Evaluation of pancreatic cancer influence on liver and kidneys metabolic functions

Abstract

Pancreatic cancer is the fourth leading cause of cancer mortality, with approximately 45,220 new cases and 38,460 deaths expected by the American National Cancer Institute (NCI) in 2013. Resection of the tumor at early stage offers the only chance for relative cure, even in patients that undergo resection of the tumor. The Overall Survival (OS) following primary resection ranges between 11% and 28%. The major causes of persistence of the disease are cancer migration to distant tissues, as such liver and other gastrointestinal (GIT) structures, and chronic loss of metabolic functionality of the supporting GIT during administration of chemotherapy. Liver is the primary recurrence site of the disease, with associated metastasis rate of 62%. Monitoring of the hepatic metabolic processes, as well as evaluation of the renal function, are the most important clinical markers for prescription and design of the therapeutic strategy involving chemo and radiation therapies. Blood and histological analysis, as well as imaging techniques compose the scope of gold standard techniques often used to assess stage diagnostic, functionality and metastatic levels in pancreatic cancer. Bridging nanotechnology and cancer therapy, becomes possible to associate biomagnetic detection techniques to biocompatible magnetic nanoparticles (MNP) in order to access physiological properties. One alternative to evaluate flow of iron-magnetic substances trough GIT organs is the Alternating Current Biosusceptometry (ACB) technique. The ACB sensor measures any displacement or concentration variation of magnetic particles near to the sensor. Thus, it is possible to evaluate transit properties by acquiring the tracer concentration and its variation through time. It is also possible to obtain magnetic images regarding the particles distribution over a tissue or an organ. In this scenario, we propose to investigate the use of ACB technique in combination with MNP to access metabolic functions of pancreas, kidneys and liver in preclinical models of pancreatic cancer. At first, a series of control measurements with the ACB system will be performed using healthy animals in order to calibrate the response of the experimental system to normal standards of metabolic function. Nude mice weighing between 200g and 250g will compound the control group that will receive poly-ethylene glycol (PEG) coated MNPs (pMNPs) intravenously before imaging with both MRI and ACB system. Additionally, organs and blood will be collected in different time points in order to determine the dynamics of nanoparticles' biodistribution. Zinc and Manganese-doped Iron Oxide nanoparticles coated with PEG will be used and intravenously administrated in all the in vivo experiments. The transit profile of MNPs trough organs of interest will be studied along the time by using ACB, and a set of MRIs will be acquired for data comparison. Biodistribution of the MNPs will be studied in two levels: whole organ analysis (integrated ACB system measurements versus ion coupled plasma mass spectroscopy (ICP-MS) of the post-measurement collected organ), and spatial distribution within each organ of interest (ACB measurements versus MRI). Once calibrated for transit flow of MNPs trough healthy organs, the ACB system will be employed to evaluate malfunctioning areas of the cancerous pancreas, liver and kidney at different stages of the disease, as such confined early-stage cancer, spread out disease in the pancreas, and lethal stage in the primary site. Additionally, groups with metastasis in the liver will be monitored along the stages of cancer migration and secondary-tumor growth in the metastatic sites. The results from this step will be compared to the analysis obtained from the control study, in order to elucidate and study morphological and functional patterns of transit flow in organs of interest for pancreatic cancer therapy. (AU)