The use of cationic microbubbles to improve ultrasound-targeted gene delivery to the ischemic myocardium

Sun, Lu; Huang, Chun-Chao; Wu, Jun; Chen, Ko-Jie; Li, Shuhong; Weisel, Richard D.; Rakowski, Harry; Sung, Hsing‐Wen; Li, Ren‐Ke

doi:10.1016/j.biomaterials.2012.11.041

Cited by 76 publications

(61 citation statements)

References 23 publications

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“…Studies have also indicated that CMBs may protect the bound DNA against the endonuclease degradation, resulting in an increased DNA concentration at the target site 10. Sun et al reported that UTMD via CMBs enhances gene transfection efficiency and improves the cardiac function in the rat ischemic myocardium compared with the commercially available Definity MBs 11. Additionally, Panje et al demonstrated that CMBs enhance UTMD-mediated gene delivery to mouse skeletal muscle relative to neutral MBs 12.…”

Section: Introductionmentioning

confidence: 99%

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction

Zhang¹,

Sun²,

Ren³

et al. 2017

Theranostics

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Hypoxia-inducible factor 1α (HIF-1α) plays a critical protective role in ischemic heart disease. Under normoxic conditions, HIF-1α was degraded by oxygen-dependent prolyl hydroxylase-2 (PHD2). Gene therapy has become a promising strategy to inhibit the degradation of HIF-1α and to improve cardiac function after ischemic injury. However, conventional gene delivery systems are difficult to achieve a targeted and localized gene delivery into the ischemic myocardia. Here, we report the localized myocardial delivery of shRNA against PHD2 through ultrasound-targeted microbubble destruction (UTMD) for protection the heart from acute myocardial infarction. In this study, a novel cationic microbubble was fabricated by using of the thin-film hydration and sonication method. The resulting microbubbles had a 28.2 ± 2.21 mV surface zeta potential and could greatly improve DNA binding performance, achieving 17.81 ± 1.46 μg of DNA loading capacity per 5 × 108 microbubbles. Combined with these cationic microbubbles, UTMD-mediated gene delivery was evaluated and the gene transfection efficiency was optimized in the H9C2 cardiac cells. Knockdown of PHD2 gene was successfully realized by UTMD-mediated shPHD2 transfection, resulting in HIF-1α-dependent protective effects on H9C2 cells through increasing the expression of HIF-1α, VEGF and bFGF. We further employed UTMD-mediated shPHD2 transfection into the localized ischemic myocardia in a rat ischemia model, demonstrating significantly reduced infarct size and greatly improved the heart function. The silencing of PHD2 and the up-regulation of its downstream genes in the treated myocardia were confirmed. Histological analysis further revealed numbers of HIF-1α- and VEGF-, and CD31-positive cells/mm2 in the shPHD2-treated group were significantly greater than those in the sham or control vector groups (P < 0.05). In conclusion, our study provides a promising strategy to realize ultrasound-mediated localized myocardial shRNA delivery to protect the heart from acute myocardial infarction via cationic microbubbles.

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Section: Introductionmentioning

confidence: 99%

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction

Zhang¹,

Sun²,

Ren³

et al. 2017

Theranostics

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“…Recently microbubble-mediated ultrasound (MUS) has been increasingly used to improve the therapeutic effects of ultrasound in the fields of transdermal drug delivery, thrombolysis, and transfection of gene vectors [11, 12]. Microbubbles have a gas-filled structure, stabilized by a protein, lipid, or polymer shell; some microbubbles have been clinically approved as contrast agent.…”

Section: Introductionmentioning

confidence: 99%

Microbubble-Mediated Ultrasound Enhances the Lethal Effect of Gentamicin on PlanktonicEscherichia coli

Zhu

Cai

Shi

et al. 2014

BioMed Research International

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Previous research has found that low-intensity ultrasound enhanced the lethal effect of gentamicin on planktonic E. coli. We aimed to further investigate whether microbubble-mediated low-intensity ultrasound could further enhance the antimicrobial efficacy of gentamicin. The planktonic E. coli (ATCC 25922) was distributed to four different interventions: control (GCON), microbubble only (GMB), ultrasound only (GUS), and microbubble-mediated ultrasound (GMUS). Ultrasound was applied with 100 mW/cm2 (average intensity) and 46.5 KHz, which presented no bactericidal activity. After 12 h, plate counting was used to estimate the number of bacteria, and bacterial micromorphology was observed with transmission electron microscope. The results showed that the viable counts of E. coli in GMUS were decreased by 1.01 to 1.42 log10 CFU/mL compared with GUS (P < 0.01). The minimal inhibitory concentration (MIC) of gentamicin against E. coli was 1 μg/mL in the GMUS and GUS groups, lower than that in the GCON and GMB groups (2 μg/mL). Transmission electron microscopy (TEM) images exhibited more destruction and higher thickness of bacterial cell membranes in the GMUS than those in other groups. The reason might be the increased permeability of cell membranes for gentamicin caused by acoustic cavitation.

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“…Cardiac function by ejection fraction was also enhanced with UMGD of AKT, as well as the perfusion intensity analysis by contrast-enhanced echocardiography. 74 In addition to small animal models, cardiac UMGD has been shown to be effective in larger animals, namely canine cardiac models. Yuan et al in 2012 studied the effects of UMGD by direct injection of the gene vector into the canine heart using a therapeutic gene, HGF.…”

Section: Therapeutic Applications Of Umgdmentioning

confidence: 99%

Ultrasound-targeted cardiovascular gene therapy

Lee

Matkar

Kuliszewski

et al. 2014

Cardiac Regeneration and Repair

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The use of cationic microbubbles to improve ultrasound-targeted gene delivery to the ischemic myocardium

Cited by 76 publications

References 23 publications

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction

Localized Delivery of shRNA against PHD2 Protects the Heart from Acute Myocardial Infarction through Ultrasound-Targeted Cationic Microbubble Destruction

Microbubble-Mediated Ultrasound Enhances the Lethal Effect of Gentamicin on PlanktonicEscherichia coli

Ultrasound-targeted cardiovascular gene therapy

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