The 5-year mortality rate for heart failure borders on 50%. The main cause is an ischaemic cardiac event where blood supply to the tissue is lost and cell death occurs. Over time, this damage spreads and the heart is no longer able to pump efficiently. Increasing vascularisation of the affected area has been shown to reduce patient symptoms. The growth factors required to do this have short half-lives making development of an efficacious therapy difficult. Herein, the angiogenic growth factor Vascular Endothelial Growth Factor (VEGF) is complexed electrostatically with star-shaped or linear polyglutamic acid (PGA) polypeptides. Optimised PGA-VEGF nanomedicines provide VEGF encapsulation of > 99% and facilitate sustained release of VEGF for up to 28 days in vitro. The star-PGA-VEGF nanomedicines are loaded into a percutaneous delivery compliant hyaluronic acid hydrogel. Sustained release of VEGF from the composite nano-in-gel system is evident for up to 35 days and the released VEGF has comparable bioactivity to free, fresh VEGF when tested on both Matrigel® and scratch assays. The final star-PGA-VEGF nanomedicine-loaded hydrogel is biocompatible and provides sustained release of bioactive VEGF. Therefore, we report the development of novel, self-assembling PGA-VEGF nanomedicines and their incorporation into a hyaluronic acid hydrogel that is compatible with medical devices to enable minimally invasive delivery to the heart. The final star-PGA-VEGF nanomedicine-loaded hydrogel is biocompatible and provides sustained release of bioactive VEGF. This formulation provides the basis for optimal spatiotemporal delivery of an angiogenic growth factor to the ischaemic myocardium.

Department of Chemistry RCSI Dublin 2 Ireland

Department of Chemistry RCSI Dublin 2 Ireland CÚRAM SFI Research Centre for Medical Devices National University of Ireland Galway and RCSI Galway Ireland AMBER the SFI Centre for Advanced Materials and Bioengineering NUIG RCSI and TCD Dublin Ireland

Drug Delivery and Advanced Materials Team School of Pharmacy and Biomolecular Sciences Royal College of Surgeons in Ireland and RCSI Galway Ireland AMBER the SFI Centre for Advanced Materials and Bioengineering NUIG RCSI and TCD Dublin Ireland

Drug Delivery and Advanced Materials Team School of Pharmacy and Biomolecular Sciences Royal College of Surgeons in Ireland Dublin 2 Ireland

Drug Delivery and Advanced Materials Team School of Pharmacy and Biomolecular Sciences Royal College of Surgeons in Ireland St Stephen's Green Dublin 2 Ireland

R and D Department Contipro Dolni Dobrouc 401 561 02 Dolni Dobrouc Czech Republic

R and D Department Contipro Dolni Dobrouc 401 561 02 Dolni Dobrouc Czech Republic Faculty of Chemistry Institute of Physical Chemistry Brno University of Technology Purkynova 464 118 612 00 Brno Czech Republic

Tissue Engineering Research Group Department of Anatomy and Regenerative Medicine RCSI 1st Floor Ardilaun House and RCSI Galway Ireland AMBER the SFI Centre for Advanced Materials and Bioengineering NUIG RCSI and TCD Dublin Ireland Anatomy School of Medicine College of Medicine Nursing and Health Sciences NUIG Galway Ireland

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