Imaging Tumor Microenvironment / IBB-CNR

The scientific activity is directed towards the development and characterization of contrast agents for Magnetic Resonance Imaging (MRI) based on i) paramagnetic coordination complexes of Gd (III) and / or other lanthanides as responsive probes or with high-relaxivity, ii) molecules of natural origin (natural compounds, proteins, polymers) as biocompatible and safe contrast agents and iii) iodinated compounds used in computed tomography (CT) applications as innovative contrast agents for  CEST (Chemical Exchange Saturation Transfer) imaging at the preclinical level. These new contrast agents are exploited for developing new procedures for the evaluation of the tumor microenvironment (vascularization, acidosis) and to quantify the therapeutic response to drugs in several murine pathological models.

A first line of research has concerned the development of molecules as pH responsive agents, to be able to quantify pH in vivo using magnetic resonance imaging. The candidate contributed to advance the understanding of tumor acidosis, a key aspect of tumor metabolism, through the development and validation of pH-responsive contrast agents and of new methods for the measurement of the tissue pH, for image acquisition and to improve its quantification. For the first time it was possible to measure the acidification of the tumor microenvironment in vivo with high spatial resolution, accuracy and on the whole tumor allowing to demonstrate in vivo the association between acidity of the tumor environment and aggressiveness and providing a new non-invasive method to evaluate the efficacy of innovative anticancer drugs acting on tumor metabolism (Figure 1).

A second line of research concerned the use and development of new methods for measuring pH at the level of the kidneys, promoting their use to evaluate renal function and to evaluate damage and recovery. The kidney is a highly complex organ consisting of well-defined structures that function in a deeply coordinate fashion to allow for fine regulation of pH homeostasis. Although the principal role of the kidney is the maintenance of acid–base balance, current imaging approaches are unable to assess this important parameter and clinical biomarkers are not robust enough in evaluating the severity of kidney damage. Therefore, our lab is developing novel noninvasive imaging approaches to assess the acid–base homeostasis in vivo and to monitor pH evolution following kidney injury (Figure 2). 

A third line of research concerns the development of new molecules, both synthetic and natural, such as new contrast agents for MRI with the aim of improving the efficiency of the contrast or as alternatives to gadolinium complexes to solve the problems of accumulation following repeated injections of the same gadolinium-based agents. On this issue, the results have led to fundamental contributions in the development of contrast agents based on natural compounds with a high safety index, such as pharmaceutical excipients, sugars and glucose derivatives, or manganese complexes or iodinated agents (currently used as a contrast medium for computed tomography) or coordination complexes with paramagnetic ions other than gadolinium or nanosystems demonstrating their use as alternatives to gadolinium which is currently used in clinical investigations by MRI.

A fourth line of research involved the development of macromolecular compounds such as gadolinium-based contrast agents to characterize tumor vasculature and to evaluate response to antiangiogenic drugs or immunotherapies, combined with the development of low-field (1 Tesla) MRI scanners where these contrast agents, following the interaction with macromolecules, have a higher contrast efficiency. Within this vein I have developed new computational methods to predict the interaction with albumin and to characterize the contrast efficiency which led to the development of probes with an efficiency of superior contrast to that of gadolinium-based contrast agents commonly used in the clinic for the development of protocols for DCE-MRI having as application the study of vascularization and permeability/perfusion changes following the angiogenic switch, or to study therapies that target angiogenesis on different tumor models (Figure 3).