Abstract: FR-PO992
Kidney-Targeting Nanoparticles for Drug Delivery in Polycystic Kidney Disease
Session Information
- PKD Cellular Pathogenesis, ARPKD, ADTKD, Ciliopathies
October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidney
- 1001 Genetic Diseases of the Kidney: Cystic
Authors
- Chung, Eun ji, University of Southern California, Los Angeles, California, United States
- Wang, Jonathan, University of Southern California, Los Angeles, California, United States
- Li, Hui, University of Southern California, Los Angeles, California, United States
- Hallows, Kenneth R., Keck School of Medicine of USC, Los Angeles, California, United States
Background
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive kidney cyst growth and leads to ESRD. Currently, one drug, tolvaptan has been recently FDA-approved to decrease cyst expansion, although repurposed drugs such as metformin and rapamycin used for diabetes and immunosuppression, have also been proposed. Unfortunately, these drugs suffer from short half-life, poor bioavailability, and adverse side effects. To mitigate these limitations, we describe the development of kidney-targeting multimodal micelles (KMs) that accumulate in the kidneys and can deliver therapy for ADPKD via oral administration.
Methods
KKEEE3K is synthesized on an automated peptide synthesizer, and conjugated to DSPE-PEG2000. Metformin, cy7, and peptide amphiphiles are purified by HPLC and mass spectrometry. Upon micelle construction, nanoparticles were characterized by dynamic light scattering, transmission electron microscopy (TEM), and zeta potential. To assess therapeutic efficacy in vitro, mouse cortical collecting duct cells were treated with metformin-KMs and AMPK activation measured by immunoblotting against phospho-AMPK and ENaC current. Towards oral delivery of nanoparticles, KMs were encapsulated into chitosan nanocapsules to enhance mucoadhesion and passage through the GI tract.
Results
KMs and non-targeting (NT) micelles were found to have an average diameter of 15.0 and 12 nm, and zeta potential -7.8 and -1.4 mV, respectively. To test therapeutic effciacy, mouse cortical collecting duct cells incubated with 300 uM metformin-KMs showed enhanced activation of phospho-AMPK and decreased ENaC current compared to metformin-NT micelles or free metformin. Chitosan nanocapsules were developed by ionic gelation using sodium tripolyphosphate. TEM images showed chitosan particles were between 20-150 nm in diameter, which is large enough to encapsulate KMs. Current work includes investigating additional factors affecting chitosan particle size, stability, and mucoadhesive strength, such as deacetylation, molecular weight, and tri-methylation of chitosan, and assessing metformin-KM release kinetics, adhesion to CaCo-2 cells, and in vivo therapeutic studies in ADPKD mouse models.
Conclusion
Our approach is the first nanomedicine effort for ADPKD and will provide many new insights as well as potentially establish a novel therapeutic for ADPKD.
Funding
- Other NIH Support