Development of Heterodyne Coherent Anti-Stokes Raman Scattering Microscopy for Monitoring Nanoparticle Drug Delivery

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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.Nanoparticle drug delivery is known to greatly improve the effectiveness of a pharmaceutical and has found a wide range of applications, with different routes of administration including oral, intravenous, transcutaneous and ocular. However, the mechanisms by which these nanoparticles travel through, interact with, and modify tissues and how this relates to the improved drug performance are still unclear. These are critical questions that need to be answered in order to develop future pharmaceuticals, with lower dosing rates and reduced side effects. Our ability to answers these questions is greatly hindered by that fact that there is currently no imaging modality available to directly visualise such small particles and the structure and function of the surrounding tissue, without the aid of contrast agents. Current imaging modalities derive image contrast of the nanoparticles by means of external labels. Moreover, with these techniques it not possible to detect when and how the nanoparticles release the drug without replacing the drug with an active contrast agent. We propose to test the feasibility of a novel type of optical microscopy for performing label-free measurements.Coherent Anti-Stokes Raman Scattering, or CARS, microscopy is an optical technique in which image contrast is derived from the intrinsic chemical makeup of a sample. Preliminary work has shown that CARS can be used to image nanoparticle drug carriers against a background of biological tissues. However, modifications are required to the instrument before the technique can be fully exploited. In this proposal we plan to make such modifications and test the effectiveness of the new system for monitoring nanoparticle drug delivery to tissues and cells.A successful outcome of this project will produce a tool that can provide new information of the fundamental mechanisms underlying nanoparticle drug delivery. It will allow pharmacologists to rationally design more efficient, safer, and less invasive drug delivery systems.