title: Dynamic contrast enhanced MRI detects changes in vascular transport rate constants following treatment with thermally-sensitive liposomal doxorubicin.
abstract: Temperature-sensitive liposomal formulations of chemotherapeutics, such as doxorubicin, can achieve locally high drug concentrations within a tumor and tumor vasculature while maintaining low systemic toxicity. Further, doxorubicin delivery by temperature-sensitive liposomes can reliably cure local cancer in mouse models. Histological sections of treated tumors have detected red blood cell extravasation within tumors treated with temperature-sensitive doxorubicin and ultrasound hyperthermia. We hypothesize that the local release of drug into the tumor vasculature and resulting high drug concentration can alter vascular transport rate constants along with having direct tumoricidal effects. Dynamic contrast enhanced MRI (DCE-MRI) coupled with a pharmacokinetic model can detect and quantify changes in such vascular transport rate constants. Here, we set out to determine whether changes in rate constants resulting from intravascular drug release were detectable by MRI. We found that the accumulation of gadoteridol was enhanced in tumors treated with temperature-sensitive liposomal doxorubicin and ultrasound hyperthermia. While the initial uptake rate of the small molecule tracer was slower (k1=0.0478±0.011s-1versus 0.116±0.047s-1) in treated compared to untreated tumors, the tracer was retained after treatment due to a larger reduction in the rate of clearance (k2=0.291±0.030s-1versus 0.747±0.24s-1). While DCE-MRI assesses a combination of blood flow and permeability, ultrasound imaging of microvascular flow rate is sensitive only to changes in vascular flow rate; based on this technique, blood flow was not significantly altered 30min after treatment. In summary, DCE-MRI provides a means to detect changes that are associated with treatment by thermally-activated particles and such changes can be exploited to enhance local delivery.
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, CA 95616, USA. Electronic address: bzfite@ucdavis.edu.
authors.forename: Brett Z
authors.initials: BZ
authors.lastname: Fite
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, CA 95616, USA. Electronic address: akheirolomoom@ucdavis.edu.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Kheirolomoom
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, CA 95616, USA. Electronic address: jlfoiret@ucdavis.edu.
authors.forename: Josquin L
authors.initials: JL
authors.lastname: Foiret
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, CA 95616, USA. Electronic address: jwseo@ucdavis.edu.
authors.forename: Jai W
authors.initials: JW
authors.lastname: Seo
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, CA 95616, USA. Electronic address: lmmahakian@ucdavis.edu.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Mahakian
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, CA 95616, USA. Electronic address: esingham@ucdavis.edu.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Ingham
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, CA 95616, USA. Electronic address: smjohns@ucdavis.edu.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Tam
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Davis, CA 95616, USA. Electronic address: adborowsky@ucdavis.edu.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Borowsky
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, CA 95616, USA. Electronic address: fecurry@ucdavis.edu.
authors.forename: Fitz-Roy E
authors.initials: FE
authors.lastname: Curry
authors.affiliation: Department of Biomedical Engineering, University of California, Davis, CA 95616, USA. Electronic address: kwferrara@ucdavis.edu.
authors.forename: Katherine W
authors.initials: KW
authors.lastname: Ferrara
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D001692:Biological Transport; D002199:Capillary Permeability; D003287:Contrast Media / Q000008:administration & dosage / Q000493:pharmacokinetics; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D065546:Drug Liberation; D005260:Female; D005682:Gadolinium / Q000008:administration & dosage / Q000493:pharmacokinetics; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008819:Mice, Nude; D045423:Microbubbles; D009369:Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism / Q000628:therapy*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D014464:Ultrasonic Therapy
chemical_list: D000903:Antibiotics, Antineoplastic; D003287:Contrast Media; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin; D005682:Gadolinium
keywords: DCE-MRI; Doxorubicin; Hyperthermia; Liposomes; Vascular permeability