Abstract: SA-PO638
Pharmacokinetics and Intra-Renal Accumulation of the Drug Delivery Biopolymer Elastin-Like Polypeptide Is Dependent on its Molecular Weight
Session Information
- Pharmacokinetics, Pharmacodynamics, Pharmacogenomics
November 04, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
Category: Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics
- 1601 Pharmacokinetics, Pharmacodynamics, Pharmacogenomics
Authors
- Kuna, Marija, University of Mississippi Medical Center, Jackson, Mississippi, United States
- Mcgowan, Jeremy William doxie, University of Mississippi Medical Center, Jackson, Mississippi, United States
- Mahdi, Fakhri, University of Mississippi Medical Center, Jackson, Mississippi, United States
- Bidwell, Gene L., University of Mississippi Medical Center, Jackson, Mississippi, United States
Background
The number of patients suffering from chronic kidney disease (CKD) and end-stage renal disease (ESRD) is rising, highlighting the need to identify novel therapies to slow down, stop or possibly reverse progression of the disease. Our lab focuses on the development of a drug delivery system based on a bioengineered protein polymer called elastin-like polypeptide (ELP) and on development of ELP-fusion proteins for renal therapy. Considering our interest in the development of ELP for kidney-targeted drug delivery, the aim of this study is to investigate how the physical characteristics of ELP, particularly its molecular weight (MW), affect its plasma clearance, biodistribution, kidney accumulation, and intra-renal distribution.
Methods
ELP proteins were synthesized, purified and characterized by SDS-PAGE, DLS and turbidity assays. Fluorescently labeled ELPs were used to assess in vitro degradation and in chronic and acute mice studies to define the pharmacokinetics and biodistribution.
Results
Our data show that increasing the ELP MW from 25 kDa to 86 kDa resulted in an increase of the hydrodynamic radius from 4 to almost 7 nm. Degradation studies demonstrated that the proteins are stable for 10 days with negligible degradation at 4°C in both plasma and PBS. The proteins were also stable at 37°C in PBS, but showed time-dependent degradation in plasma at 37°C. After 24 hours, 12-15% degradation was present, and these levels increased to 50% for ELPb-63 (25 kDa) and 24% for ELPb-191 (74 kDa) over the 10-day experiment. However, these degradation rates were slow compared to the plasma clearance rate. ELP plasma half-life increased from 0.84 to 7.05 h with an increase in MW from 25 to 74 kDa. As expected, ELPs accumulated predominantly in the kidneys, with ELPb-63 levels significantly different from the larger proteins. ELPb-63 accumulated mostly in the cortex, while increasing MW resulted in more ELP deposition in the medulla.
Funding
- Other NIH Support