Nanotechnology has the potential to become a powerful tool in addiction medicine and may lead to the development of diagnostic tools, targeted delivery systems and repair platforms. The K08 candidate is a physician whose major area of interest is to develop novel nanotechnology applications for addiction research. As a clinician-scientist she is interested in developing bio-nanotechnology tools that can be used for molecular imaging, diagnosis, prognosis and treatment of drug addiction and associated neuropsychiatric disorders. She has worked on designing and testing (both in vitro and ex vivo) clathrin-based nanoplatforms, nano-computing devises, intelligent nano-scale biosensors and drug/contrast delivery systems that can cross the blood brain barrier (BBB). The proposed K08 training would provide the candidate with the opportunity to gain additional expertise in the areas of MRI and PET imaging methods, and behavioral pharmacology of drug addiction, preparing her to conduct additional multilevel in vivo preclinical and clinical research studies. I doing so, K08 training would further her translational career goals by preparing her for a long-term scientific career conducting innovative, challenging, independent, multidisciplinary research studies in molecular imaging of drug addiction, which would be adaptable to other neuropsychiatric disorders. Methamphetamine (METH) abuse and dependence represent major mental health problems in the US and abroad. PET studies consistently reveal that chronic use of METH results in a reduction in dopamine transporter (DAT) density in the striatum. The DAT is primarily localized in striatum, nucleus accumbens and substantial nigra, and has been implicated in drug abuse as an important target for therapeutic drugs. PET scans have facilitated major advances in studies of METH addiction and drug abuse in general, by using probes selective for DAT and for dopamine receptors. MR-based imaging has low sensitivity for visualization of molecular targets and has not been used for imaging of DAT or dopamine receptors. Thus, the training goals of this K08 application is to learn how to develop non-radioactive bio-nanoparticles that can be used in addiction research for transporter or receptor-based imaging with conventional MRI scanners, which would serve as a solid complement to the already well-developed PET research findings. Because MRI facilities are more plentiful than PET, this research could widen the application of neuroimaging to addiction studies. Two-part nanoprobes (< 100 nanometers) will be designed. One part is a molecular cage carrier containing an MRI contrast agent that will be constructed out of clathrin, a naturally occurring protein the body uses for transporting materials inside cells. The second component will be a molecule that binds with high affinity and high specificity to DAT; this component will be attached to polyethylene glycol molecules coating the carrier. A series of studies will ascertain the specificity and biodistribution of these nanoprobes in vivo. The feasibility of developing MRI tools to detect DAT changes will be demonstrated in the proposed imaging studies of animals exposed to METH. Non-radioactive nanoprobe are valuable because they can be used repeatedly to monitor progression of the disease and recovery process, which may be useful in chronic METH users since their DAT recovery correlated with duration of abstinence. Once these K08 goals are fulfilled, the newly acquired skills will permit the candidate to develop new nanotechnology tools and techniques for MRI molecular imaging that, in theory, could provide similar sensitivity to PET. The development of high-sensitivity, non-radioactive stable molecular nanoprobes will provide a major new research tool for research of receptor and transporter abnormalities in addiction and drug abuse. This new nanotechnology may have utility as an agent to enhance diagnosis, and may serve as a drug-delivery system that can specifically target relevant brain systems.
The proposed K08 training would provide me with the opportunity to gain additional expertise in the areas of MRI and PET imaging methods, and enable me to develop high-resolution stable MRI molecular nanoprobes. Non-radioactive nanoprobes will provide a major new research tool for research of transporter abnormalities in addiction and drug abuse. This new nanotechnology may have utility as an agent to enhance diagnosis, and may serve as a drug-delivery system that can specifically target relevant brain systems.
