Encapsulated ultrasound microbubbles: Therapeutic application in drug/gene delivery

Liu, Yiyao; Miyoshi, Hirokazu; Nakamura, Michihiro

doi:10.1016/j.jconrel.2006.05.018

Cited by 288 publications

(202 citation statements)

References 67 publications

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“…During long ultrasound exposure, intense mixing caused by cavitation activity was expected to keep the solution homogenous. It is envisioned that microbubbles of the relatively high concentrations used in this study could be obtained in the body by local catheter release of microbubbles [23] or by targeted microbubbles [14,31].…”

Section: Experimental Protocolmentioning

confidence: 99%

“…A novel approach to targeting drug and gene administration is the method of ultrasoundenhanced delivery [13][14][15]. Ultrasound-enhanced delivery often exploits cavitation bubble activity, which can be produced by the pressure oscillations of ultrasound [16].…”

Section: Introductionmentioning

confidence: 99%

“…Cavitation-mediated cellular disruptions can allow uptake of small molecules, macromolecules (e.g., proteins), and genetic material (e.g., plasmid DNA or siRNA). Furthermore, ultrasound-enhanced delivery has been studied in a variety of in vitro and in vivo scenarios and has demonstrated promising therapeutic results after intracellular uptake of drugs and gene expression [14,16,21]. Most importantly, ultrasound can be targeted in the body by non-invasive extracorporeal focused ultrasound [22] or by minimally invasive catheter-based transducers [23].…”

Section: Introductionmentioning

confidence: 99%

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Ultrasonically targeted delivery into endothelial and smooth muscle cells in ex vivo arteries

Hallow

Mahajan

Prausnitz

2007

Journal of Controlled Release

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This study tested the hypothesis that ultrasound can target intracellular uptake of drugs into vascular endothelial cells (ECs) at low to intermediate energy and into smooth muscle cells (SMCs) at high energy. Ultrasound-enhanced delivery has been shown to enhance and target intracellular drug and gene delivery in the vasculature to treat cardiovascular disease, but quantitative studies of the delivery process are lacking. Viable ex vivo porcine carotid arteries were placed in a solution containing a model drug, TO-PRO ® -1, and Optison ® microbubbles. Arteries were exposed to ultrasound at 1.1 MHz and acoustic energies of 5.0, 66, or 630 J/cm 2 . Using confocal microscopy and fluorescent labeling of cells, the artery endothelium and media were imaged to determine the localization and to quantify intracellular uptake and cell death. At low to intermediate ultrasound energy, ultrasound was shown to target intracellular delivery into viable cells that represented 9 -24% of exposed ECs. These conditions also typically caused 7 -25% EC death. At high energy, intracellular delivery was targeted to SMCs, which was associated with denuding or death of proximal ECs. This work represents the first known in-depth study to evaluate intracellular uptake into cells in tissue. We conclude that significant intracellular uptake of molecules can be targeted into ECs and SMCs by ultrasound-enhanced delivery suggesting possible applications for treatment of cardivascular diseases and dysfunctions.

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Section: Experimental Protocolmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Ultrasonically targeted delivery into endothelial and smooth muscle cells in ex vivo arteries

Hallow

Mahajan

Prausnitz

2007

Journal of Controlled Release

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“…Ultrasound can cause a transient, nonlethal perforation of the capillary and cell membranes because of cavitation effects and thereby improve transfection and drug delivery efficiencies. In many studies, ultrasound-enhanced gene/drug delivery techniques combined with microbubbles encasing an expression vector have been shown to enhance gene transfection and drug delivery [10,11] . These studies focused mainly on cancer and the vascular system.…”

Section: Introductionmentioning

confidence: 99%

“…These studies focused mainly on cancer and the vascular system. The cavitation of microbubbles under an ultrasound field will lead to an increase in microvascular permeability and induce small gaps between capillary endothelial cells due to the cavitation energy, which will enable drugs to leak from the vessel and reach the target location [9,11,12] . Recently, Ohta et al used microbubble-enhanced sonoporation to achieve ectopic and transient gene expression in several embryonic organs, including embryonic chick limb bud mesenchymes [13] .…”

Section: Introductionmentioning

confidence: 99%

Vascular gene transfer and drug delivery in vitro using low-frequency ultrasound and microbubbles

Yang

Liu

et al. 2010

Acta Pharmacol Sin

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Aim: To determine the effects of ultrasound exposure in combination with a microbubble contrast agent (SonoVue) on the cellular uptake and delivery of drugs/genes into human umbilical vein endothelial cells (HUVECs) as well as their biological effects on migration. Methods: HUVECs in suspension were exposed to pulsed ultrasound with a 10% duty cycle in combination with various concentrations of a microbubble contrast agent (SonoVue) using a digital sonifier at a frequency of 20 kHz and an intensity of 3.77 W/cm 2 on the surface of a horn tip. Cell culture inserts were used to determine the cell migration ability. Results: Exposure to pulsed ultrasound resulted in enhanced green fluorescent protein (EGFP) gene transfection efficiencies ranging from 0.2% to 2%. The transfection efficiency of HUVECs was approximately 3-fold higher in the presence of SonoVue than in its absence at the effective exposure time of 6 s. For drug delivery to HUVECs using ultrasound, the delivery efficiencies of a lowmolecular-weight model drug (TO-PRO ® -1, M W 645.38) were significantly higher when compared to drug delivery without ultrasound, with a maximum efficiency of approximately 34%. However, the delivery efficiencies of a high-molecular-weight model drug (DextranRhodamine B, M W 70 000) were low, with a maximum delivery efficiency of nearly 0.5%, and gene transfection results were similarly poor. The migration ability of HUVECs exposed to ultrasound was also lower than that of the control (no exposure). Conclusion: The use of low-frequency and low-energy ultrasound in combination with microbubbles could be a potent physical method of increasing drug/gene delivery efficiency. This technique is a promising nonviral approach that can be used in cardiovascular disease therapy.

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Design Parameters Modulating Intracellular Drug Delivery: Anchoring to Specific Cellular Epitopes, Carrier Geometry, and Use of Auxiliary Pharmacological Agents

Muro

Muzykantov

2010

Organelle‐Specific Pharmaceutical Nanotechnology

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Encapsulated ultrasound microbubbles: Therapeutic application in drug/gene delivery

Cited by 288 publications

References 67 publications

Ultrasonically targeted delivery into endothelial and smooth muscle cells in ex vivo arteries

Ultrasonically targeted delivery into endothelial and smooth muscle cells in ex vivo arteries

Vascular gene transfer and drug delivery in vitro using low-frequency ultrasound and microbubbles

Design Parameters Modulating Intracellular Drug Delivery: Anchoring to Specific Cellular Epitopes, Carrier Geometry, and Use of Auxiliary Pharmacological Agents

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