Targeted delivery of galunisertib attenuates fibrogenesis in an integratedex vivorenal transplant and fibrosis model

Abstract

Normothermic machine perfusion is an emerging preservation technique for kidney allografts to reduce post-transplant complications, including interstitial fibrosis and tubular atrophy. This technique, however, could be improved by adding antifibrotic molecules to perfusion solutions. We established Machine perfusion and Organ slices as a Platform for Ex vivo Drug delivery (MOPED), to explore fibrogenesis suppression strategies. We perfused porcine kidneys ex vivo with galunisertib, a potent inhibitor of the transforming growth factor beta signaling pathway. To determine whether effects persisted, we also cultured precision-cut tissue slices prepared from the respective kidneys. Galunisertib supplementation improved the general viability, without negatively affecting renal function or elevating levels of injury markers or byproducts of oxidative stress. Galunisertib also reduced inflammation and more importantly, strongly suppressed the onset of fibrosis, especially when the treatment was continued in slices. Our results illustrate the value of targeted drug delivery, using isolated organ perfusion, for reducing post-transplant complications.

Microfluidic‐Assisted Production of Gastro‐Resistant Active‐Targeted Diatomite Nanoparticles for the Local Release of Galunisertib in Metastatic Colorectal Cancer Cells

“…[10] However, even though cancer treatment has benefited from the NP-based formulations that have reached the market, only a few studies have investigated the delivery of galunisertib via NPs. [11,12] Therefore, the potential of galunisertib-loaded NPs for the oral treatment of CRC remains poorly explored. Our group demonstrated that the loading of galunisertib in gelatin-modified diatomite NPs (DNPs) enhances the antimetastatic effect of the drug in CRC cells due to a matrix metalloproteinase-triggered release from the gelatin matrix.…”