB with phospholipids (LC-AMB) were prepared by a nanoprecipitation technique. Their toxicity and efficacy against Leishmania donovani were investigated. More recently, we have focused on the combination of AMB with another lipophilic antileishmanial agent, miltefosine (HePC), with the aim of reducing doses and thus preventing the occurrence of resistance.
Host: Astrid Bårdgard <astrid.bardgard[@]fa.uib.no>, Department of Research Management