The 26th International Symposium on Controlled Release of Bioactive Materials was held in Boston, United States, from June 20 to 25. We report here highlights from a programme that set a new record with more than 600 papers and posters and some 100 exhibits
Presentations given at the symposium reflected a growing interest in novel cell- and molecular-based approaches to the study of cellular and intracellular targeting. It is conceivable that future developments in site-specific targeting and the outcome of therapeutic end-results all depend on advances that are being made in cell and molecular biology, as well as understanding the molecular basis of diseases. In medical imaging, such advances may allow direct visualisation of the appropriate site as well as receptor density quantification.
Dr MOEIN MOGHIMI (University of Brighton, United Kingdom) discussed recent developments in design and engineering of nanosized colloids for site-specific medical imaging. He emphasised that, apart from the fact that intravenous administration of radiopharmaceutical particles could enhance detection of liver lesions by scintigraphy, the liver might constitute an obstacle for imaging of spleen and other pathological sites within the cardiovascular system. The use of poloxamer and poloxamine co-polymer non-ionic surfactants for the design of long-circulatory and spleen-specific nanoparticles was therefore reviewed.
Physical adsorption of the co-polymer poloxamine 908 on to the surface of model polystyrene particles (60nm in diameter) had been shown to produce long-circulatory entities (also known as phagocyte-resistant particles). However, adsorption of poloxamine 908 on to the surface of larger beads (200-250nm) produced splenotropic particles (a prototype for detection of abnormal spleen positions, occupying lesions and focal defects, splenic enlargement, and demonstration of accessory spleens after splenectomy).
Data also showed that intravenously injected uncoated small (60nm) and large (250nm) size model polystyrene particles, which were cleared rapidly from the blood by macrophages of the reticuloendothelial system, could be converted in vivo to long-circulatory and splenotropic particles, respectively, if such particles were injected shortly after an appropriate dose of certain non-ionic co-polymers. Interestingly, three days after administration, such co-polymers also stimulated macrophage functions, including phagocytosis. After such stimulation, macrophages were able to recognise and clear long-circulatory particles from the blood.
This observation was useful for scintigraphy of selected pathological sites. Prior administration of poloxamine 908, at an appropriate time before the injection of poloxamine 908-coated particles, reduced the level of circulating particles in scintigraphic studies of inflammation and tumours with leaky vasculature (improving signal-to-noise ratios).
Finally, Dr Moghimi pointed out the importance of realising that considerable heterogeneity existed between different types of macrophages and even among macrophages of the same tissue. Effort was being concentrated on designing nanoparticles with specificity for imaging of stimulated hepatic macrophages, newly recruited monocytes to the liver, and macrophages residing in vulnerable atherosclerotic plaques.
During a two-day session on targeted drug delivery, two presentations were given by Professor BAN-AN KHAW (Northeastern University and Massachusetts General Hospital, Boston, US). In the first, Professor Khaw demonstrated that technetium-99m glucaric acid (T-GA), a dicarboxylic six-carbon sugar, was a myocardial necrosis-avid (and not apoptosis) agent. Professor Khaw suggested that after membrane damage T-GA entered the cytosol and binded to reduced mitochondrial and nuclear proteins. The mechanism of nuclear entry remained to be unravelled.
It was also reported that T-GA could localise to liver and kidney and that this localisation could be increased by insulin administration. Presumably, the T-GA uptake by these organs was mediated via an identical glucose uptake mechanism.
Professor Khaw further pointed out that T-GA could be used for imaging of breast cancer in xenografts as well as in patients. The uptake of T-GA by the tumour, however, was not sensitive to the glycaemic state. Therefore, when imaging with T-GA for cancer diagnosis, a fasting state might provide lower liver activity without concomitant decrease in the tumour target activity.
