Ultrasound-Targeted Microbubble Destruction-Mediated Co-Delivery of Cxcl12 (Sdf-1alpha) and Bmp2 Genes for Myocardial Repair.

Acute myocardial infarction (AMI) is a serious threat to human health. Stem cells can serve as ideal seed cells for myocardial repair and regeneration; however, insufficient homing to the infarcted areas and poor myocardial differentiation limit their further clinical application. Chemokine (C-X-C motif) ligand 12 (CXCL12) is an important stem cell homing factor, and Bone morphogenetic protein-2 (BMP2) is a differentiation-promoting factor. In this study, we designed microbubbleadenovirus complexes and investigated the functional benefit of co-delivery of Cxcl12 and Bmp2 genes in adenoviral vectors by ultrasound-targeted microbubble destruction (UTMD) for myocardial repair in AMI rats. By transfection of rat bone marrow mesenchymal stem cells (BMSCs), high transfection efficiency was achieved under ultrasound irradiation, and successful myocardial differentiation of the transfected BMSCs was induced after ultrasound-mediated-transfection of Bmp2 in vitro. In the AMI rat model, co-delivery of Cxcl12 and Bmp2 at a ratio of 2:1 may result in significantly higher myocardial repair efficacy compared to transfection of Cxcl12 or Bmp2 only. Higher myocardial repairing efficacy was achieved with co-delivery of Cxcl12 and Bmp2 at a ratio of 2:1 than using a ratio of 1:1 or 1:2, as evidenced by smaller infarction size, higher micro-vessel density, and better recovery of cardiac function at 28 days after treatment. Hence, UTMD-mediated co-transfection of Cxcl12 and Bmp2 significantly promoted the repair/regeneration of the infarcted myocardium, thereby providing a promising approach for the repair of cardiac injury.