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Development of a nanomedicine-loaded hydrogel for sustained delivery of an angiogenic growth factor to the ischaemic myocardium

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Abstract

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.

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Acknowledgements

The authors acknowledge the support of Brenton Cavanagh for assistance with imaging and Matrigel® analysis.

Funding

Financial support for this project was provided by Science Foundation Ireland (SFI) under an Investigator Award grant number 13/IA/1840 and the AMCARE consortium, a European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 604531.

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Authors and Affiliations

  1. Drug Delivery & Advanced Materials Team, School of Pharmacy & Biomolecular Sciences, Royal College of Surgeons in Ireland (RCSI), Dublin 2, Ireland

    Joanne O’Dwyer, Eimear B. Dolan & Sally Ann Cryan

  2. Tissue Engineering Research Group, Department of Anatomy & Regenerative Medicine, RCSI, 1st Floor, Ardilaun House (Block B), St. Stephen’s Green, Dublin 2, Ireland

    Joanne O’Dwyer, Eimear B. Dolan, Garry P. Duffy & Sally Ann Cryan

  3. Trinity Centre for Biomedical Engineering, Trinity College Dublin (TCD), Dublin 2, Ireland

    Joanne O’Dwyer, Garry P. Duffy & Sally Ann Cryan

  4. Department of Chemistry, RCSI, Dublin 2, Ireland

    Robert Murphy & Andreas Heise

  5. R&D Department, Contipro, Dolni Dobrouc 401, 561 02, Dolni Dobrouc, Czech Republic

    Lenka Kovarova, Martin Pravda & Vladimir Velebny

  6. Faculty of Chemistry, Institute of Physical Chemistry, Brno University of Technology, Purkynova 464/118, 612 00, Brno, Czech Republic

    Lenka Kovarova

  7. CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway (NUIG) & RCSI, Galway, Ireland

    Andreas Heise, Garry P. Duffy & Sally Ann Cryan

  8. AMBER, the SFI Centre for Advanced Materials and Bioengineering, NUIG, RCSI & TCD, Dublin, Ireland

    Andreas Heise, Garry P. Duffy & Sally Ann Cryan

  9. Anatomy, School of Medicine, College of Medicine, Nursing and Health Sciences, NUIG, Galway, Ireland

    Garry P. Duffy

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  1. Joanne O’Dwyer
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Correspondence to Sally Ann Cryan.

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O’Dwyer, J., Murphy, R., Dolan, E.B. et al. Development of a nanomedicine-loaded hydrogel for sustained delivery of an angiogenic growth factor to the ischaemic myocardium. Drug Deliv. and Transl. Res. 10, 440–454 (2020). https://doi.org/10.1007/s13346-019-00684-5

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