The goal of Project 3 is to develop imaging-based methods for elucidating the in-vivo mechanism of action of ErbB-based therapeutic strategies. The imaging technologies proposed, MRI, PET and SPECT, bring combined capabilities for quantitative measurement of anatomic. metabolic and functional properties of tumors and the physical and biological changes brought about by treatment.
The specific aims of this project are organized around the 1) development of imaging probes for SPECT/PET (Specific Aim 1) and MRI (Specific Aim 2) for mapping the biodistribution of ErbB-targeted therapy and measuring receptor density levels; 2) testing of these probes for assessment of therapeutic effects of anti-ErbB2 ILs in experimental models (Specific Aim 3); and 3) evaluation of imaging methods in Phase I1I1 clinical studies of anti-ErbB2 IL therapy (Specific Aim 4). In the first phase of this project, nuclear imaging studies (PET/SPECT) will be directed toward quantitative measurement of the ErbB receptor density and receptor internalization. We will prepare positron and single photon labeled ErbB targeted human single chain Fv antibody fragments. We will evaluate their distribution and metabolism in order to optimize the imaging characteristics and validate their ability to detect changes in receptor status. The MR imaging studies will be directed toward development of a quantitative and non-invasive method to measure the amount of drug-containing liposome delivered to tumors and map its spatial distribution. MR-visible (gadolinium-containing) anti-ErbB immunoliposomes (Gd-ILs) will be used to study the expected distribution of analogous therapy-containing ILs. We will first optimize the signal enhancement characteristics of Gd-ILs in tumors and develop methods to quantify liposome concentrations in-vivo. Gd-ILs will allow us to optimize drug delivery strategies by studying the spatial distribu1ions and time dependence of accumulated liposomes in tumors, blood and liver . In the second phase we will utilize the imaging tools emerging from phase one to investigate the mechanisms of delivery and efficacy of anti-ErbB targeted therapies. Cohorts of mice with ErbB-negative and varying levels of ErbB-positive tumor xenografts will be monitored before and during therapy. Tumor bearing mice will be imaged by both MRI and nuclear modalities. We will study the influence of both tumor and treatment variables on response. Image processing and computational capabilities will be developed so that information from the multiple modalities can be correlated. Phase I/II clinical evaluations of ErbB targeted immunoliposomes carrying doxorubicin are scheduled to begin in the later years of this grant. We will follow patients with the imaging probes and techniques developed in this project to correlate imaging markers with treatment effects.
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