Developing supramolecular heparin-peptide materials as injectable anticoagulant depots
Open Access
- Author:
- Pimcharoen, Sopida
- Area of Honors:
- Biomedical Engineering
- Degree:
- Bachelor of Science
- Document Type:
- Thesis
- Thesis Supervisors:
- Scott H Medina, Thesis Supervisor
William O Hancock, Thesis Honors Advisor
Justin L Brown, Faculty Reader - Keywords:
- Heparin
Anticoagulation
Peptide
Drug Delivery
Depot - Abstract:
- Heparin, a potent naturally derived carbohydrate anticoagulant, is a widely accepted blood thinner used in several therapeutic settings, including deep vein thrombosis and cerebral hemorrhage (stroke). Heparin is typically administered as an intravenous infusion, and due to its short serum half-life (approx. 60-90 minutes) must be administered frequently to counter its rapid clearance. However, frequent dosing increases the likelihood of user error and infuser malfunction, both of which can lead to heparin overdosing. This can lead to severe bleeding complications and death, particularly in neonates and small children. Herein, we develop an injectable material that sustainably releases heparin to allow for less frequent dosing of patients and reduce the incidence of overdose complications. The biomimetic platform is prepared via electrostatic interaction of the anionic glycan heparin sulfate and a de novo designed MAD1 peptide (Mycomembrane-Associated Disruption 1 sequence). Although originally designed as an antimicrobial therapy for Tuberculosis, MAD1 shows strong molecular interactions with heparin, leading to the supramolecular assembly of Heparin-MAD1 Granules (HMG). Under physiologic conditions HMG complexes remain stable at the macro-scale, while controllably releasing heparin via material erosion. Moreover, MAD1 is shown to impart an additional mode of precision by preferentially targeting pre-formed clots by binding to platelet membranes, thereby locally delivering heparin to actively forming thrombi. Furthermore, HMG complexes were highly biocompatible, showing minimal hemolytic and cytotoxic activity in model red blood cells and vascular endothelium. We show that HMG complexes are gradually cleared by macrophage cells to restore blood clotting abilities and avoid long term anticoagulation. And last, we conducted systemic in vivo demonstration to show that our HMG formulations were able to prolong anticoagulation activity of Heparin for an order of magnitude higher. In conclusion, we have developed supramolecular materials that act as subcutaneous injectable vehicles to allow for less frequent dosing of patients and reduce the incidence of overdose complications. In addition, the shelf-stable, easy-to-administer heparin formulations described here may also open opportunities for their use in non-clinical settings (e.g., battlefield).