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.
Successful application of anticancer therapy, and especially photodynamic therapy (PDT) mediated by type I1 (PDTII) processes, depends on the oxygen content within the tumor before, during and after treatment. The high consumption of oxygen during type I1 PDT imposes constraints on therapy strategies. Although rates of oxygen consumption and repletion during PDTII were suggested by theoretical studies, direct measurements have not been reported. Application of a novel oxygen sensor allowed continuous and direct in sifu measurements (up to a depth of 8-9 mm from the tumor surface and for several hours) of temporal variations in the oxygen partial pressure (pOz) during PDT. Highly pigmented M2R mouse melanoma tumors implanted in CD1 nude mice were treated with bacteriochlorophyll+erine (Bchl-Ser; a new photodynamic reagent) and were subjected to fractionated illumination (700 < A < 900 nm) at a fluence rate of 12 mW cm+. This illumination led to total oxygen depletion with an average consumption rate of 7.2 pM(Oz) s-l. Spontaneous reoxygenation (at an average rate of 2.5 pM(O,)/s) was observed during the following dark period. These rates are in good agreement with theoretical considerations (Foster et al., Radiat. Res. 126, 296,1991 and Henning et al., Radiut. Res. 142,221,1995). The observed patterns of oxygen consumption and recovery during prolonged periods of Iightldark cycles were interpreted in terms of vasculature damage and sensitizer clearance. The presented data support the previously suggested advantages of fractionated illumination for type I1 photodynamic processes.
The Cesium salt of BSSB (Cs4B24H22S2), a common boron-neutron-capture-therapy (BNCT) agent, was injected into M2R mouse melanoma xenografts, and detected in vivo by 1H-observed, 10B-edited NMR spectroscopy. The technique of spin-echo difference spectroscopy, in which a proton spin-echo is detected following the alternating presence and absence of a 10B 180 degrees pulse was used. This method provides much higher sensitivity than direct 10B NMR detection, and should thus be suitable for in vivo detection in patients about to undergo BNCT treatment, where the infused agents are 95% isotopically enriched in 10B.
Longitudinal and transverse relaxation rates for the 11B resonances in sodium borocaptate (BSH) at varying concentrations were measured in undiluted horse serum in a 4.7 Tesla field. The results could be fit by a model that assumes fast exchange of the BSH molecule between a free and a bound state, using values of 0.77+/-0.7 MHz for the 11B quadrupole coupling constant and (6.3+/-0.9) x 10(-9) s for the rotational correlation time in the bound state. These results were used as a basis for assessing the requirements and limitations of quantitative determination of BSH concentrations in vivo, using 11B NMR. Surface coil 11B NMR spectroscopy was performed on a total of 14 mice injected with BSH. Some of the animals (n=9) had implanted M2R melanoma tumors grown to various sizes in the rear thigh, in which case the surface coil was placed against the tumor, whereas for the other animals (without tumor), the coil was placed against the rear thigh muscle. NMR spectra were acquired under fully relaxed conditions. The spectra were quantitated by peak integration; apparent absolute BSH concentrations were derived by comparison with spectra from a phantom with known BSH concentration, using extrapolation of the time-domain data to zero preacquisition delay. The results indicate significantly higher 11B BSH signal intensities in tumors, compared with muscle tissue, whereas the uptake and clearance kinetics were similar.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.