Abstract
ObjectiveThe 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.MethodsCT26.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.ResultsThe 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.ConclusionDCE-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.
Highlights
Photodynamic therapy (PDT) is a photochemistry-based approach for the minimally-invasive local treatment of cancer
After PDT complete vascular shutdown was observed in large parts of the tumors and reduced uptake in remaining tumor tissue
We evaluated changes in T1, T2, apparent diffusion coefficient (ADC), and dynamic contrast-enhanced (DCE)-Magnetic resonance imaging (MRI) derived vascular parameters upon PDT in a mouse cancer model up to 72 h after treatment
Summary
Photodynamic therapy (PDT) is a photochemistry-based approach for the minimally-invasive local treatment of cancer. It consists of administration of a light-activated chemical, termed a photosensitizer (PS), followed by local irradiation of the tumor with light of the appropriate wavelength, resulting in the generation of cytotoxic species including singlet oxygen [1]. The light that is used for PDT is in the 600–800 nm wavelength range. PDT is clinically approved and routinely used for treatment of premalignant and malignant non-melanoma skin tumors [2]. PDT has shown to be promising in the treatment and palliation of head and neck tumors [3], digestive system tumors (e.g. Barrett’s esophagus [4]), and prostate cancer [5]. A comprehensive review on PDT principles and applications can be found in Agostinis et al [6]
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