Abstract: PO0173
Triptolide Treats Renal Tubular Injury Induced by Renal Ischemia-Reperfusion Through Specific Delivery of Kidney-Targeting Nanoplatform
Session Information
- AKI Mechanisms - 1
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Tao, Zeng, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
- Li, Aiqing, Southern Medical University Nanfang Hospital, Guangzhou, Guangdong, China
Background
Triptolide (TP) has been proved to be effective in the treatment of a variety of kidney diseases. Unfortunately, its clinical application is limited because of its high toxicity and low specificity. Here, we report a novel and safe kidney-targeting nano-platform for specific delivery of TP.
Methods
Nano-polymer MNPs-TP was synthesized by encapsulating TP in a mesoscale nanoparticles (MNPs) with kidney targeting ability. MNPs-TP was injected into mice via tail vein to evaluate its toxicity to organs and immune system, and compared with free TP. The targeting and mechanisms of MNPs-TP treatment were explored by organ imaging, Transwell and other experimental methods. Finally, the model of renal ischemia-reperfusion injury (IRI) in mice was established, and the protective effects and mechanisms of TP and MNPs-TP on renal tubules in different concentrations were compared.
Results
Toxicity test showed serious pathological changes in liver,testes and the proportion of CD4+/cd8+ in blood of mice in TP group,while MNPs-TP showed no obvious toxic effect on these organs and immune system. The organ imaging and pharmacokinetic experiments indicated that free TP showed a fast metabolism and no specificity in the distribution of free TP in various organs, while the MNPs-TP showed longer metabolic cycle and clear kidney targeting. Immunofluorescence assay of kidney sections showed that MNP-TP was mainly concentrated in the cytoplasm of renal tubular cells.After administration of TP at the dose of 0.1mg/kg body weight to the IRI mice, the renal function represented by BUN and SCr of IRI mice was alleviated .Down-regulation of p-ERK and NGAL suggested that TP could help protect the renal tubules by down-regulating MEK-ERK pathway and alleviated apoptosis of renal tubules. Free TP at the dose of 0.01mg/kg lacked these protective effects, and surprisingly, MNPs-TP kept the protection,which demonstrated that the effective therapeutic dose of MNPs-TP was significantly lower relative to free TP.
Conclusion
MNPs-TP showed superior therapeutic effect on renal ischemia-reperfusion injury in comparison with TP. Furthermore, MNPs-TP conjugate presented much lower hepatotoxicity and no adverse effect on the immune and genital system. The kidney-targeting MNPs may provide a promising drug delivery platform of hydrophobic drugs for treatment of renal diseases.