ICUS Weekly News Monitor 6-24-2016

1.  Chemical & Engineering News,  Jun 20, 2016,  Ultrasound implant safely opens blood-brain barrier in patients; New method could help anticancer drugs reach brain tumors
By Michael Torrice
2.  PLOS ONE,  Jun 20, 2016,  Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration     Authors: Donghee Park, et al
Chemical & Engineering News
Volume 94 Issue 25 | p. 6 | News of The Week
Issue Date: June 20, 2016 | Web Date: June 17, 2016
Jun 20, 2016
Ultrasound implant safely opens blood-brain barrier in patients
New method could help anticancer drugs reach brain tumors
By Michael Torrice
The cells lining blood vessels in the brain form tight, tough-to-penetrate junctions that prevent toxic molecules from slipping into the brain.
Unfortunately, this blood-brain barrier also blocks cancer drugs from reaching tumor cells in the brain, creating a significant drug-delivery problem.
Now, preliminary results from a Phase I/II clinical trial suggest that a small implant that emits ultrasound waves can safely open the blood-brain barrier in people, potentially allowing drugs in (Sci. Transl. Med. 2016, DOI: 10.1126/scitranslmed.aaf6086).
Scientists have previously tested ultrasound methods in animals and found that the techniques can aid drug delivery to the brain. These methods often rely on injecting microbubbles—typically fluorinated gases encapsulated in lipid spheres. The sound waves cause these bubbles to expand and compress. That mechanical energy helps loosen the junctions between endothelial cells lining blood vessels.
To translate such a treatment into people, the company CarThera, founded by Alexandre Carpentier, a neurosurgeon at Pitié-Salpêtrière Hospital, in Paris, developed SonoCloud, an 11.5-mm-diameter ultrasound transducer that surgeons can implant in a hole in patients’ skulls. Carpentier envisions a brain-cancer patient receiving such an implant after a tumor biopsy or a surgery to remove parts of a tumor.
In the new study, the team reported data from 15 glioblastoma patients who had received the implant. Before these patients were treated with the cancer drug carboplatin, they received a 2.5-minute ultrasound session.
By using magnetic resonance imaging to watch a gadolinium contrast agent enter the brain, the researchers found that these sessions opened the blood-brain barrier. And the patients didn’t experience adverse effects from the ultrasound—no signs of hemorrhaging, no complaints of pain, and no indications that speech or motor control was disrupted.
CarThera will start a Phase III trial in 2017 to assess how ultrasound treatments can improve chemotherapy for brain cancer patients. Also, Carpentier is interested in determining if the device can help treat Alzheimer’s disease. Some studies in animals suggest that ultrasound can clear out toxic protein plaques from the brain, in part, by temporarily opening the blood-brain barrier.
Nathan McDannold of Harvard Medical School says the clinical trial data are an impressive milestone for the ultrasound therapy field. He is working on similar methods that don’t rely on an implant and instead use an external array of 1,000 ultrasound transducers to focus on a target in the brain. So, he says, although the SonoCloud is more invasive, it is a simpler system.
Jun 20, 2016
Sonophoresis Using Ultrasound Contrast Agents: Dependence on Concentration
Authors: Donghee Park, Gillsoo Song, Yongjun Jo, Jongho Won, Taeyoon Son, Ohrum Cha, Jinho Kim, Byungjo Jung, Hyunjin Park, Chul-Woo Kim, Jongbum Seo
Donghee Park, Chul-Woo Kim
Department of Pathology, Tumor Immunity Medical Research Center, Cancer Research Institute, Seoul National University College of Medicine, Jongno-gu, Seoul, Republic of Korea
Gillsoo Song, Jongho Won, Taeyoon Son, Ohrum Cha, Jinho Kim, Byungjo Jung, Jongbum Seo
Department of Biomedical Engineering, Yonsei University, Wonju, Gangwon-do, Republic of Korea
Yongjun Jo
Gumi Electronics & Information Technology Research Institute, Gumi, Gyeongsangbuk-do, Republic of Korea
Hyunjin Park
School of Electronic Electrical Engineering, Sungkyunkwan University, Suwon, Gyeonggi-do, Republic of Korea
Correspondence:  This email address is being protected from spambots. You need JavaScript enabled to view it.
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.

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