Ultrasound-triggered microbubble destruction in combination with cationic lipid microbubbles enhances gene delivery

Zhang, Li; Lin, Yingying; Xiang, Guangya; Lv, Qing; Huang, Gui; Yang, Yali; Zhang, Yanrong; Song, Yue; Zhou, Huan; Xie, Mingxing

doi:10.1007/s11596-011-0147-3

Cited by 9 publications

(8 citation statements)

References 34 publications

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“…The studies of ultrasound technique combined with microbubbles such as UCAs have shown that it enhances the local delivery of genes and drugs to specific target tissues. 44 In the case of lipid microbubbles encapsulated with gas, such as SonoVue, the lifetime is significantly longer than that of free microbubbles with air in the same conditions. Hence, SonoVue injected into the peritoneal cavity can act as active seeds of cavitation near tumor cells during sonication.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of in vivo antitumor effects of ANT2 shRNA delivered using PEI and ultrasound with microbubbles

et al. 2015

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Gene therapy using RNA interference can be directed against tumors through various strategies, but has been hindered owing to the inefficiency of non-viral delivery. To evaluate the antitumor effects of adenine nucleotide translocase-2 (ANT2) short hairpin RNA (shRNA) by intraperitoneal injection using the polyethylenimine (PEI) and an ultrasound gene delivery method, human breast carcinoma MDA-MB-231 cells were injected subcutaneously into NOG (NOD/Shi-scid/IL-2Rγ(null)) mice. The results showed greater tumor regression (*P<0.05) as well as an increased survival rate in the group receiving ANT2 shRNA+two types of enhancer relative to the groups receiving ANT2 shRNA without enhancer. These findings demonstrate that the introduction of PEI and ultrasound with SonoVue exerted enhanced antitumor effects in vivo. Although the combination of jet-PEI and ultrasound provided the best results with respect to tumor regression, the antitumor effects from the individual enhancers were approximately equivalent. In addition, we confirmed that there was no toxicity on aspartate aminotransferase and alanine aminotransferase levels in the liver and albumin, blood urea nitrogen or creatine kinase levels in the kidney following the various gene delivery methods.

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Section: Discussionmentioning

confidence: 99%

Evaluation of in vivo antitumor effects of ANT2 shRNA delivered using PEI and ultrasound with microbubbles

et al. 2015

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“…Although many techniques have been explored, the optimal delivery method for miRNA remains to be well determined. Recently, some reports have shown that ultrasound technique combined with microbubble could enhance miRNA delivery to specific target tissues employing different frequencies . The most useful advantage of ultrasound as a therapeutic system is that ultrasound can focus on a specific area .…”

Section: Discussionmentioning

confidence: 99%

Evaluation of in vivo antitumor effects of low‐frequency ultrasound‐mediated miRNA‐133a microbubble delivery in breast cancer

Han

Shao

et al. 2016

Cancer Medicine

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MicroRNAs (miRNAs), as a novel class of small noncoding RNAs, have been identified as important transcriptional and posttranscriptional inhibitors of gene expression. Ultrasound‐targeted microbubble destruction (UTMD) is a noninvasive method for microRNA delivery. We aimed to investigate the effect of UTMD of miR‐133a on breast cancer treatment. It has been reported that miRNA‐133a is involved in various cancers. miR‐133a was lowly expressed in breast cancer tissues and breast cancer cell lines MCF‐7 and MDA‐MB‐231. The miR‐133a expression was significantly upregulated under exogenous miRNA‐133a treatment in MCF‐7 and MDA‐MB‐231 cells analyzed by qRT‐PCR. Exogenous miR‐133a promoted the cell proliferation as determined by diphenyl tetrazolium bromide (MTT) assay and 5‐ethynyl‐2′‐deoxyuridine (EdU) staining. Epidermal growth factor receptor (EGFR) expression and Akt phosphorylation were significantly suppressed after miR‐133a transfection by western blot detection. We prepared the miR‐133a‐microbubble and injected it into breast cancer xenografts. The miR‐133a‐microbubble injection prolonged miR‐133a circulatory time by detecting the amount of miRNA‐133a in the plasma. No significant toxicity was observed on alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels at liver and albumin, blood urea nitrogen, or creatine kinase levels at kidney after miR‐133a‐microbubble injection. The tumor size of miR‐133a‐microbubble‐injected mice was smaller than that of the control group. Furthermore, the delivery efficiency of miR‐133a with low frequency was higher than that with common frequency. miR‐133a suppressed cell proliferation by suppressing the expression of EGFR and the phosphorylation of Akt. UTMD of miR‐133a inhibited the tumor growth and improved the survival rate in breast cancer mice. Our study provides new evidence that UTMD of miRNA is a promising platform for breast cancer therapy.

