title: Imaging and modification of the tumor vascular barrier for improvement in magnetic nanoparticle uptake and hyperthermia treatment efficacy.
abstract: The predicted success of nanoparticle based cancer therapy is due in part to the presence of the inherent leakiness of the tumor vascular barrier, the so called enhanced permeability and retention (EPR) effect. Although the EPR effect is present in varying degrees in many tumors, it has not resulted in the consistent level of nanoparticle-tumor uptake enhancement that was initially predicted. Magnetic/iron oxide nanoparticles (mNPs) have many positive qualities, including their inert/nontoxic nature, the ability to be produced in various sizes, the ability to be activated by a deeply penetrating and nontoxic magnetic field resulting in cell-specific cytotoxic heating, and the ability to be successfully coated with a wide variety of functional coatings. However, at this time, the delivery of adequate numbers of nanoparticles to the tumor site via systemic administration remains challenging. Ionizing radiation, cisplatinum chemotherapy, external static magnetic fields and vascular disrupting agents are being used to modify the tumor environment/vasculature barrier to improve mNP uptake in tumors and subsequently tumor treatment. Preliminary studies suggest use of these modalities, individually, can result in mNP uptake improvements in the 3-10 fold range. Ongoing studies show promise of even greater tumor uptake enhancement when these methods are combined. The level and location of mNP/Fe in blood and normal/tumor tissue is assessed via histopathological methods (confocal, light and electron microscopy, histochemical iron staining, fluorescent labeling, TEM) and ICP-MS. In order to accurately plan and assess mNP-based therapies in clinical patients, a noninvasive and quantitative imaging technique for the assessment of mNP uptake and biodistribution will be necessary. To address this issue, we examined the use of computed tomography (CT), magnetic resonance imaging (MRI), and Sweep Imaging With Fourier Transformation (SWIFT), an MRI technique which provides a positive iron contrast enhancement and a reduced signal to noise ratio, for effective observation and quantification of Fe/mNP concentrations in the clinical setting.
authors.affiliation: Thayer School of Engineering, Dartmouth College, 14 Engineering Dr., Hanover, NH USA 03755 ; Geisel School of Medicine, Dartmouth College, 1 Rope Ferry Rd., Hanover, NH USA 03755.
authors.forename: P Jack
authors.initials: PJ
authors.lastname: Hoopes
authors.affiliation: Thayer School of Engineering, Dartmouth College, 14 Engineering Dr., Hanover, NH USA 03755.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: Petryk
authors.affiliation: Thayer School of Engineering, Dartmouth College, 14 Engineering Dr., Hanover, NH USA 03755.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Tate
authors.affiliation: Geisel School of Medicine, Dartmouth College, 1 Rope Ferry Rd., Hanover, NH USA 03755.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Savellano
authors.affiliation: Geisel School of Medicine, Dartmouth College, 1 Rope Ferry Rd., Hanover, NH USA 03755.
authors.forename: Rendall R
authors.initials: RR
authors.lastname: Strawbridge
authors.affiliation: Thayer School of Engineering, Dartmouth College, 14 Engineering Dr., Hanover, NH USA 03755 ; Geisel School of Medicine, Dartmouth College, 1 Rope Ferry Rd., Hanover, NH USA 03755.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Giustini
authors.affiliation: Geisel School of Medicine, Dartmouth College, 1 Rope Ferry Rd., Hanover, NH USA 03755.
authors.forename: Radu V
authors.initials: RV
authors.lastname: Stan
authors.affiliation: Geisel School of Medicine, Dartmouth College, 1 Rope Ferry Rd., Hanover, NH USA 03755.
authors.forename: Barjor
authors.initials: B
authors.lastname: Gimi
authors.affiliation: Center for Magnetic Resonance Research University of Minnesota, 2021 Sixth Street SE, Minneapolis, MN 55455.
authors.forename: Michael
authors.initials: M
authors.lastname: Garwood
keywords: EPR effect; Imaging; Magnetic nanoparticle; Tumor vascular modification