Clayton Zoë E, Santos Miguel, Shah Haisam, Lu Juntang, Chen Siqi, Shi Han, Kanagalingam Shaan, Michael Praveesuda L, Wise Steven G, Chong James J H
Westmead Institute for Medical Research, Sydney, NSW, Australia.
Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
Front Bioeng Biotechnol. 2023 Jun 20;11:1127996. doi: 10.3389/fbioe.2023.1127996. eCollection 2023.
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. 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 and . We delivered PPN-PDGF-AB to human cardiac cells and directly to the injured rodent heart. We found no evidence of cytotoxicity after delivery of PPN or PPN-PDGFAB to cardiomyocytes 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. 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.
心肌梗死所致心力衰竭是一种进行性且使人衰弱的病症，影响着全球数百万人。迫切需要新的治疗策略来尽量减少心肌梗死后的心肌细胞损伤，并促进受损心肌的修复和再生。等离子体聚合纳米颗粒（PPN）是一类新型纳米载体，可通过分子负载实现简便的一步功能化。在此，我们将血小板衍生生长因子AB（PDGF-AB）与PPN偶联，构建了一种稳定的纳米制剂，通过最佳的流体动力学参数（包括流体动力学尺寸分布、多分散指数（PDI）和zeta电位）得以证明，并且进一步证明了其安全性、生物活性。我们将PPN-PDGF-AB递送至人心脏细胞，并直接递送至受损的啮齿动物心脏。通过活力和线粒体膜电位测定确定，将PPN或PPN-PDGFAB递送至心肌细胞后，未发现细胞毒性证据。然后我们测量了人干细胞衍生心肌细胞的收缩幅度，发现PPN对心肌细胞收缩性无有害影响。我们还证实，当与PPN结合时，PDGF-AB仍保持功能，PDGF受体α阳性的人冠状动脉血管平滑肌细胞和心脏成纤维细胞对PPN-PDGF-AB表现出与未结合的PDGF-AB相同的迁移和表型反应。在我们的心肌梗死后PPN-PDGF-AB治疗的啮齿动物模型中，我们发现与接受PPN治疗的心脏相比，接受PPN-PDGF-AB治疗的心脏的心脏功能有适度改善，尽管这并未伴有梗死瘢痕大小、瘢痕组成或边缘区血管密度的变化。这些结果证明了PPN平台直接向心肌递送治疗药物的安全性和可行性。未来的工作将优化PPN-PDGF-AB制剂用于全身递送，包括有效剂量和给药时间，以提高疗效和生物利用度，并最终改善PDGF-AB在治疗心肌梗死所致心力衰竭中的治疗益处。