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“…EGFP-N3 was used to transfect the 293T cells in the presence or absence of UTMD. Following 48 h of incubation at 37°C in the incubator, the 293T cells were observed under an inverted fluorescence microscope to determine the presence of the EGFP-N3 plasmid ( 15 ). The transfected cells were allowed to incubate at 37°C for a further 6 h after which they were removed by trypsinization and washed in PBS.…”

Section: Methodsmentioning

confidence: 99%

Ultrasound-targeted microbubbles combined with a peptide nucleic acid binding nuclear localization signal mediate transfection of exogenous genes by improving cytoplasmic and nuclear import

Jiang

Chen

Cao

et al. 2017

Molecular Medicine Reports

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The development of an efficient delivery system is critical for the successful treatment of cardiovascular diseases using non-viral gene therapies. Cytoplasmic and nuclear membrane barriers reduce delivery efficiency by impeding the transfection of foreign genes. Thus, a gene delivery system capable of transporting exogenous genes may improve gene therapy. The present study used a novel strategy involving ultrasound-targeted microbubbles and peptide nucleic acid (PNA)-binding nuclear localization signals (NLS). Ultrasound-targeted microbubble destruction (UTMD) and PNA-binding NLS were used to improve the cytoplasmic and nuclear importation of the plasmid, respectively. Experiments were performed using antibody-targeted microbubbles (AT-MCB) that specifically recognize the SV40T antigen receptor expressed on the membranes of 293T cells, resulting in the localization of ultrasound microbubbles to 293T cell membranes. Furthermore, PNA containing NLS was inserted into the enhanced green fluorescent protein (EGFP)-N3 plasmid DNA (NLS-PNA-DNA), which increased nuclear localization. The nuclear import and gene expression efficiency of the AT-MCB with PNA-binding NLS were compared with AT-MCB alone or a PNA-binding NLS. The effect of the AT-MCB containing PNA-binding NLS on transfection was investigated. The ultrasound and AT-MCB delivery significantly enhanced the cytoplasmic intake of exogenous genes and maintained high cell viability. The nuclear import and gene expression of combined microbubble- and PNA-transfected cells were significantly greater compared with cells that were transfected with AT-MCB or DNA with only PNA-binding NLS. The quantity of EGFP-N3 plasmids in the nuclei was increased by >5.0-fold compared with control microbubbles (CMCB) and NLS-free plasmids. The gene expression was ~1.7-fold greater compared with NLS-free plasmids and 1.3-fold greater compared with control microbubbles. In conclusion, UTMD combined with AT-MCB and a PNA-binding NLS plasmid significantly improved transfection efficiency by increasing cytoplasmic and nuclear DNA import. This method is a promising strategy for the noninvasive and effective delivery of target genes or drugs for the treatment of cardiovascular diseases.

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Ultrasound-triggered microbubble destruction in combination with cationic lipid microbubbles enhances gene delivery

Cited by 9 publications

References 34 publications

Evaluation of in vivo antitumor effects of ANT2 shRNA delivered using PEI and ultrasound with microbubbles

Evaluation of in vivo antitumor effects of ANT2 shRNA delivered using PEI and ultrasound with microbubbles

Evaluation of in vivo antitumor effects of low‐frequency ultrasound‐mediated miRNA‐133a microbubble delivery in breast cancer

Ultrasound-targeted microbubbles combined with a peptide nucleic acid binding nuclear localization signal mediate transfection of exogenous genes by improving cytoplasmic and nuclear import

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