Enhancement of Angiogenesis by Ultrasound-Targeted Microbubble Destruction Combined with Nuclear Localization Signaling Peptides in Canine Myocardial Infarction

Abstract

Objective This study aimed to develop a gene delivery system using ultrasound-targeted microbubbles destruction (UTMD) combined with nuclear localization signal (NLS) and investigate its efficacy and safety for therapeutic angiogenesis in canine myocardial infarction (MI) model. Methods Fifty MI dogs were randomly divided into 5 groups and transfected with Ang-1 gene plasmid: (i) group A: only injection of microbubbles and Ang-1 plasmid; (ii) group B: only UTMD mediated gene transfection; (iii) group C: UTMD combined with classical NLS mediated gene transfection; (iv) group D: UTMD combined with mutational NLS mediated transfection; and (v) group E: UTMD combined with classical NLS in the presence of a nucleus transport blocker. The mRNA and protein expression of Ang-1 gene, microvessel density (MVD) cardiac troponin I (cTnI), and cardiac function were determined after transfection. Results The expression of mRNA and protein of Ang-1 gene in group C was significantly higher than that of the other groups (all P < 0.01). The MVD of group C was 10.2-fold of group A and 8.1-fold of group E (P < 0.01). The cardiac function in group C was significant improvement without cTnI rising. Conclusions The gene delivery system composed of UTMD and NLS is efficient and safe.

Nanomaterials as Ultrasound Theragnostic Tools for Heart Disease Treatment/Diagnosis

“…In this way, they can favor angiogenesis [20], restore the presence of miR-21, which is essential for proper heart functioning [17], downregulate the expression of certain genes such as Gal-7 or (GSK)-3β genes to suppress a local immune response in the heart and hence allow heart grafting [17], or restore atherosclerotic plaque stability [52]. It has been suggested that the gene delivery method for the treatment of heart diseases such as myocardial infarction can be improved by combining UTMD with nuclear localization signal (NLS), which can facilitate DNA transfer from the cytoplasm to nucleus [53]. Through the activation of acidic fibroblast growth factor (FGF1 or aFGF-P), MBs can promote fibroblast development in cardiac tissue to prevent heart failure [18].…”