Renal-Targeted Inulin-Based Gd/Zn Hybrids for Safe MRI Contrast and Early Fibrosis Mitigation

Dandan Wang,1,2,* Wenyi Zhang,2,* Lin Chen,2,* Yunxiao Mai,2 Haoran Wang,2 Zhenwei Miao,1 Yang Zhao2 1Department of Radiology, Tianjin Medical University Baodi Hospital, Tianjin, People’s Republic of China; 2Department of Radiology, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yang Zhao, Department of Radiology, The Second Hospital of Tianjin Medical University, Tianjin, People’s Republic of China, Email [email protected] Zhenwei Miao, Department of Radiology, Tianjin Medical University Baodi Hospital, Tianjin, People’s Republic of China, Email [email protected]: Gadolinium-based contrast agents (GBCAs), which are indispensable for magnetic resonance imaging (MRI), carry a severe risk of nephrogenic systemic fibrosis (NSF) in patients with chronic kidney disease (CKD), particularly in those with advanced renal impairment. This critical safety concern necessitates the development of biocompatible alternatives that do not compromise diagnostic efficacy.Materials and Methods: Inulin-based nanoparticles (Inulin@Gd/Zn NPs) were synthesized by chelating inulin with gadolinium and zinc ions, aimed at being used as contrast agents that can replace conventional GBCAs. The morphology, size, and zeta potential of the nanoparticles were determined. The anti-fibrotic ability of Inulin@Gadolinium/zinc nanoparticles (Inulin@Gd/Zn NPs) was evaluated in vitro and in vivo, as well as their MRI imaging ability and metabolic performance in normal and fibrotic kidneys. A unilateral ureteral obstruction (UUO) model was created in mice and was used to evaluate the in vivo anti-fibrotic efficacy.Results: The ultra-small Inulin@Gd/Zn NPs (< 10 nm) exhibited high stability and T1 relaxivity. Compared to Gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA), Inulin@Gd/Zn NPs demonstrated precise kidney targeting, excellent T1-weighted MRI capabilities, and rapid renal clearance. In vitro studies showed that Inulin@Gd/Zn NPs had very low cytotoxicity for HK-2 cells up to 100 μM. Further, the NPs were able to reduce reactive oxygen species generation in hydrogen peroxide–stimulated HK-2 cells. Negligible levels of hemolysis and organ toxicity were confirmed in vivo. Further, in the UUO model, administration of Inulin@Gd/Zn NPs was found to significantly inhibit fibrosis. Both in vitro and in vivo experiments demonstrated that Inulin@Gd/Zn alleviated GBCA-induced early tubulointerstitial fibrosis by inhibiting the transforming growth factor-β 1 (TGF-β 1) signaling pathway.Conclusion: Inulin@Gd/Zn NPs represent a promising strategy for clinical application of GBCAs. It addresses the diagnostic and therapeutic challenges in patients with CKD, offering a paradigm shift in the safe application of GBCAs in high-risk populations, indicating the need for further clinical trials to enable clinical applications.Keywords: renal fibrosis, chronic kidney disease, GBCAs, magnetic resonance imaging