Quantitative Multi-Parametric Magnetic Resonance Imaging of Tumor Response to Photodynamic Therapy.
OBJECTIVE
The aim of this study was to characterize response to photodynamic therapy (PDT) in a mouse cancer model using a multi-parametric quantitative MRI protocol and to identify MR parameters as potential biomarkers for early assessment of treatment outcome.


METHODS
CT26.WT colon carcinoma tumors were grown subcutaneously in the hind limb of BALB/c mice. Therapy consisted of intravenous injection of the photosensitizer Bremachlorin, followed by 10 min laser illumination (200 mW/cm2) of the tumor 6 h post injection. MRI at 7 T was performed at baseline, directly after PDT, as well as at 24 h, and 72 h. Tumor relaxation time constants (T1 and T2) and apparent diffusion coefficient (ADC) were quantified at each time point. Additionally, Gd-DOTA dynamic contrast-enhanced (DCE) MRI was performed to estimate transfer constants (Ktrans) and volume fractions of the extravascular extracellular space (ve) using standard Tofts-Kermode tracer kinetic modeling. At the end of the experiment, tumor viability was characterized by histology using NADH-diaphorase staining.


RESULTS
The therapy induced extensive cell death in the tumor and resulted in significant reduction in tumor growth, as compared to untreated controls. Tumor T1 and T2 relaxation times remained unchanged up to 24 h, but decreased at 72 h after treatment. Tumor ADC values significantly increased at 24 h and 72 h. DCE-MRI derived tracer kinetic parameters displayed an early response to the treatment. Directly after PDT complete vascular shutdown was observed in large parts of the tumors and reduced uptake (decreased Ktrans) in remaining tumor tissue. At 24 h, contrast uptake in most tumors was essentially absent. Out of 5 animals that were monitored for 2 weeks after treatment, 3 had tumor recurrence, in locations that showed strong contrast uptake at 72 h.


CONCLUSIONS
DCE-MRI is an effective tool for visualization of vascular effects directly after PDT. Endogenous contrast parameters T1, T2, and ADC, measured at 24 to 72 h after PDT, are also potential biomarkers for evaluation of therapy outcome.
Biomedical NMR, Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
Tom J L
TJ
Schreurs
Department of Radiology, Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
Stefanie J
SJ
Hectors
Biomedical NMR, Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
Igor
I
Jacobs
Biomedical NMR, Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.|Department of Oncology Solutions, Philips Research, Eindhoven, The Netherlands.
Holger
H
Grüll
Biomedical NMR, Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
Klaas
K
Nicolay
Biomedical Engineering and Physics, Academic Medical Center, Amsterdam, The Netherlands.
Gustav J
GJ
Strijkers
D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D003287:Contrast Media; D008279:Magnetic Resonance Imaging; D051379:Mice; D008807:Mice, Inbred BALB C; D010778:Photochemotherapy; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects
D003287:Contrast Media