Optical Imaging of Targeted Anti-Cancer Drug Delivery Kinetics: Project Summary Kevin Webb and Philip Low, Purdue University We propose to determine anti-cancer drug delivery kinetics in vivo using an optical molecular imaging method with nanometer length scale sensitivity. This imaging method will extract fluorescence resonance energy transfer (FRET) parameter images from heavily scattered light through optical diffusion tomography (ODT). Our goal is to establish efficacy in determining targeted anti-cancer drug delivery kinetics. To improve image quality and reduce the computational burden, the subject geometry will be determined using a laser line scan, and an unstructured mesh diffusion model will describe the optical transport. With a folate-targeted FRET indicator, mouse tumors will be imaged in vivo and results compared with those from the euthanized, dissected mice. Once a folate-FRET chemical is internalized into a cancer cell, a disulfide bond reduction causes the acceptor that acted as a quencher to be cleaved from the donor. This cleavage results in increased donor emission and reduced acceptor emission associated with the increase in distance between the donor and acceptor fluorophores. These FRET parameters imaged over time will provide the necessary information to develop spatial maps of the release kinetics. Prior studies have shown that conjugation of either the FRET chemical or the anti-cancer drug to folate does not affect the folate uptake into cancer cells, meaning that the folate-FRET parameters will offer accurate information about folate-drug kinetics. The proposed work will result in quantitative in vivo spatial maps of the number of released acceptor fluorophores as a function of time. Although anti-cancer drugs will not be used in this research, inference for their performance follows because of the identical release process, upon which the drug is activated. Once established, this optical imaging approach will become a tool in the design of new anti-cancer drugs.
Optical Imaging of Targeted Anti-Cancer Drug Delivery Kinetics: Relevance Kevin Webb and Philip Low, Purdue University The proposed work to study folate kinetics will have a significant impact on cancer treatment because 40% of all human cancers, including ovarian, lung, breast, kidney, brain and colon cancer, over-express folate receptors. Additionally, activated macrophages associated with inflammation also over-express folate receptors, allowing folate-targeted treatment and imaging, of importance in cardiovascular disease, which is responsible for 38% of all deaths in North America.
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