Diffusion-weighted MRI for monitoring tumor response to photodynamic therapy

Photodynamic therapy (PDT) is an emerging therapy that has shown promise for treating various cancers in both preclinical and clinical studies (1). PDT uses laser light with appropriate wavelength to activate preadministered tumor-localized photosensitizer. With oxygen presence, the activation of the photosensitizer generates singlet oxygen species that react with cellular structure and effectively ablate tumors either through direct cell destruction or local vasculature damage (2). PDT can be localized at planned regions, consequently minimizing injury to the surrounding normal tissue. PDT with different photosensitizer drugs has shown potentials for treating a variety of cancers including prostate cancer (3–6). PDT effect is determined by several parameters that include drug choice, drug dose, light dose, light delivery rate, and light delivery pattern. It is valuable if a technique can be used to monitor the tumor response to PDT and predict treatment efficacy at an early time; thereby, immediate prognosis and early consideration of adjuvant treatment are allowed. Traditionally, treatment efficacy assessment was determined by the variation of tumor size and thus may require weeks or months after therapy. Noninvasive imaging such as MRI can provide in vivo information about tissue physiology and morphology, whereby allow assessment of the tumor response by monitoring the change of treatment-induced tissue properties. A variety of MRI techniques have also been studied for assessing tumor response to PDT. MRI was used to study the therapeutic effect of PDT in normal rat brain (7). It has been shown that both T1 (8,9) and T2 values (6,8) increased after PDT. High-field MRI has been used to evaluate PDT-induced treatment effect (6,10). Gadolinium contrast-enhanced MRI revealed a decrease of tissue perfusion 5 h after PDT in rat borne tumors (11) and detected vascular lesion formation of recurrent prostate tumors 7 days after PDT (12). One week after the vascular-targeted PDT of locally recurrent prostate tumors (13), Gd contrast-enhanced MRI depicted irregular margins of the therapeutic effect. Blood oxygenation level-dependent (BOLD) contrast MRI was applied to monitor PDT in a solid tumor model (14), where 25–40% BOLD signal attenuation was detected in the treated tumors. Another MRI technique of 31P MR spectroscopy (MRS) was used to image zinc phthalocyanine-based PDT of RIF-1 murine fibrosarcoma in mice (15). 19F MRS was also applied to study the pharmacokinetic profile of a fluorinated photosensitizer in a RIF tumor model (16). Diffusion weighted MRI (DW-MRI) detects displacement of water molecules and several studies have demonstrated its potential for monitoring tumor response to PDT. A biphasic change in the apparent diffusion coefficient (ADC) derived from DW-MRI has been reported within the first 24 h after TOOKAD-based PDT of prostatic adenocarcinoma in mice (17). Another TOOKAD-PDT study found a markedly decrease of ADC values in the necrotic regions 7 days after PDT in a normal canine prostate model (18). DW-MRI with high-b-value shows potentials for predicting treatment outcome in a study of PDT of colon carcinoma in mice (19). Both MRI and positron emission tomography (PET) have been used to study the tumor response to Pc 4-PDT (6,20,21). Assessment of therapeutic effect was improved by fusion of MRI anatomical and PET functional information (22). We are developing noninvasive imaging and quantitative analysis techniques to identify potential biomarkers of early tumor response to PDT. In present study, we evaluate the capability of DW-MRI for identifying early therapeutic efficacy of Pc 4-PDT in a CWR22 human prostate cancer model. CWR22 is androgen dependent and prostate specific antigen (PSA) level can be measured as an independent parameter of therapeutic efficacy. This study suggests that the change of tumor ADC in response to Pc 4-PDT could eventually be useful for monitoring Pc 4-PDT of prostate cancer in the clinic.