The present and future role of ultrasound targeted microbubble destruction in preclinical studies of cardiac gene therapy

Abstract

Multiple limitations for cardiac pharmacologic therapies like intolerance, individual variation in effectiveness, side effects, and high cost still remain, despite the recent progress in diagnosis and health support. Gene therapy is poised to be an attractive alternative in various ways for the future, refractory cardiac diseases being one aspect of it. As a novel therapy to deliver the objective gene to organs of living animals, ultrasound targeted microbubble destruction (UTMD) has therapeutic potential in cardiovascular disorders. UTMD, which binds microbubbles with DNA or RNA carriers into the shell and destroys the located microbubbles with low frequency and high mechanical index ultrasound can release target agents to specific organs. UTMD has the ability to transfect markedly through sonoporation, cavitation and other effects by way of intravenous injection that is minimally invasive and highly specific for gene deliverance. Here, we have summarized the present role of UTMD in pre-clinical studies of cardiac gene therapy which covers myocardial infarction, regeneration, ischaemia/reperfusion injury, hypertension, diabetic cardiomyopathy, adriamycin cardiomyopathy and some discussion for further studies.

Materials promoting viral gene delivery

“…Physical methods such as microinjection, 68,69 microfluidic, 70,71 sonication, 72,73 centrifugation, 74 cellular deformation, 75 laser irradiation 76,77 or electroporation 78,79 induce or facilitate cell entry of vectors by mechanical force, mainly through disrupting the plasma membrane. They are commonly applied in non-viral gene delivery because they transport the genetic information easily without the need for carriers and the otherwise low infectivity.…”

Ultrasound Microbubbles for Diagnosis and Treatment of Cardiovascular Diseases

“…Nevertheless, there is still a need for a better optimization of the microbubble composition, especially in the field of drug or gene delivery, as the loading capacity of the pharmaceutical agent should be increased but the microbubble acoustic properties have to be maintained. 23 Furthermore, targeting strategies of microbubbles to molecules expressed on vessels with high shear stress needs to be improved to increase the sensitivity in detecting these targets. Next to the microbubble composition, new technical inventions like the introduction of real three-dimensional US transducers can lead to a better plaque characterization and endoleak detection.…”

“…21,22 Furthermore, microbubbles can be used as theranostic agents by incorporation of drugs or genes into the shell or the gas core. 12 The drugs or genes can be released precisely at the target tissue by con-trolled destruction of the microbubbles using an US pulse with high mechanical index 23 (►Fig. 1).…”

“…46,47 Despite the significant potential of CEUS-based therapies, there is still a need to optimize treatment parameters, as many adverse events, like microvascular leakage, intracardiac hemolysis, capillary rupture, or inflammatory cell infiltration have been described in rodents. 23…”

Assessment of the Preventive Effect Against Diabetic Cardiomyopathy of FGF1-Loaded Nanoliposomes Combined With Microbubble Cavitation by Ultrasound

“…It is difficult to maximize the efficacy of the drug in cardiac aggregation. Combined with UTMD, the cavitation effect and mechanical action produced by the instantaneous blasting of ultrasound microbubbles can cause temporary open pores (Chen et al, 2013;Qian et al, 2018;Zhao et al, 2018) on the endothelial cell membrane and capillaries of the myocardium. The target delivery of FGF1-nlip to the myocardium can realize the rapid release of the target and rapid penetration, thus realizing the myocardial transmission of FGF1 and exerting its biological function.…”