Plasma polymerized nanoparticles are a safe platform for direct delivery of growth factor therapy to the injured heart

Zoë E Clayton; Miguel Santos; Haisam Shah; Juntang Lu; Siqi Chen; Han Shi; Shaan Kanagalingam; Praveesuda L Michael; Steven G Wise; James J H Chong

doi:10.3389/fbioe.2023.1127996

Plasma polymerized nanoparticles are a safe platform for direct delivery of growth factor therapy to the injured heart

Front Bioeng Biotechnol. 2023 Jun 20:11:1127996. doi: 10.3389/fbioe.2023.1127996. eCollection 2023.

Authors

Zoë E Clayton^{1

2}, Miguel Santos^{3

4}, Haisam Shah^{1

2}, Juntang Lu⁵, Siqi Chen¹, Han Shi^{1

2}, Shaan Kanagalingam¹, Praveesuda L Michael^{3

4}, Steven G Wise^{3

4}, James J H Chong^{1

2

5}

Affiliations

¹ Westmead Institute for Medical Research, Sydney, NSW, Australia.
² Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
³ School of Medical Sciences, Faculty of Health and Medicine, The University of Sydney, Sydney, NSW, Australia.
⁴ Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia.
⁵ Cardiology Department, Westmead Hospital, Sydney, NSW, Australia.

Abstract

Introduction: Heart failure due to myocardial infarction is a progressive and debilitating condition, affecting millions worldwide. Novel treatment strategies are desperately needed to minimise cardiomyocyte damage after myocardial infarction and to promote repair and regeneration of the injured heart muscle. Plasma polymerized nanoparticles (PPN) are a new class of nanocarriers which allow for a facile, one-step functionalization with molecular cargo. Methods: Here, we conjugated platelet-derived growth factor AB (PDGF-AB) to PPN, engineering a stable nano-formulation, as demonstrated by optimal hydrodynamic parameters, including hydrodynamic size distribution, polydisperse index (PDI) and zeta potential, and further demonstrated safety and bioactivity in vitro and in vivo. We delivered PPN-PDGF-AB to human cardiac cells and directly to the injured rodent heart. Results: We found no evidence of cytotoxicity after delivery of PPN or PPN-PDGFAB to cardiomyocytes in vitro, as determined through viability and mitochondrial membrane potential assays. We then measured contractile amplitude of human stem cell derived cardiomyocytes and found no detrimental effect of PPN on cardiomyocyte contractility. We also confirmed that PDGF-AB remains functional when bound to PPN, with PDGF receptor alpha positive human coronary artery vascular smooth muscle cells and cardiac fibroblasts demonstrating migratory and phenotypic responses to PPN-PDGF-AB in the same manner as to unbound PDGF-AB. In our rodent model of PPN-PDGF-AB treatment after myocardial infarction, we found a modest improvement in cardiac function in PPN-PDGF-AB treated hearts compared to those treated with PPN, although this was not accompanied by changes in infarct scar size, scar composition, or border zone vessel density. Discussion: These results demonstrate safety and feasibility of the PPN platform for delivery of therapeutics directly to the myocardium. Future work will optimize PPN-PDGF-AB formulations for systemic delivery, including effective dosage and timing to enhance efficacy and bioavailability, and ultimately improve the therapeutic benefits of PDGF-AB in the treatment of heart failure cause by myocardial infarction.

Keywords: cardiac fibroblast; cardiomyocytes; coronary artery smooth muscle cells; myocardial infarction; nanoparticles; platelet derived growth factor (PDGF).

Grants and funding

This work was partially funded by a grant from the Sydney Cardiovascular Initiative. The CVI Catalyst Award provided seed funding to conduct the in vitro experiments presented in this manuscript. JJHC was supported by an Investigator Grant APP1194139 from National Health and Medical Research Council of Australia and a Clinician Researcher grant from the Ministry of Health, New South Wales.