title: Ultrasound increases nanoparticle delivery by reducing intratumoral pressure and increasing transport in epithelial and epithelial-mesenchymal transition tumors.
abstract: Acquisition of the epithelial-mesenchymal transition (EMT) tumor phenotype is associated with impaired chemotherapeutic delivery and a poor prognosis. In this study, we investigated the application of therapeutic ultrasound methods available in the clinic to increase nanotherapeutic particle accumulation in epithelial and EMT tumors by labeling particles with a positron emission tomography tracer. Epithelial tumors were highly vascularized with tight cell-cell junctions, compared with EMT tumors where cells displayed an irregular, elongated shape with loosened cell-cell adhesions and a reduction in E-cadherin and cytokeratins 8/18 and 19. Without ultrasound, the accumulation of liposomal nanoparticles administered to tumors in vivo was approximately 1.5 times greater in epithelial tumors than EMT tumors. When ultrasound was applied, both nanoaccumulation and apparent tumor permeability were increased in both settings. Notably, ultrasound effects differed with thermal and mechanical indices, such that increasing the thermal ultrasound dose increased nanoaccumulation in EMT tumors. Taken together, our results illustrate how ultrasound can be used to enhance nanoparticle accumulation in tumors by reducing their intratumoral pressure and increasing their vascular permeability.
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, California 95616, USA.
authors.forename: Katherine D
authors.initials: KD
authors.lastname: Watson
authors.forename: Chun-Yen
authors.initials: CY
authors.lastname: Lai
authors.forename: Shengping
authors.initials: S
authors.lastname: Qin
authors.forename: Dustin E
authors.initials: DE
authors.lastname: Kruse
authors.forename: Yueh-Chen
authors.initials: YC
authors.lastname: Lin
authors.forename: Jai Woong
authors.initials: JW
authors.lastname: Seo
authors.forename: Robert D
authors.initials: RD
authors.lastname: Cardiff
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mahakian
authors.forename: Julie
authors.initials: J
authors.lastname: Beegle
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Ingham
authors.forename: Fitz-Roy
authors.initials: FR
authors.lastname: Curry
authors.forename: Rolf K
authors.initials: RK
authors.lastname: Reed
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D015820:Cadherins / Q000032:analysis; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D053538:Keratin-18 / Q000032:analysis; D053539:Keratin-19 / Q000032:analysis; D053533:Keratin-8 / Q000032:analysis; D008081:Liposomes / Q000008:administration & dosage; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage*; D009369:Neoplasms / Q000188:drug therapy*; D049268:Positron-Emission Tomography; D013016:Sound; D014407:Tumor Cells, Cultured
chemical_list: D015820:Cadherins; D053538:Keratin-18; D053539:Keratin-19; D053533:Keratin-8; D008081:Liposomes