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The aim of this project is to investigate the feasibility of using non-linear optical enhancement to boost weak molecular signals. The project will require two lines of investigation: (1) development of novel detection schemes to heighten discrimination of molecular signals over the metallic response. (2) A comprehensive and methodical investigation into how the non-linear response of metallic nanostructures can be altered by geometric factors, exploring high Q structures such as ring resonators which can exhibit high local-field enhancements outside the metal.
The aim of this project is to develop a strategy for using nanoparticles as contrast agents that are suitable for both MRI and optical microscopy. The motivation is to provide a tool to correlate the uptake of pharmaceuticals at the tissue scale (measured with MRI) with the location of the pharmaceutical on the cellular scale (measured with optical microscopy).
The Grand Challenge is the treatment of brain diseases. Brain diseases span pain, sleep disorders, schizophrenia, mood disorders and neurodegenerative conditions. At any time 450 million persons worldwide are living with mental, neurological or behavioural illnesses and 24 million people worldwide suffer from dementias. The treatment of brain diseases is hampered by the blood brain barrier (BBB), a barrier between the blood and the brain which does not permit the passage of most drug molecules, due to the tightness of the intercellular capillary junctions, low uptake activity of capillary cells and the activity of efflux transporters. Previous attempts to target drugs to the brain and cross the BBB have involved the use of targeting ligands, e.g. mouse monoclonal antibodies for carrier mediated uptake or the inhibition of the above mentioned efflux transporters. However all of the particulate-based strategies (including the use of mouse monoclonal antibodies) that have been investigated over the last two decades have yet to yield any clinical products and the inhibition of the high capacity efflux transporters, which incidentally are not merely confined to the BBB, is not a viable clinical option.
Development of Heterodyne Coherent Anti-Stokes Raman Scattering Microscopy for Monitoring Nanoparticle Drug Delivery
At present, 95% of all potential new drug compounds cannot be directly administered as a pharmaceutical due to poor biocompatibility, i.e. they have poor solubility, unacceptable levels of toxicity, or become metabolised by the body before reaching the site of interest. Nanoparticle drug delivery can overcome these problems by encapsulating the compounds in particles less than 1 thousandth of a millimetre in size. Moreover, nanoparticles can act as depositories for controlled drug release and can be tailored to actively target specific sites within the body.
Metal oxide nanomaterials are being used for an increasing number of commercial applications, such as fillers, opacifiers, catalysts, semiconductors, cosmetics, microelectronics, and as drug delivery vehicles. The effects of these nanoparticles on the physiology of animals and in the environment are largely unknown and their potential associated health risks are currently a topic of hot debate. Information regarding the entry route of nanoparticles into exposed organisms and their subsequent localization within tissues and cells in the body are essential for understanding their biological impact. However, there is currently no imaging modality available that can simultaneously image these nanoparticles and the surrounding tissues without disturbing the biological structure.Due to their large nonlinear optical susceptibilities, which are enhanced by two-photon electronic resonance, metal oxides are efficient sources of coherent anti-Stokes Raman Scattering (CARS). We have shown that CARS microscopy can provide localization of metal oxide nanoparticles within biological structures at the cellular level.
Imaging has been mainly focused on articular cartilage to see if this technique can show early changes related to osteoarthritis. Cartilage has been imaged with both second harmonic generation (SHG) and two photon fluorescence (TPF), with the SHG showing the collagen fibres and the TPF mapping indigenous fluorophores. In these images the cells can clearly be resolved and in the TPF rings of increased intensity can be seen surrounding the cells corresponding to the pericellular matrix. Images at lesion sites show changes in both the structure of the matrix and the cells. Additional information on the order of the collagen fibres is provided by polarization sensitive SHG microscopy. SHG intensity depends on the polarization of the excitation laser beam with respect to the collagen fibres. Therefore polarization sensitive studies of the SHG have been used to see structural changes which occur in cartilage at an osteoarthritic lesion. Other collagen based tissues such as pericardium, intervertebral disc and arteries are also being investigated. Non-linear microscopy is a very promising technique for these tissues as both the collagen and elastin fibres in these tissues can be clearly seen and distinguished with the collagen fibres producing SHG and the elastin fibres producing TPF at a longer wavelength.
Raman scattering is a well-established technique for structural analysis of biophysical molecules. A Raman spectrum contains information
relating to both molecular composition and conformation making it an ideal technique for analysis of complex biophysical systems such as
intracellular signalling pathways. However, the low scattering cross-section associated with the technique restricts its sensitivity and
has prevented its application in such areas. The scattering cross-section can be greatly increased by combining Raman spectroscopy with
the exciting properties of metallic nanostructures, a techniques known as surface enhanced Raman scattering (SERS) which results in a vast
amplification of the Raman signal when molecules are absorbed onto specific metallic nanometre-scale structures.
In this project we propose to combine SERS with colloidal immunostaining to investigate intracellular signalling.
Antibody labelled gold nanoparticles will be used to enhance the Raman signal from specific cell receptors.
This technique will be applied to detect conformational changes in cell receptor proteins arising from various
external stimuli. Multiphoton imaging will be used to verify the location of the nanoparticles.