Abstract: TH-PO759
Glomerular Disease Augments Kidney Accumulation of Synthetic Polymers
Session Information
- Bioengineering
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Bioengineering
- 300 Bioengineering
Authors
- Liu, Gary, University of Washington, Seattle, Washington, United States
- Prossnitz, Alexander, University of Washington, Seattle, Washington, United States
- Eng, Diana G., University of Washington, Seattle, Washington, United States
- Cheng, Yilong, University of Washington, Seattle, United States
- Pippin, Jeffrey W., University of Washington, Seattle, Washington, United States
- Shankland, Stuart J., University of Washington, Seattle, Washington, United States
- Pun, Suzie, University of Washington, Seattle, Washington, United States
Background
Targeted polymeric drug carriers can significantly improve the solubility and therapeutic profiles of their drug cargoes, while minimizing side effects and toxicity. Physicochemical properties of the carriers drive organ accumulation and are therefore important in the design process. However, carrier properties such as polymer size and charge that are important for kidney targeting are not well understood or reported. To answer some of these questions, here we tested the effects of polymer charge and molecular weight (MW) on kidney distribution.
Methods
A panel of low-MW (LMW) polymers with fixed MW (~25 kDa) and increasing anionic content (0, 50, 80%) was intravenously injected into mice, and tissue accumulation was quantified after 7 days. A high-MW (HMW), highly anionic (47 kDa, 80% anionic) polymer as well as mice with experimental glomerular disease were used to test the effects of MW and loss of filtration selectivity on polymer distribution.
Results
LMW polymers exhibited increasing kidney accumulation with increasing anionic content, and this trend was statistically significant (p-value < 0.0001). Confocal imaging of kidney sections revealed that polymers accumulated mostly in proximal tubules. Glomerular disease significantly augmented kidney accumulation of LMW 80%, but not HMW 80%, polymers. In vitro, LMW 80% polymers did not cause significant changes in viability in cultured proximal tubule cells, and were shown to be uptaken by active endocytosis. Dextran sulfate, a competitor of scavenger receptors, significantly reduced polymer uptake (p-value < 0.0001).
Conclusion
This study revealed important features of polymers that drive kidney accumulation: highly anionic polymers with MW ~25 kDa preferentially accumulate in the kidneys and specifically in proximal tubules, and glomerular disease enhances accumulation. Importantly, these polymers were not cytotoxic in vitro, and were uptaken by endocytosis and/or anionic scavenger receptors. These findings establish an important foundation in developing targeted drug carriers for kidney disease applications.
Funding
- Other U.S. Government Support