NanoKFT

Fibrosis is defined as an excessive accumulation of extracellular matrix (ECM) components such as certain collagens, and is the leading cause of morbidity and mortality in chronic diseases. Major efforts have focused on preventing ECM synthesis, but these have been unsuccessful and conceptually unsuitable for the clinical situation where fibrosis is usually detected at an advanced stage of the disease, when organs already display advanced fibrotic lesions. The NanoKFT project proposes to change the paradigm of fibrosis treatment by focusing on ECM degradation instead of on ECM synthesis in the context of chronic kidney disease. Interstitial collagen accumulation depends on the balance between synthesis and proteolytic degradation. A partially uncoiled conformation of the collagen fiber is necessary for proteases to have an optimal physical access to their cleavage site. Increasing the temperature is a way to promote uncoiling of collagen fibers, thereby facilitating their degradation. This can be achieved by using the properties of nanoparticles capable of releasing thermal energy upon exposure to alternating high frequency magnetic fields. In NanoKFT, we propose a highly innovative, non-invasive anti-fibrotic strategy using targeted nanotherapy. We aim to generate moderate and non-lethal hyperthermia in the fibrotic kidney ex-vivo (WP1) and in vivo (WP2) using functionalized iron oxide nanoparticles (IONPs) designed to specifically target interstitial collagen fibers. The hypothesis is that localized hyperthermia will cause collagen fibers to uncoil, thereby promoting the accessibility of endogenous proteases to their cleavage site and thus the degradation of interstitial collagen. To carry out this ambitious interdisciplinary project, NanoKFT brings together experts in renal fibrosis and targeted nanotherapy.