Ultrasound combined with targeted cationic microbubble-mediated angiogenesis gene transfection improves ischemic heart function

Abstract

The present study aimed to construct targeted cationic microbubbles (TCMBs) by synthesizing cationic microbubbles conjugated to an intercellular adhesion molecule-1 (ICAM-1) antibody, and then to use the TCMBs to deliver the angiopoietin-1 (Ang-1) gene into infarcted heart tissue using ultrasound-mediated microbubble destruction. It was hypothesized that the TCMBs would accumulate in higher numbers than non-targeted cationic microbubbles (CMBs) in the infarcted heart, and would therefore increase the efficiency of targeted Ang-1 gene transfection and promote angiogenesis. The results of the study demonstrated that the ability of TCMBs to target inflammatory endothelial cells was 18.4-fold higher than that of the CMBs in vitro. The accumulation of TCMBs was greater than that of CMBs in TNF-α-stimulated human umbilical cord veins, indicated by a 212% higher acoustic intensity. In vivo, the TCMBs specifically accumulated in the myocardial infarct area in a rabbit model. Three days after ultrasound microbubble-mediated gene transfection, Ang-1 protein expression in the TCMB group was 2.7-fold higher than that of the CMB group. Angiogenesis, the thickness of the infarct region and the heart function of the TCMB group were all significantly improved compared with those in the CMB and control groups at 4 weeks following gene transfection (all P<0.01). Therefore, the results of the current study demonstrate that ultrasound-mediated TCMB destruction effectively delivered the Ang-1 gene to the infarcted myocardium, resulting in improved cardiac morphology and function in the animal model. Ultrasound-mediated TCMB destruction is a promising strategy for improving gene therapy in the future.

Microbubbles and Nanobubbles with Ultrasound for Systemic Gene Delivery

“…This is due to the accumulation of bubbles by specific ligands for the target site could allow for the enhancement, not only of the imaging effects, but also of the delivery efficiency. For these purposes, antibody-modified bubbles have been developed [ 55 , 56 , 57 , 58 , 59 ] ( Figure 3 d). For instance, the targeted microbubbles using antibodies against mucosal addressin cell adhesion molecule-1 (MAdCAM-1) or vascular adhesion molecule-1 (VCAM-1) were useful in the ultrasound imaging and gene therapy in crohn’s disease [ 55 ].…”

“…For instance, the targeted microbubbles using antibodies against mucosal addressin cell adhesion molecule-1 (MAdCAM-1) or vascular adhesion molecule-1 (VCAM-1) were useful in the ultrasound imaging and gene therapy in crohn’s disease [ 55 ]. In case of myocardial infarction, antibodies against matrix metalloproteinase-2 (MMP2) or intercellular adhesion molecule-1 (ICAM-1) could enhance the ability of the microbubbles to increase the effects of imaging and delivery [ 56 , 58 ]. Similarly, it has been reported that the CD105 (endoglin) antibody was available for antiangiogenic tumor therapy, and that microtubule-associated protein-2 (MAP-2) antibody could elevate the therapeutic efficacy in spinal cord injury [ 57 , 59 ].…”

Cationic gas-filled microbubbles for ultrasound-based nucleic acids delivery

“…However, despite a good acoustic response of these MBs, the level of gene transfer was rather low likely due the large size of the resulting particles (>1 µm) and the intracellular fate of pDNA. Cationic MBs targeted CD105 [ 73 ] or ICAM-1 [ 74 ] protein have been developed for gene delivery of endostatin or angiopoietin-1 respectively.…”

<p>Ultrasound-Mediated Co-Delivery of miR-34a and sPD-1 Complexed with Microbubbles for Synergistic Cancer Therapy</p>

“…20 Over the years, ultrasound microbubble-mediated gene therapy research has never been interrupted, including tumors, thrombosis and cardiovascular disease. 21,22 As a cavitation nucleus, microbubbles can oscillate, shrink, swell or even rupture under ultrasonic radiation of a certain frequency. Cavitation and somatoporation enhance cell membrane permeability and promote gene release.…”