A crosslinked dextran sulfate-chitosan nanoparticle for delivery of therapeutic heparin-binding proteins

Negatively charged dextran sulfate (DS)-chitosan nanoparticles (DSCS NPs) contain a DS outer shell with binding properties similar to those of heparin and are useful for the incorporation and delivery of therapeutic heparinbinding proteins. These particles, however, are unstable in physiological salt solutions due to their formation through electrostatic interactions. In the present study, a method was developed to covalently crosslink chitosan in the core of the DSCS NP with a short chain dicarboxylic acid (succinate), while leaving the outer shell of the particle untouched. The crosslinked particles, XDSCS NPs, are stable in NaCl solutions up to 3 M. XDSCS NPs were able to incorporate heparin-binding proteins (VEGF and SDF-1 alpha) rapidly and efficiently, and maintain the full biological activity of the proteins. The incorporated proteins were not released from the particles after a 14day incubation period at 37 degrees C in PBS, but retained the same activity as those stored at 4 degrees C. When aerosolized for delivery to the lungs of rats, XDSCS NP-incorporated SDF-1 alpha showed a similar to 17-fold greater retention time compared to that of free protein. These properties suggest that XDSCS NPs could be beneficial for the delivery of therapeutic heparin-binding proteins to achieve sustained in vivo effects.

Automated summary

A stable form of XDSCS NPs has been developed, which can rapidly and efficiently incorporate heparin-binding proteins while maintaining their full biological activity in vivo. XDSCS NPs exhibit high stability in physiological salt solutions and have potential for therapeutic delivery of heparin-binding proteins.