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Joo Ha Hwang

Email

jooha@u.washington.edu

Phone

206-685-2283

Publications

2000-present and while at APL-UW

Focused ultrasound for immuno-adjuvant treatment of pancreatic cancer: An emerging clinical paradigm in the era of personalized oncotherapy

Maloney, E., T. Khokhlova, V.G. Pillarisetty, G.R. Schade, E.A. Repasky, Y.-N. Wang, L. Giuliani, M. Primavera, and J.H. Hwang, "Focused ultrasound for immuno-adjuvant treatment of pancreatic cancer: An emerging clinical paradigm in the era of personalized oncotherapy," Int. Rev. Immunol., 36, 338-351, doi:10.1080/08830185.2017.1363199, 2017.

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29 Sep 2017

Current clinical treatment regimens, including many emergent immune strategies (e.g., checkpoint inhibitors) have done little to affect the devastating course of pancreatic ductal adenocarcinoma (PDA). Clinical trials for PDA often employ multi-modal treatment, and have started to incorporate stromal-targeted therapies, which have shown promising results in early reports. Focused ultrasound (FUS) is one such therapy that is uniquely equipped to address local and systemic limitations of conventional cancer therapies as well as emergent immune therapies for PDA. FUS methods can non-invasively generate mechanical and/or thermal effects that capitalize on the unique oncogenomic/proteomic signature of a tumor. Potential benefits of FUS therapy for PDA include: (1) emulsification of targeted tumor into undenatured antigens in situ, increasing dendritic cell maturation, and increasing intra-tumoral CD8+/ T regulatory cell ratio and CD8+ T cell activity; (2) reduction in intra-tumoral hypoxic stress; (3) modulation of tumor cell membrane protein localization to enhance immunogenicity; (4) modulation of the local cytokine milieu toward a Th1-type inflammatory profile; (5) up-regulation of local chemoattractants; (6) remodeling the tumor stroma; (7) localized delivery of exogenously packaged immune-stimulating antigens, genes and therapeutic drugs. While not all of these results have been studied in experimental PDA models to date, the principles garnered from other solid tumor and disease models have direct relevance to the design of optimal FUS protocols for PDA. In this review, we address the pertinent limitations in current and emergent immune therapies that can be improved with FUS therapy for PDA.

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.

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Inventions

Imaging Bubbles in a Medium

Patent Number: 9,743,909

Oleg Sapozhnikov, Mike Bailey, Joo Ha Hwang, Tatiana Khokhlova, Vera Khokhlova, Tong Li, Matthew O'Donnell

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Patent

29 Aug 2017

A method for imaging a cavitation bubble includes producing a vibratory wave that induces a cavitation bubble in a medium, producing one or more detection waves directed toward the induced cavitation bubble, receiving one or more reflection waves, identifying a change in one or more characteristics of the induced cavitation bubble, and generating an image of the induced cavitation bubble using a computing device on the basis of the identified change in the one or more characteristics. The one or more received reflection waves correspond to at least one of the one or more produced detection waves reflection from the induced cavitation bubble. The identified change in one or more characteristics corresponds to the one or more received reflection waves.

Methods and Systems for Non-invasive Treatment of Tissue Using High Intensity Focused Ultrasound Therapy

Patent Number: 9,700,742

Michael Canney, Mike Bailey, Larry Crum, Joo Ha Hwang, Tatiana Khokhlova, Vera Khokhlova, Wayne Kreider, Oleg Sapozhnikov

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Patent

11 Jul 2017

Methods and systems for non-invasive treatment of tissue using high intensity focused ultrasound ("HIFU") therapy. A method of non-invasively treating tissue in accordance with an embodiment of the present technology, for example, can include positioning a focal plane of an ultrasound source at a target site in tissue. The ultrasound source can be configured to emit HIFU waves. The method can further include pulsing ultrasound energy from the ultrasound source toward the target site, and generating shock waves in the tissue to induce boiling of the tissue at the target site within milliseconds. The boiling of the tissue at least substantially emulsifies the tissue.

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

Disclosure

1 Jun 2016

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
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