Donghee Park

Sonophoresis in transdermal drug deliverys

Transdermal drug delivery (TDD) has several significant advantages compared to oral drug delivery, including elimination of pain and sustained drug release. However, the use of TDD is limited by low skin permeability due to the stratum corneum (SC), the outermost layer of the skin. Sonophoresis is a technique that temporarily increases skin permeability such that various medications can be delivered noninvasively. For the past several decades, various studies of sonophoresis in TDD have been performed focusing on parameter optimization, delivery mechanism, transport pathway, or delivery of several drug categories including hydrophilic and high molecular weight compounds. Based on these various studies, several possible mechanisms of sonophoresis have been suggested. For example, cavitation is believed to be the predominant mechanism responsible for drug delivery in sonophoresis. This review presents details of various studies on sonophoresis including the latest trends, delivery of various therapeutic drugs, sonophoresis pathways and mechanisms, and outlook of future studies.

A physical method to enhance transdermal delivery of a tissue optical clearing agent: combination of microneedling and sonophoresis.

Various physical methods, such as microneedling, laser ablation, sonophoresis, and sandpaper, have been widely studied to enhance the transdermal delivery of tissue optical clearing (TOC) agents. A previous study demonstrated that the microneedling method could effectively enhance the permeability of a TOC agent through the skin barrier.

Transdermal Drug Delivery Aided by an Ultrasound Contrast Agent: An In Vitro Experimental Study

Sonophoresis temporarily increases skin permeability such that medicine can be delivered transdermally. Cavitation is believed to be the predominant mechanism in sonophoresis. In this study, an ultrasound contrast agent (UCA) strategy was adopted instead of low frequency ultrasound to assure that cavitation occurred, and the efficacy of sonophoresis with UCA was quantitatively analyzed by optical measurements. The target drug used in this study was 0.1 % Definity® in 70% glycerol, which was delivered into porcine skin samples. Glycerol was used because it is an optical clearing agent, and the efficiency of glycerol delivery could be analyzed with optical measurements. The applied acoustic pressure was approximately 600 kPa at 1 MHz ultrasound with a 10% duty cycle for 60 minutes. Experimental results indicated that the measured relative contrast (RC) after sonophoresis with UCA was approximately 80% higher than RC after sonophoresis without UCA. In addition, the variance of RC was also reduced by more than 50% with the addition of a UCA. The use of a UCA appeared to increase cavitation, demonstrating that the use of a UCA can be effective in transdermal drug delivery (TDD).

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

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-2Rγnull) 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.

Sound Packing DNA: packing open circular DNA with low-intensity ultrasound

Supercoiling DNA (folding DNA into a more compact molecule) from open circular forms requires significant bending energy. The double helix is coiled into a higher order helix form; thus it occupies a smaller footprint. Compact packing of DNA is essential to improve the efficiency of gene delivery, which has broad implications in biology and pharmaceutical research. Here we show that low-intensity pulsed ultrasound can pack open circular DNA into supercoil form. Plasmid DNA subjected to 5.4 mW/cm2 intensity ultrasound showed significant (p-values <0.001) supercoiling compared to DNA without exposure to ultrasound. Radiation force induced from ultrasound and dragging force from the fluid are believed to be the main factors that cause supercoiling. This study provides the first evidence to show that low-intensity ultrasound can directly alter DNA topology. We anticipate our results to be a starting point for improved non-viral gene delivery.

Synthesis of Laboratory Ultrasound Contrast Agents

Ultrasound Contrast Agents (UCAs) were developed to maximize reflection contrast so that organs can be seen clearly in ultrasound imaging. UCAs increase the signal to noise ratio (SNR) by linear and non-linear mechanisms and thus help more accurately visualize the internal organs and blood vessels. However, the UCAs on the market are not only expensive, but are also not optimized for use in various therapeutic research applications such as ultrasound-aided drug delivery. The UCAs fabricated in this study utilize conventional lipid and albumin for shell formation and perfluorobutane as the internal gas. The shape and density of the UCA bubbles were verified by optical microscopy and Cryo SEM, and compared to those of the commercially available UCAs, Definity® and Sonovue®. The size distribution and characteristics of the reflected signal were also analyzed using a particle size analyzer and ultrasound imaging equipment. Our experiments indicate that UCAs composed of spherical microbubbles, the majority of which were smaller than 1 um, were successfully synthesized. Microbubbles 10 um or larger were also identified when different shell characteristics and filters were used. These laboratory UCAs can be used for research in both diagnoses and therapies.

Enhancement of transdermal delivery of glycerol by micro-needling method combined with sonophoresis

The light does not penetrate deeply into the skin tissue because of tissue turbidity. Light penetration depth in skin tissue can be increased by using optical clearing agents such as glycerol, glucose and dimethyl sulfoxide(DMSO). The stratum corneum prevents most optical skin clearing agent from diffusing into the tissue. Previous studies demonstrated the optical tissue clearing effect using optical clearing agents and presented several physical methods to improve transdermal delivery of optical clearing agents. In previous study, we introduced a micro-needling method to enhance optical clearing efficacy against skin barrier and suggested quantitative analysis method to evaluate the optical tissue clearing efficacy. In this study, we present a new physical micro-needling method combined with sonophoresis to further enhance the optical tissue clearing efficacy. The optical tissue clearing effect was quantitatively evaluated with a modulation transfer function target placed under ex-vivo porcine skin samples. To improve transdermal delivery of glycerol, 70% glycerol solution as optimal concentration was topically applied. In conclusion, the samples treated with micro-needling method and sonophoresis resulted in noticeable optical tissue clearing effect.

Transdermal delivery of macromolecule using sonophoresis with cavitation seed: In-vivo study

In previous studies, we have found that addition of cavitation seed such as ultrasound contrast agents (UCA) in sonophoresis accelerate and increase efficiency of transdermal drug delivery (TDD). Actively-induced cavitation with low intensity ultrasound (less than 1 MPa) on the skin causes disordering of the lipid bilayers and the formation of aqueous channels. However, commercial UCAs also have limit, because mixed UCA is uniformly positioned in the water based solution, not on the skin surface. In order to enhance the TDD, the cavitation effect of cavitation seed should be generated near skin surface. For that reason, we manufactured specialized cavitation seed for TDD, which can be sank near skin surface by gravity. In order to make sure possibility of macromolecules delivery using cavitation seed, we performed in vivo experiment using sonophoresis with specialized cavitation seed.

Corrigendum: Sound Packing DNA: packing open circular DNA with low-intensity ultrasound

Scientific Reports 5: Article number: 984610.1038/srep09846; published online: April202015; updated: October052015

A high-precision angular control system for HIFU calibration

A design of high-precision angular position control system for calibrating high intensity focused ultrasound (HIFU) is presented with alignment procedures. Two independent angular controls are achieved by combining a worm gear and a belt gear system. The proposed system verifies alignment by comparing simulation data and experimental data with three different transducers and two different types of hydrophones. The performance of the proposed system is compared to that of a commercial system. The results indicate that the proposed system provides high precision angular alignment (e.g., <0.01radians) with robust reproducibility regardless of the hydrophone type.