Leibniz-Forschungsinstitut für molekulare Pharmakologie

Robert-Rössle-Straße 10

Room: A 3.26

13125 Berlin

Telephone: +49 30 947 93 279

Email: werner@fmp-berlin.de

 

Quantification of alterations in ECM composition by switchable Xe-MRI reporters

PIs: Schröder, Taupitz, Bick

Application areas: Cancer, extracellular matrix, osteoarthritis

Modality: MRI

Background: Extracellular markers like matrix metalloproteinases (MMP´s) could provide important diagnostic information related to tumor growth, invasion and metastasis. However, relaxivity-based contrast agents do not provide enough sensitivity to visualize related processes like proteolytic degradation of ECM and alteration of cell-cell/ECM interactions.

Aim: It has been shown that the survival rate of patients increases dramatically with an early stage disease detection at the earliest possible time point. By achieving this goal we can focus on the preservation of health and not on the recovery.

Methods: Xe-biosensors have the potential to detect specific disease markers at nanomolar concentrations. The combination of Xe that underwent spin exchange optical pumping (SEOP) and the indirect detection by using Chemical Exchange Saturation Transfer (Hyper-CEST) enables a theoretical 10^7-fold signal enhancement compared to normal MRI measurements. A big advantage is that the contrast which is generated can be switched on and off through the MRI pulse sequence and is not masked by the background MRI signal. Based on the group expertise in designing Xe-biosensors and by using novel hyper-CEST methods we will pursue a two-fold approach to detect ECM changes: a) by addressing enzymes such as MMPs that are the cause of the degradation and b) by visualizing the loss of certain collagens that are result of ECM alteration.  The first part will be based on novel Hyper-CEST methods using a smart sensor activated by MMP-induced hairpin cleavage. The second aspect of this project will be the detection of collagen II in the context of osteoarthritis and the interaction of MMP2, MMP9 with collagen IV due to related ECM digestion. This also links to the migration of metastatic cells in different animal cancer models. To support our results, the quantification of the ECM structural changes will be correlated to histology and biophysical methods.