Antivascular Treatment of Solid Melanoma Tumors with Bacteriochlorophyll–serine-based Photodynamic Therapy¶

Abstract

We describe here a strategy for photodynamic eradica-tion of solid melanoma tumors that is based on photo-induced vascular destruction. The suggested protocol relies on synchronizing illumination with maximal circulating drug concentration in the tumor vasculature attained within the first minute after administrating the sensitizer. This differs from conventional photodynamic therapy (PDT) of tumors where illumination coincides with a maximal concentration differential of sensitizer in favor of the tumor, relative to the normal surrounding tissue. This time window is often achieved after a delay (3-48 h) following sensitizer administration. We used a novel photosensitizer, bacteriochlorophyll-serine (Bchl-Ser), which is water soluble, highly toxic upon illumination in the near-infrared (max 765-780 nm) and clears from the circulation in less than 24 h. Nude CD1 mice bearing malignant M2R melanotic melanoma xenografts (76-212 mm 3) received a single complete treatment session. Massive vascular damage was already apparent 1 h after treatment. Changes in vascular permeability were observed in vivo using contrast-enhanced magnetic resonance imaging (MRI), with the contrast reagent Gd-DTPA, by shortening spin-spin relaxation time because of hemorrhage formation and by determination of vas-cular macromolecular leakage. Twenty-four hours after treatment a complete arrest of vascular perfusion was observed by Gd-DTPA-enhanced MRI. Histopathology performed at the same time confirmed primary vascular damage with occlusive thrombi, hemorrhage and tumor necrosis. The success rate of cure of over 80% with Bchl-Ser indicates the benefits of the short and effective treatment protocol. Combining the sensitizer administration and illumination steps into one treatment session (30 min) suggests a clear advantage for future PDT of solid tumors. ¶Posted on the website on 20 December 2000.

Engineering of relevant photodynamic processes through structural modifications of metallotetrapyrrolic photosensitizers

“…As a result, the efficacy of PDT can be lowered. In order to avoid the case when oxygen consumption becomes a limiting factor, fractionation of light enabling tissue re-oxygenation has been proposed [32][33][34][35]. Unfortunately, tumor tissue oxygenation exhibits a very heterogeneous response to PDT [36,37].…”

“…Unfortunately, tumor tissue oxygenation exhibits a very heterogeneous response to PDT [36,37]. For photosensitizers that have the vasculature as the main target [35,38,39], the supply of oxygen to tissue might be limited due to a vascular damage resulting from PDT. Occlusion of blood vessels and hypoxia can occur within a few minutes after beginning of PDT.…”

Manipulation of redox signaling in mammalian cells enabled by controlled photogeneration of reactive oxygen species

“…In an attempt to tightly regulate ROS doses at temporal and spatial, as well as at type-specific levels, we made use of a bacteriochlorophyll-based (Bchl) photosensitizer Scherz et al, 2000;Scherz et al, 2001;Scherz et al, 2003) which allowed for controlled, in situ generation of ROS upon illumination at a wavelength matching its absorption spectrum. This compound and other bacteriochlorophyll-based molecules have been used for generation of cytotoxic levels of ROS in photodynamic therapy (PDT) of different malignancies Preise et al, 2003;Schreiber et al, 2002;Zilberstein et al, 2001) and for modeling superoxide dismutase activity (Ashur et al, 2003). The ROS profile generated by each sensitizer has been determined using electron spin resonance (ESR)-based analyses, time resolved optical spectroscopy and photochemical products analyses under cell-free conditions (Vakrat et al, 1999;Vakrat-Haglili et al, 2002;Vakrat-Haglili et al, 2005) and have been shown to include O 2 -, OH˙and singlet oxygen.…”

Hydroxyaluminium Tetra-3-Phenylthiophthalocyanine is a New Effective Photosensitizer for Photodynamic Therapy and Fluorescent Diagnosis

“…Spectral peaks of absorption for these PS are about 770-780 and 750-760 nm, respectively. The possibility of using these agents for PDT of melanoma [15], prostatic cancer [9], and some other tumors is intensely investigated. However, modern technology of preparing these PS is very difficult.…”

“…The efficiency of PDT with bacteriophyllide serine [3,15] and palladium bacteriopheophorbide [9] was studied. Spectral peaks of absorption for these PS are about 770-780 and 750-760 nm, respectively.…”