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Joo Ha Hwang






2000-present and while at APL-UW

Enhancement of small molecule delivery by pulsed high-intensity focused ultrasound: A parameter exploration

Zhou, Y., Y.-N. Wang, N. Farr, J. Zia, H. Chen, B.M. Ko, T. Khokhlova, T. Li, and J.H. Hwang, "Enhancement of small molecule delivery by pulsed high-intensity focused ultrasound: A parameter exploration," Ultrasound Med. Biol., 42, 956-963, doi:10.1016/j.ultrasmedbio.2015.12.009, 2016.

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1 Apr 2016

Chemotherapeutic drug delivery is often ineffective within solid tumors, but increasing the drug dose would result in systemic toxicity. The use of high-intensity focused ultrasound (HIFU) has the potential to enhance penetration of small molecules. However, operation parameters need to be optimized before the use of chemotherapeutic drugs in vivo and translation to clinical trials. In this study, the effects of pulsed HIFU (pHIFU) parameters (spatial-average pulse-average intensity, duty factor and pulse repetition frequency) on the penetration as well as content of small molecules were evaluated in ex vivo porcine kidneys. Specific HIFU parameters resulted in more than 40 times greater Evans blue content and 3.5 times the penetration depth compared with untreated samples. When selected parameters were applied to porcine kidneys in vivo, a 2.3-fold increase in concentration was obtained after a 2-min exposure to pHIFU. Pulsed HIFU has been found to be an effective modality to enhance both the concentration and penetration depth of small molecules in tissue using the optimized HIFU parameters. Although, performed in normal tissue, this study has the promise of translation into tumor tissue.

Pulsed high-intensity focused ultrasound enhances delivery of doxorubicin in a preclinical model of pancreatic cancer

Li, T. Y.-N. Wang, T.D. Khokhlova, S. D'Andrea, F. Starr, H. Chen, J.S. McCune, L.J. Risler, A. Mashadi-Hossein, and J.H. Hwang, "Pulsed high-intensity focused ultrasound enhances delivery of doxorubicin in a preclinical model of pancreatic cancer," Cancer Res., 75, 3738-3746, doi:10.1158/0008-5472.CAN-15-0296, 2015.

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15 Sep 2015

Pancreatic cancer is characterized by extensive stromal desmoplasia, which decreases blood perfusion and impedes chemotherapy delivery. Breaking the stromal barrier could both increase perfusion and permeabilize the tumor, enhancing chemotherapy penetration. Mechanical disruption of the stroma can be achieved using ultrasound-induced bubble activity-cavitation. Cavitation is also known to result in microstreaming and could have the added benefit of actively enhancing diffusion into the tumors. Here, we report the ability to enhance chemotherapeutic drug doxorubicin penetration using ultrasound-induced cavitation in a genetically engineered mouse model (KPC mouse) of pancreatic ductal adenocarcinoma. To induce localized inertial cavitation in pancreatic tumors, pulsed high-intensity focused ultrasound (pHIFU) was used either during or before doxorubicin administration to elucidate the mechanisms of enhanced drug delivery (active vs. passive drug diffusion). For both types, the pHIFU exposures that were associated with high cavitation activity resulted in disruption of the highly fibrotic stromal matrix and enhanced the normalized doxorubicin concentration by up to 4.5-fold compared with controls. Furthermore, normalized doxorubicin concentration was associated with the cavitation metrics (P < 0.01), indicating that high and sustained cavitation results in increased chemotherapy penetration. No significant difference between the outcomes of the two types, that is, doxorubicin infusion during or after pHIFU treatment, was observed, suggesting that passive diffusion into previously permeabilized tissue is the major mechanism for the increase in drug concentration. Together, the data indicate that pHIFU treatment of pancreatic tumors when resulting in high and sustained cavitation can efficiently enhance chemotherapy delivery to pancreatic tumors.

Endoscopic high-intensity focused US: Technical aspects and studies in an in vivo porcine model

Li, T., T. Khokhlova, E. Maloney, Y.-N. Wang, S. D'Andrea, F. Starr, N. Farr, K. Morrison, G. Keilman, and J.H. Hwang, "Endoscopic high-intensity focused US: Technical aspects and studies in an in vivo porcine model," Gastrointest. Endoscopy, 81, 1243-1250, doi:0.1016/j.gie.2014.12.019, 2015.

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1 May 2015

High-intensity focused US (HIFU) is becoming more widely used for noninvasive and minimally invasive ablation of benign and malignant tumors. Recent studies suggest that HIFU can also enhance targeted drug delivery and stimulate an antitumor immune response in many tumors. However, targeting pancreatic and liver tumors by using an extracorporeal source is challenging due to the lack of an adequate acoustic window. The development of an EUS-guided HIFU transducer has many potential benefits including improved targeting, decreased energy requirements, and decreased potential for injury to intervening structures.

The transducer successfully created lesions in gel phantoms and ex vivo bovine livers. In vivo studies demonstrated that targeting and creating lesions in the porcine pancreas and liver are feasible. An EUS-guided HIFU transducer was successfully designed and developed with dimensions that are appropriate for endoscopic use. The feasibility of performing EUS-guided HIFU ablation in vivo was demonstrated in an in vivo porcine model. Further development of this technology will allow endoscopists to perform precise therapeutic ablation of periluminal lesions without breaching the wall of the gastric tract.

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Methods and Devices for Improved Cavitation-Induced Drug Delivery Using Pulsed Focused Ultrasound with Shocks

Record of Invention Number: 47734

Vera Khokhlova, Joo Ha Hwang, Tatiana Khokhlova, Wayne Kreider, Adam Maxwell, Oleg Sapozhnikov


1 Jun 2016

Method of Detecting Microbubbles in Tissue and Tissue Phantoms Using "Twinkling" Artifact of Doppler Imaging

Record of Invention Number: 46179

Oleg Sapozhnikov, Mike Bailey, Joo Ha Hwang, Tatiana Khokhlova, Vera Khokhlova


10 Aug 2012

Enhanced Drug Delivery Using Endoscopic HIFU

Record of Invention Number: 8507D

Yak-Nam Wang, Joo Ha Hwang, Yufeng Zhou


29 Oct 2009

More Inventions

Acoustics Air-Sea Interaction & Remote Sensing Center for Environmental & Information Systems Center for Industrial & Medical Ultrasound Electronic & Photonic Systems Ocean Engineering Ocean Physics Polar Science Center