Endobronchial Phototoxicity of WST 09 (Tookad®), a New Fast-Acting Photosensitizer for Photodynamic Therapy: Preclinical Study in the Pig¶

Abstract

Photodynamic therapy (PDT) has been used for many years for both palliative and curative treatment of bronchial carcinomas. However, prolonged skin phototoxicity and reduced depth of penetration has limited the widespread use of PDT. We studied the endobronchial phototoxicity of a novel photosensitizer, WST 09 (Tookad Ò ). Fourteen pairs of Large White-Landrace male piglets were given intravenous WST 09 followed by laser light illumination of the left mainstem bronchus. Different settings for light dose (fluence), fluence rate (FR), drug dose (D) and drug-light interval (DLI) were applied to each pair. Bronchial toxicity was assessed with repeat bronchoscopic photographic evaluation as well as by pathologic examination following autopsy. Animals developed no toxicity, moderate toxicity or severe toxicity. Increased toxicity was seen with increasing D and fluence and decreasing DLI, whereas no increased toxicity was seen with higher FR. PDT-related histological changes in the normal bronchus confirm the vascular effect of WST 09. Depending on the parameter settings for fluence, D and DLI, the lesions ranged from focal intramucosal ischemia to transmural infarction with subsequent acute inflammation and fibrosis. Clinically feasible parameters for drug and light dosimetry were documented. These data will be important in determining safe starting doses for human phase I/II studies.

New Two-Photon Activated Photodynamic Therapy Sensitizers Induce Xenograft Tumor Regressions after Near-IR Laser Treatment through the Body of the Host Mouse

“…Although the originally approved sensitizers, such as Photofrin and Foscan, show a limited preference for localization in tumor cells over normal cells, this does not provide much clinical advantage, and many groups are now investigating more effective methods of tumor and endothelial cell targeting (2,20,21). The utility of PDT is currently limited to topical, s.c., and endoscopic applications because the light typically used to generate singlet oxygen does not penetrate deeply into tissue (22). A phototherapeutic window exists between 780 and 950 nm, where tissues have relatively high transparency to light ( Fig.…”

“…Tookad (Pd-bacteriopheophorbide; ref. 22) is the only sensitizer being used (experimentally) in man that exhibits a light absorbance wavelength, k = 763 nm, close to the phototherapeutic window. However, no currently approved PDT agent can approach the potential 5 to 10 cm depth efficacy.…”

Photodynamic Actinometry Using Microspheres: Concept, Development and Responsivity ¶

“…An exception to this may be endogenous photosensitizers such as aminolevulinic acid‐induced protoporphyrin IX, which are synthesized within the mitochondria of cells(43). For photosensitizers whose action is predominantly vascular, such as WST 09 (Tookad TM ) (44,45) and to a lesser extent benzoporphyrin derivative (Verteporfin TM )(46), intravenous administration of smaller microspheres that do not extravasate or that remain external to the cells may prove valuable as a means of discerning PDT dose in vasculature(47). A very attractive characteristic of this microsphere actinometer approach is the timeintegrating measurement of the fluence and the ROS load which as a consequence becomes independent of changes in the light propagation due to PDT treatment or photosensitizer bleaching.…”

Determination of the radiance of cylindrical light diffusers: design of a one-axis charge-coupled device camera-based goniometer setup

“…Significant variations in the irradiance can lead to localized hot and cold spots resulting in undesirable irradiation effects. The usage of "long" wavelengths, above 700 nm, to excite photosensitizers, such as those developed for prostate cancer and bronchial PDT, [10][11][12] further enhances the impact of a heterogeneous illumination, e.g., unanticipated necrosis geometries, due to the increased penetration depth. Paradoxically, manufacturers often supply only a radial light emission measurement as proof of quality.…”