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Video monitoring of neovessel occlusion induced by photodynamic therapy with verteporfin (Visudyne), in the CAM model.

ABSTRACT: The aim of the present study was to monitor photodynamic angioocclusion with verteporfin in capillaries. Details of this process were recorded under a microscope in real-time using a high-sensitivity video camera. A procedure was developed based on intravenous (i.v.) injection of a light-activated drug, Visudyne, into the chorioallantoic membrane (CAM) of a 12-day-old chicken embryo. The effect of light activation was probed after 24 h by i.v. injection of a fluorescent dye (FITC dextran), and analysis of its fluorescence distribution. The angioocclusive effect was graded based on the size of the occluded vessels, and these results were compared with clinical observations. The time-resolved thrombus formation taking place in a fraction of the field of view was video recorded using a Peltier-cooled CCD camera. This vessel occlusion in the CAM model was reproducible and, in many ways, similar to that observed in the clinical use of verteporfin. The real-time video recording permitted the monitoring of platelet aggregation and revealed size-selective vascular closure as well as some degree of vasoconstriction. Platelets accumulated at intravascular junctions within seconds after verteporfin light activation, and capillaries were found to be closed 15 min later at the applied conditions. Larger-diameter vessels remained patent. Repetition of these data with a much more sensitive camera revealed occlusion of the treated area after 5 min with doses of verteporfin and light similar to those used clinically. Consequently, newly developed light-activated drugs can now be studied under clinically relevant conditions.

SUBMITTER: Debefve E

PROVIDER: S-EPMC2494573 | biostudies-other | 2008

REPOSITORIES: biostudies-other

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Project description:Objective: Monitoring emerging vascular-targeted photodynamic therapy (VTP) and understanding the time-dynamics of treatment effects remains challenging. We interrogated whether handheld multispectral optoacoustic tomography (MSOT) could noninvasively monitor the effect of VTP using WST11, a vascular-acting photosensitizer, on tumor tissues over time using a renal cell cancer mouse model. We also investigated whether MSOT illumination can induce VTP, to implement a single-modality theranostic approach. Materials and Methods: Eight BalB/c mice were subcutaneously implanted with murine renal adenocarcinoma cells (RENCA) on the flank. Three weeks later VTP was performed (10 min continuous illumination at 753 nm following intravenous infusion using WST11 or saline as control. Handheld MSOT images were collected prior to VTP administration and subsequently thereafter over the course of the first hour, at 24 and 48 h. Data collected were unmixed for blood oxygen saturation in tissue (SO2) based on the spectral signatures of deoxy- and oxygenated hemoglobin. Changes in oxygen saturation over time, relative to baseline, were examined by paired t-test for statistical significance (p < 0.05). In-vivo findings were corroborated by histological analyses of the tumor tissue. Results: MSOT is shown to prominently resolve changes in oxygen saturation in tumors within the first 20 min post WST11-VTP treatment. Within the first hour post-treatment, SO2 decreased by more than 60% over baseline (p < 0.05), whereas it remained unchanged (p > 0.1) in the sham-treated group. Moreover, unlike in the control group, SO2 in treated tumors further decreased over the course of 24 to 48 h post-treatment, concomitant with the propagation of profound central tumor necrosis present in histological analysis. We further show that pulsed MSOT illumination can activate WST11 as efficiently as the continuous wave irradiation employed for treatment. Conclusion: Handheld MSOT non-invasively monitored WST11-VTP effects based on the SO2 signal and detected blood saturation changes within the first 20 min post-treatment. MSOT may potentially serve as a means for both VTP induction and real-time VTP monitoring in a theranostic approach.

Project description:ObjectiveInflammation is a well-known consequence of surgery. Although surgical debulking of tumor is beneficial to patients, the onset of inflammation in injured tissue may impede the success of adjuvant therapies. One marker for postoperative inflammation is IL-6, which is released as a consequence of surgical injuries. IL-6 is predictive of response to many cancer therapies, and it is linked to various molecular and cellular resistance mechanisms. The purpose of this study was to establish a murine model by which therapeutic responses to photodynamic therapy (PDT) can be studied in the context of surgical inflammation.Materials and methodsMurine models with AB12 mesothelioma tumors were treated with either surgical resection or sham surgery with tumor incision but no resection. The timing and extent of IL-6 release in the tumor and/or serum was measured using enzyme-linked immunosorbent assay (ELISA) and compared to that measured in the serum of 27 consecutive, prospectively enrolled patients with malignant pleural mesothelioma (MPM) who underwent macroscopic complete resection (MCR).ResultsMPM patients showed a significant increase in IL-6 at the time MCR was completed. Similarly, IL-6 increased in the tumor and serum of mice treated with surgical resections. However, investigations that combine resection with another therapy make it necessary to grow tumors for resection to a larger volume than those that receive secondary therapy alone. As the larger size may alter tumor biology independent of the effects of surgical injury, we assessed the tumor incision model. In this model, tumor levels of IL-6 significantly increased after tumor incision.ConclusionThe tumor incision model induces IL-6 release as is seen in the surgical setting, yet it avoids the limitations of surgical resection models. Potential mechanisms by which surgical induction of inflammation and IL-6 could alter the nature and efficacy of tumor response to PDT are reviewed. These include a wide spectrum of molecular and cellular mechanisms through which surgically-induced IL-6 could change the effectiveness of therapies that are combined with surgery. The tumor incision model can be employed for novel investigations of the effects of surgically-induced, acute inflammation on therapeutic response to PDT (or potentially other therapies). Lasers Surg. Med. 50:440-450, 2018. © 2018 Wiley Periodicals, Inc.

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Video monitoring of neovessel occlusion induced by photodynamic therapy with verteporfin (Visudyne), in the CAM model.

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