title: Pulsed High-Intensity Focused Ultrasound Enhances Delivery of Doxorubicin in a Preclinical Model of Pancreatic Cancer.
abstract: 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. .
authors.affiliation: Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, Washington.
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.affiliation: Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, Washington.
authors.forename: Yak-Nam
authors.initials: YN
authors.lastname: Wang
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Tatiana D
authors.initials: TD
authors.lastname: Khokhlova
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Samantha
authors.initials: S
authors.lastname: D'Andrea
authors.affiliation: Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, Washington.
authors.forename: Frank
authors.initials: F
authors.lastname: Starr
authors.affiliation: Center for Industrial and Medical Ultrasound, Applied Physics Laboratory, University of Washington, Seattle, Washington.
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pharmacy, University of Washington, Seattle, Washington. Department of Pharmaceutics, University of Washington, Seattle, Washington.
authors.forename: Jeannine S
authors.initials: JS
authors.lastname: McCune
authors.affiliation: Department of Pharmacy, University of Washington, Seattle, Washington. Department of Pharmaceutics, University of Washington, Seattle, Washington.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Risler
authors.affiliation: Department of Biostatistics, University of Washington, Seattle, Washington.
authors.forename: Afshin
authors.initials: A
authors.lastname: Mashadi-Hossein
authors.forename: Sunil R
authors.initials: SR
authors.lastname: Hingorani
authors.forename: Amy
authors.initials: A
authors.lastname: Chang
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Washington, Seattle, Washington. Jooha@medicine.washington.edu.
authors.forename: Joo Ha
authors.initials: JH
authors.lastname: Hwang
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004058:Diffusion; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000295:instrumentation / Q000379:methods*; D004867:Equipment Design; D019220:High-Energy Shock Waves; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D015612:Phonophoresis / Q000295:instrumentation / Q000379:methods*; D011897:Random Allocation; D017154:Stromal Cells / Q000473:pathology; D053719:Tandem Mass Spectrometry
chemical_list: D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin