Kinetic Modeling of the Molecular Probe 18F-FHBG for Improved PET Reporter Gene Imaging of Stem Cell Therapy
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Imaging by positron emission tomography (PET) has been used for about forty years as an effective tool in the imaging of cancer. This powerful imaging modality now has many uses, both proposed and in practice, in other medical areas. One of these is the relatively new field of regenerative medicine, regeneration of organs or tissues damaged by chronic conditions such as diabetes or liver disease. Often, regenerative medicine depends on cell therapy to achieve its goals and molecular imaging is the only effective way to quantify the resulting data. Molecular imaging includes PET, but the traditional methods of using PET are focused mainly on imaging of cancer. Cell therapy has generally relied on a different type of molecular imaging – optical. Optical imaging involves placing genes (reporter genes) that control bioluminescence or fluorescence in certain organisms into cells that do not contain them. Coupled with cell therapy, measurement of the cells’ expression of added therapeutic gene can be performed by measurement of light produced through bioluminescence or fluorescence. The drawback of optical imaging is that it does not work in deep tissue and therefore will not work in patients. PET, as the name tomography suggests, does not have this issue and will work at any depth. PET also utilizes reporter genes, but also requires the use of molecular probe molecules – positron emitting radionuclides that are analogues of naturally occurring molecules acted on by the proteins produced by the reporter genes. In the traditional use in cancer imaging, the probe molecule is 18F-Fluorodeoxyglucose, an analogue of glucose, with the reporter gene being the naturally occurring hexokinase used in glycolysis. A probe proposed for imaging of cell therapy, the probe being studied in this research, is 18F-Fluorohydroxymethylbutylguanine (FHBG), an analogue of Penciclovir, itself an analogue of guanosine and thymidine, with the reporter gene being the gene for thymidine kinase from the herpes simplex virus (HSV1-tk). The issue with PET imaging is in its sensitivity, five orders of magnitude less than the sensitivity of optical imaging. Previous studies place the number of cells that can be imaged in PET at around 200 million, with any attempts to image fewer cells prevented by an inability to separate signal from background. Therefore, the overall goal of this project is to figure out a way to improve PET sensitivity to optical imaging levels or determine any possible limiting factors that might prevent imaging at that level of sensitivity through the use of mathematical kinetic modeling. The models created for this Master’s dissertation were three compartment models - a recreation of a model described in previous work, a model describing the system as a semibatch bioreactor, an unsteady diffusion-reaction model in rectangular coordinates, a model based on the pre-existing Krogh Cylinder model, and a diffusion-reaction model in cylindrical coordinates not based on any specific model. This final kinetic model was broken into steady state models with a single cell layer in the third compartment, a 100 cell layer in the third compartment, and unsteady models of the first two compartments.