Direct In Vivo Visualization of Intravascular Destruction of Microbubbles by Ultrasound and its Local Effects on Tissue

Skyba, Danny M.; Price, Richard J.; Linka, André; Skalak, Thomas C.; Kaul, Sanjiv

doi:10.1161/01.cir.98.4.290

Cited by 443 publications

(283 citation statements)

References 11 publications

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“…30 Some collateral lesions exhibit red blood cell extravasations and even rupture of microvessels in the exposed area. 34,41 In vivo studies of ultrasound-microbubble-mediated transfection have shown apoptosis in 17% of exposed cells in the rabbit brain 42 and less than 1% of all treated skeletal muscle of rats. 43 Amabile et al 44 reported apoptosis in 26% of vascular endothelial cells following endovascular ultrasound delivery of adenovirus-expressing gene.…”

Section: Discussionmentioning

confidence: 99%

Ultrasound-contrast agent mediated naked gene delivery in the peritoneal cavity of adult rat

et al. 2007

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Gene transfer into the peritoneal cavity by nonviral methods may provide an effective therapeutic approach for peritoneal diseases. Herein, we investigated the feasibility and the effectiveness of ultrasound-microbubble-mediated delivery of naked plasmid DNA into the peritoneal cavity in rats. Following the intraperitoneal or the intravenous administration of a mixture of plasmid DNA (100 mg) and ultrasound contrast agent microbubbles, an ultrasound transducer was applied on the abdominal wall. The reporter pTRE plasmid encoding Smad7 was used to evaluate transfection efficiency. Smad7 expression was induced by doxycycline in drinking water. We detected less than 10% apoptotic cells and no inflammatory reaction in peritoneal tissues following the ultrasound-microbubble-mediated transfection. More importantly, the insonation significantly improved the transfection efficiency in peritoneal tissues. The transfection efficiency by intraperitoneal delivery route was higher than the intravenous route. The reporter gene, pTRE-Smad7, was readily detected in the parietal peritoneum, mesentery, greater omentum and adipose tissue. The peak of transgene expression occurred 2 days after transfection and the transgene expression diminished in a time-dependent manner thereafter. Overall, the effectiveness and simplicity of the ultrasound-microbubble-mediated system may provide a promising nonviral means for improving gene delivery for treating peritoneal diseases in vivo.

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Section: Discussionmentioning

confidence: 99%

Ultrasound-contrast agent mediated naked gene delivery in the peritoneal cavity of adult rat

et al. 2007

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“…Insonation of microbubbles at a sufficiently high concentration or with a sufficiently high mechanical stress (low frequency, high acoustic pressure) results in changes in the permeability of capillary wall, with resulting extravasation of particles into the interstitial space [9,10]. In such cases, convective transport can result in transport of drugs or particles over distances on the order of tens of microns from the vessel wall and therefore far from the location of the microbubble oscillation.…”

