LAUSR

Heparan sulfate (HS) is a sulfated polysaccharide with a wide range of biological activities. There is increasing interest in the development of structurally homogeneous HS oligosaccharides as therapeutics. However, the factors influencing the pharmacokinetic properties of HS-based therapeutics remain unknown. Here we report the pharmacokinetic properties of a panel of dodecasaccharides (12-mers) with varying sulfation patterns in healthy mice and uncover the pharmacokinetic properties of an octadecasaccharide (18-mer) in acutely injured mice. In the 12-mer panel, one 12-mer, known as dekaparin, is anticoagulant, and three 12-mers are non-anticoagulant. The concentrations of 12-mers in plasma and urine were determined by the disaccharide analysis using a liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We observed a striking difference between anticoagulant and non-anticoagulant oligosaccharides in the 12-mer panel, showing that anticoagulant dekaparin had a 4.6-to-8.6-fold slower clearance and 4.4-to-8-fold higher plasma exposure, compared to non-anticoagulant 12-mers. We also observed that the clearance of HS oligosaccharides is impacted by disease conditions. Using an anti-inflammatory 18-mer, we discovered that the clearance of 18-mer is reduced 2.8-fold in a liver failure mouse model compared to healthy mice. Our results suggest that oligosaccharides are rapidly cleared renally if they have low interaction with circulating proteins. We observed that the clearance rate of oligosaccharides is inversely associated with the degree of binding to target proteins, which can vary in response to pathophysiological conditions. Our findings uncover a contributing factor for the plasma and renal clearance of oligosaccharides which will aid the development of HS-based therapeutics.