In a second presentation, Professor Khaw demonstrated successful delivery of galactosidase plasmid vector to hypoxic cardiocyte cultures (H9C2 cells) with cytoskeleton-antigen specific immunoliposomes. Hypoxia was a necessary condition of transient cell injury for successful transfection via immunoliposome-cell fusion. The immunoliposomes plugged and sealed membrane lesions in ischaemic cells, and Professor Khaw suggested that the system was more efficient and target specific than cationic lipids.
The increased efficiency of transfection could be because of direct delivery of the vectors into the cytosol, thereby by-passing the lysosomal degradation of the vectors, a process that was usually encountered by cationic lipid delivery methods. There might be some concern regarding this approach for gene transfer or drug delivery to hypoxic cardiocytes in vivo, as immunoliposomes could activate the complement system. However, such an approach seemed desirable for transfection of skeletal muscle following hypoxia.
Professor PHILIP THORPE (Maine Medical Centre research institute, United States) examined the possibility of targeting the extracellular domain of the human coagulation-inducing protein, tissue factor, to vascular cell adhesion molecule-1 (VCAM-1) and E-selectin on the vasculature of human Hodgkin's tumours growing in mice.
A coaguligand was constructed, consisting of rat IgG against murine VCAM-1 chemically linked to tissue factor. After intravenous injection, the construct caused a profound thrombosis in 40-70 per cent of the tumour vessels.
Professor Thorpe pointed out that the vasculature of the heart and the lungs in all tumour-bearing animals was resistant to the thrombotic action of the coaguligand construct, despite the localisation of the conjugate to VCAM-1-positive vessels of both organs. This suggested that normal vessels might lack an ancillary molecule needed to support the coaguligand's action. Subsequently, the ancillary molecule on tumour endothelium was identified as phosphatidylserine (PS). This phospholipid was known to participate in thrombic reactions by binding and concentrating coagulation factors II, VII, IX and X. Therefore, such coaguligands directed against VCAM-1 and E-selectin might be selective thrombotic agents for the treatment of solid tumours.
A remarkable point, deserving further investigation, was the expression of PS by tumour endothelium, as PS was believed to be an apoptotic marker.
This splendid approach by Professor Thorpe must be viewed cautiously from the clinical point of view; on the event of release from tumour vessels the thrombo-emboli might cause a sudden vascular occlusion in vital organs (eg, lung).
Professor VLADIMIR TORCHILIN (Northeastern university, United States), discussing the concept of antibody therapeutics, demonstrated that certain monoclonal antinuclear autoantibodies (monANAs) originating from healthy ANA-positive mice of a non-autoimmune strain showed strong reactivity against the surfaces of many cancer cells of human and rodent origin, but not against normal cells. These monANAs showed specificity for nucleosomes that were expressed on the surface of tumour cells, where they acted as inhibitors of natural killer cells. Professor Torchilin postulated a beneficial role of antinucleosome autoantibodies as tumour-protective agents for an ageing host or for antibody-mediated cancer therapy.
Dr M. SUZUKI (National Institute of Health, Bethesda, United States) introduced the concept of immunotoxin construction for cancer therapy. He presented an interesting strategy that endowed cytotoxicity to human ribonucleases by sterically blocking their binding to ribonuclease inhibitor. — Contributed by Dr S. M. Moghimi (school of pharmacy and biomolecular sciences, University of Brighton).
Polymeric systems for drug delivery and tissue engineering
In a plenary lecture reviewing the application of polymeric systems for drug delivery and tissue engineering, Professor ROBERT LANGER (Massachusetts Institute of Technology, United States) placed emphasis on bioerodible polymers, particularly polyanhydrides, that had been approved by the Food and Drug Administration for human use and had been explored as vehicles to release both large and small bioactive molecules.
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Role of physiology in tumour drug delivery
In a plenary lecture, Professor RAKESH JAIN (Harvard medical school) discussed the role of physiology in drug delivery into tumours, including microcirculatory barriers and its implications for novel therapies, such as antiangiogenic therapy. To obtain an insight into microcirculatory barriers, Professor Jain and his colleagues had developed genetically engineered mice to monitor gene expression in vivo.
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