Abstract: SA-PO066
Kidney-Targeting Nanoplatform for the Specific Delivery of Triptolide to Treat Renal Ischemia-Reperfusion Injury
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Tao, Zeng, State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Li, Aiqing, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Li, Jiawen, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
Background
Triptolide (TP) has been proved with a therapeutic effect on a few kinds of kidney diseases. However, its clinical application is limited due to high toxicity and low specificity. Herein, we report a novel kidney-targeting, safe nanoplatform for the specific delivery of TP.
Methods
TP was wrapped in a kind of meso-scale nanoparticles (MNPs) with promising kidney-targeting ability to synthesize the nano-polymer MNPs-TP. TP and then it was administrated to mice through tail vein to evaluate its toxicity to organs and immune system. The targets of MNPs-TP and its mechanism were explored by organ imaging, Transwell and other experimental methods. Finally, a mouse model of renal ischemia/reperfusion injury (IRI) was applied to explore the protective effects and mechanism of different concentrations of TP and MNPs-TP on renal tubules.
Results
The toxicity test showed serious pathological changes in liver and the proportion of CD4+/cd8+ also decreased in TP group, suggesting immune function was damaged. However, MNPs-TP showed no obvious toxic effect on organs and immune system. The pharmacokinetic experiments showed that free TP had no specificity in the distribution in various organs, while the MNPs-TP showed longer metabolic cycle and clear kidney targeting. Transwell experiments showed that renal tubular epithelial cells could ingest MNPs-TP from the basal medium and transport it to the apical side, suggesting that the uptake of MNPs-TP is related to their endocytosis and exocytosis. After administration of TP at the dose of 0.1mg/kg body weight to the IRI mice, the renal function assessed by BUN and SCr was alleviated .The lower score of renal tubular injury, and the down-regulation of p-ERK and NGAL further verified the therapeutic effect of TP. However, free TP at the dose of 0.01mg/kg lacked these protective effects, and surprisingly, MNPs-TP still showed 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 (IRI) model 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.
Funding
- Government Support - Non-U.S.