Imaging, Nuclear Targeting and Modulation of DNA Damage Responses by Polyfunctionalized Nanoparticles in Tumour Cells

Looking small thinking big - what is nanotechnology? One of the definitions of nanotechnology describes it as:
?The design, characterization, production, and application of structures, devices, and systems by controlled manipulation of size and shape at the nanometer scale (atomic, molecular, and macromolecular scale) that produces structures, devices, and systems with at least one novel/superior characteristic or property.? There are quite a few other definitions as well and some confusion about what nanotechnology really means. In simple terms we can say that nanotechnology is a science of small bits of man-made materials that are about thousand to ten thousand times smaller than the thickness of human hair. The ?man-made? is important because otherwise all natural molecules and material particles would have to be included. What is also important is that these small bits of material can gain very unusual and unique properties, not found in the bigger pieces. Our research is trying to exploit these new qualities of the old materials to improve the health prospects of cancer patients. We shall change the surface properties of tiny gold and platinum spheres made in our laboratory in such a way that will allow them to find,enter and mark cancer cells so X-rays machines and other scanners used in diagnostic procedures can better see them. They will also have the ability to amplify the effects of radiation used for treating tumours and to knock-down cancer cell defences against it. Does it mean then that small is always beautiful? Not really. As much as these new tiny nanoparticles can gain the unique properties that are desirable and useful, in the same way their new qualities can be unexpectedly harmful. We shall investigate these potentially harmful effects in normal human cells, so we can select the particles that would have the most potent effects on the cancer cells whilst being the least harmful to surrounding normal cells.

Nanotechnology represents the area of science focused on the manipulation of atoms and molecules that leads to new structures in the nanometer scale range. These structures often gain unique and unexpected properties. In cancer nanotechnology the focus is on development of nanoscale devices that can diagnose, deliver therapeutic agents, and monitor cancer treatment progress. The early and efficient detection of small cancer (and, possibly, pre-cancerous) lesions remains the most important goal of diagnostic imaging. Increasing target selectivity is critical for nanovectors acting as carriers for both imaging and therapeutic payloads. Ideally, any imaging or therapeutic system would be exclusively targeted to the tumour cell clusters or tumour cell vasculature, preferably with the ability to do so at early stages of malignant transformation. Effective as all the individual approaches might be by themselves, we believe that the greatest gains will be achieved by their synergistic combination. The past decades had seen an outstanding progress in our understanding of the fundamental cancer biology, but this development was not accompanied by comparable advances in the clinic. For example the radiation therapy in humans benefited much more from the technical progress and computerization rather than from knowledge-based manipulation of the biological responses of cancer cells to therapeutic radiation. In this proposal, we introduce the development of novel, multi-functional nanocariers that would translate our understanding of DNA damage responses and new nano-imaging technologies into more efficient ways of diagnosis and treatment of cancer. Our strategy is to design and test multifunctional gold and platinum nanoparticles with following desired properties:

? Potential for in vivo imaging of targeted tumour cells
? Increased target selectivity for cancer cells
? Capability to increase the dose efficacy of radiotherapy and ability to inhibit DNA damage responses in targeted cells

In line with the MCMB Committee?s recommendations regarding our previous, more extensive, application, this is a proof-of-principle streamlined research proposal that will focus on the development of prototype polyfunctional nanoparticles with selected properties followed by testing predicted specificity of biological responses in vitro only.