A Tumor-Specific Nanoimmunocomplex Markedly Improves MR Imaging

DESCRIPTION (provided by applicant): The low rate of cure of pancreatic carcinoma is an important health problem. The American Cancer Society estimates that 32,000 Americans will be diagnosed with carcinoma of the pancreas in 2005, and 31,800 will die. Pancreatic cancer is the fourth leading cause of cancer death in the US. Early detection appears currently to be the only way of improving the high mortality rate, but is quite difficult because of the retroperitoneal location of the pancreas and the lack of symptoms in early disease. We are proposing to further develop a MR tumor targeting imaging agent with a high affinity for entering carcinoma cells. Current imaging methods for the pancreas include ultrasound, CT, MRI, and PET. Each of these is moderately to very good for imaging the pancreas and for staging pancreatic neoplasm, but each relies on indirect signs of carcinoma based on the identification of a mass, lesion vascularity, or its glucose utilization. These features are also present in the main mimicker of pancreatic carcinoma; benign masses from chronic pancreatitis. Anti-transferrin Receptor scFv-antibody fragment (TfRscFv) immunoliposome complex is a nano-construct (<300 nm) for delivery of gene therapy to tumors. It has been shown to target human pancreatic carcinoma cell lines in vivo when implanted as xenografts in athymic nude mice. By placing gadopentetate dimeglumine ("gad-d") into the immunoliposome nanocomplex, new and unique capabilities result in the delivery of gad-d directly into tumor cells which express high levels of the transferrin receptor (TfR). Most normal cells have little or no uptake of this agent. Most human pancreatic carcinoma cell lines overexpress the transferrin receptor. The TfRscFv-immunoiiposome gad-d nanocomplex (scL-gad-d) is biodegradable and the residual components are excreted by the kidney (gad-d) or secreted into the biliary system (liposome). The scL-gad-d demonstrates a high sensitivity for tumor targeting and high specificity having very low uptake into cells in the normal tissues of mice. In our preliminary work with this novel tumor targeting contrast media, we see very high tumor to background uptake in pancreatic carcinoma bearing animals (3 times that of standard gad-d). In this Phase 1 STTR project we will better characterize this agent in animal models, determine optimized dose, optimal time to imaging, and perform toxicity studies in mice in preparation for a future Phase 2 STTR submission to perform a Clinical Phase 1 dose escalation toxicity study.