There is an urgent need for non-invasive, sensitive means for quantitatively tracking the pharmacokinetics of biodistribution of agents within small animals for the purposes of therapeutic and diagnostic drug discovery. To date, the Photon Migration Laboratory (PML) at TAMU has established the use of frequency-domain photon migration (FDPM) measurements for 3-D tomographic image reconstructions within large tissue mimicking phantoms whereby the diffusion approximation to light transport applied. On the other hand, the PML, together in a collaborative effort with M.D. Anderson Cancer Center (MDACC), has established a modulated intensified charge coupled camera (ICCD) system for small animal imaging specific for targeting fluorescent contrast agents (at nanomolar dosages within mice up to 144 hours following administration). Yet to date, owing to the inability of using the diffusion approximation to predict light propagation in the small volumes (20-25 grams, 20-25 cc) of mice, there has been little success for simple-to-use small animal tomographic imaging of fluorophores for rapid, quantitative determination of biodistribution using the FDPM ICCD system. Herein, we propose to develop an FDPM ICCD tomographic imaging system at the PML and translate the system to MDACC for establishment of tomographic, small animal imaging and the Small Animal Cancer Imaging Research Facility (SACIRF) at MDACC. The imaging system is based upon filtered back projection imaging for quantitative determination of fluorophore and fluorescent-tagged agents. Developmental aims are to: (i) Construct and adapt an FDPM small animal imager for tomographic projection imaging at the PML for validation in small animal imaging at MDACC's SCAIRF; (ii) Develop, test, and validate back-projection imaging algorithms which include the appropriate level of physics of light propagation for quantitative measurement of fluorescent contrast agent from FDPM measurements simulated from Monte Carlo; (iii) Demonstrate the combined tomographic imaging measurement and algorithm by reconstructing a series of phantoms with varying optical properties and known concentrations of fluorophore; (iv) Demonstrate the measurement and algorithm using tumor bearing, nude mice injected with known quantities of near-infrared (NIR) excitable indocyanine green (ICG) conjugated to a peptide targeting the epidermal growth factor (EGF); (v) Validate the imaging results of the filtered back-projection algorithm using independent measurements of tissue concentration of fluorophore; (vi) Validate the tomographic imaging approach using an optical/nuclear imaging agent, namely 111ln-labeled, ICG-bound EGF conjugates and comparative optical tomography and gamma scintigraphy within the same tumor bearing animal; and (vii) Establish the sensitivity of the tomographic imaging approach and examine methods for combining with anatomical imaging.