Section: Changes In Tissue/vascular Transport Propertiesmentioning

confidence: 99%

Driving delivery vehicles with ultrasound

Ferrara

2008

Advanced Drug Delivery Reviews

231

162

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Therapeutic applications of ultrasound have been considered for over 40 years, with the mild hyperthermia and associated increases in perfusion produced by ultrasound harnessed in many of the earliest treatments. More recently, new mechanisms for ultrasound-based or ultrasound-enhanced therapies have been described, and there is now great momentum and enthusiasm for the clinical translation of these techniques. This dedicated issue of Advanced Drug Delivery Reviews, entitled "Ultrasound for Drug and Gene Delivery," addresses the mechanisms by which ultrasound can enhance local drug and gene delivery and the applications that have been demonstrated at this time. In this commentary, the identified mechanisms, delivery vehicles, applications and current bottlenecks for translation of these techniques are summarized. KeywordsUltrasound; Therapy; Drug delivery; Gene delivery; Sonoporation; Cavitation As an imaging modality, ultrasound is widely employed and valued for its real time applications, low cost, simplicity, and safety. Waves of alternating increased and decreased pressure propagate from the transducer, typically resulting in a maximum intensity in a focal region chosen by the operator. The dimensions of the focal region can vary from tens of microns for high frequency ultrasound to centimeters for an unfocused therapeutic beam. Most clinical instruments are engineered to effectively image from the body surface to 24 or more centimeters in depth. The ability to locally control and maximize energy deposition deep within the body facilitates a broad range of clinical opportunities for ultrasound imaging and therapy. Developing over four decades, clinical and commercial application of ultrasonic therapies spans hyperthermia, drug delivery, lipoplasty, and thrombolysis [1,2]. A complete and precise summary of the potential applications for ultrasonic enhancement of drug and gene delivery remains challenging as the mechanisms are multiple and not fully characterized. From an engineering viewpoint, the methods by which ultrasound facilitates drug and gene delivery can be summarized as direct changes in the biological or physiological properties of tissues facilitating transport, direct changes in the drug or vehicle increasing bioavailability or enhancing efficacy, and indirect effects by which ultrasound acts on the vehicle to produce changes in the surrounding tissue. While there are common mechanisms between these methods, the engineering challenges associated with the optimization of ultrasound systems and drug and vehicle design are unique for each method. Promising examples of each of these methods can be identified at this time and are addressed below.☆ This commentary is part of the Advanced Drug Delivery Reviews theme issue on "Ultrasound in Drug and Gene Delivery".

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“…These vascular alterations included changes in permeability (i.e., leakage of Evans blue dye) and integrity (i.e., petechial hemorrhages), focal endothelial cell and myocyte loss and necrosis, inflammation and replacement fibrosis (Hwang et al 2005;Li et al 2004;Miller andGies 1998,2000;Miller et al 2004Miller et al ,2005Miller and Quddus 2000;Skyba et al 1998). Arrhythmogenic changes included premature ventricular contractions in healthy adult human beings during triggered second-harmonic imaging of a CA for myocardial perfusion (van Der Wouw et al 2000); supraventricular tachycardia or nonsustained ventricular tachycardia in patients at risk for syncope, supraventricular tachycardia or ventricular tachycardia after IV administration of per-fluorocarbon-exposed sonicated dextrose albumin microbubbles (PESDA), exposure to therapeutic transthoracic low-frequency US (Chapman et al 2005) and cardiac arrhythmogenesis in a rat model (Zachary et al 2002).…”

Section: Introduction and Literaturementioning

confidence: 99%

Vascular lesions and s-thrombomodulin concentrations from auricular arteries of rabbits infused with microbubble contrast agent and exposed to pulsed ultrasound

Zachary

Blue

Miller

et al. 2006

Ultrasound in Medicine & Biology

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Arterial injury resulting from the interaction of contrast agent (CA) with ultrasound (US) was studied in rabbit auricular arteries and assessed by histopathologic evaluation and s-thrombomodulin concentrations. Three sites on each artery were exposed (2.8 MHz, 5-min exposure duration, 10-Hz pulse repetition frequency, 1.4-μs pulse duration) using one of three in situ peak rarefactional pressures (0.85, 3.9 or 9.5 MPa). Saline, saline/CA, and saline/US infusion groups (n = 28) did not have histopathologic damage. The saline/CA/US infusion group (n = 10) at exposure conditions below the FDA mechanical index limit of 1.9 did not have histopathologic damage, whereas the saline/CA/US infusion group (n = 9) at exposure conditions above the FDA limit did have damage (5 of 9 arteries). Lesions were characteristic of acute coagulative necrosis. Mean s-thrombomodulin concentrations, a marker for endothelial cell injury, were highest in rabbits exposed to US at 0.85 and 3.9 MPa, suggesting that vascular injury may be physiological and not accompanied by irreversible cellular injury.

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Direct In Vivo Visualization of Intravascular Destruction of Microbubbles by Ultrasound and its Local Effects on Tissue

Cited by 443 publications

References 11 publications

Ultrasound-contrast agent mediated naked gene delivery in the peritoneal cavity of adult rat

Ultrasound-contrast agent mediated naked gene delivery in the peritoneal cavity of adult rat

Driving delivery vehicles with ultrasound

Vascular lesions and s-thrombomodulin concentrations from auricular arteries of rabbits infused with microbubble contrast agent and exposed to pulsed ultrasound

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