Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration

Donghee Park; Gillsoo Song; Yongjun Jo; Jongho Won; Taeyoon Son; Ohrum Cha; Jinho Kim; Byungjo Jung; Hyunjin Park; Chul-Woo Kim; Jongbum Seo

doi:10.1371/journal.pone.0157707

Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration

PLoS One. 2016 Jun 20;11(6):e0157707. doi: 10.1371/journal.pone.0157707. eCollection 2016.

Authors

Affiliations

¹ Department of Pathology, Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Jongno-gu, Seoul, Republic of Korea.
² Department of Biomedical Engineering, Yonsei University, Wonju, Gangwon-do, Republic of Korea.
³ Gumi Electronics & Information Technology Research Institute, Gumi, Gyeongsangbuk-do, Republic of Korea.
⁴ School of Electronic Electrical Engineering, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea.

Abstract

Sonophoresis can increase skin permeability to various drugs in transdermal drug delivery. Cavitation is recognized as the predominant mechanism of sonophoresis. Recently, a new logical approach to enhance the efficiency of transdermal drug delivery was tried. It is to utilize the engineered microbubble and its resonant frequency for increase of cavitation activity. Actively-induced cavitation with low-intensity ultrasound (less than ~1 MPa) causes disordering of the lipid bilayers and the formation of aqueous channels by stable cavitation which indicates a continuous oscillation of bubbles. Furthermore, the mutual interactions of microbubble determined by concentration of added bubble are also thought to be an important factor for activity of stable cavitation, even in different characteristics of drug. In the present study, we addressed the dependence of ultrasound contrast agent concentration using two types of drug on the efficiency of transdermal drug delivery. Two types of experiment were designed to quantitatively evaluate the efficiency of transdermal drug delivery according to ultrasound contrast agent concentration. First, an experiment of optical clearing using a tissue optical clearing agent was designed to assess the efficiency of sonophoresis with ultrasound contrast agents. Second, a Franz diffusion cell with ferulic acid was used to quantitatively determine the amount of drug delivered to the skin sample by sonophoresis with ultrasound contrast agents. The maximum enhancement ratio of sonophoresis with a concentration of 1:1,000 was approximately 3.1 times greater than that in the ultrasound group without ultrasound contrast agent and approximately 7.5 times greater than that in the control group. These results support our hypothesis that sonophoresis becomes more effective in transdermal drug delivery due to the presence of engineered bubbles, and that the efficiency of transdermal drug delivery using sonophoresis with microbubbles depends on the concentration of microbubbles in case stable cavitation is predominant.

MeSH terms

Animals
Contrast Media / analysis*
Diffusion
Optical Phenomena
Skin / anatomy & histology
Sus scrofa
Ultrasonics / methods*

Substances

Contrast Media

Grants and funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Ministry of Science, ICT & Future Planning (MSIP) (NRF-2013R1A2A2A 04016262), (NRF-2014M3A6A3063636), (2012-0001190), (2010-00757), and by Technology Innovation Program (10052749) funded By the Ministry of Trade, industry & Energy, Republic of Korea. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.