Photodynamic therapy targeted to tumor-induced angiogenic vessels (original) (raw)
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Photodiagnosis and Photodynamic Therapy, 2007
Background: Photodynamic therapy (PDT) is being widely used for treatment of cancer and non-malignant diseases. The mechanisms of phototoxicity to solid tumor are not yet completely understood. Knowledge of the inherent sensitivity of endothelial cells in comparison to tumor cells would be helpful to predict tumor response to PDT, and thereby optimize treatment protocols. Methods and results: The intrinsic sensitivity of rodent endothelial and tumor cells to PDT was studied using an in vitro clonogenicity assay that strictly controlled for light and photosensitizer exposure, as well as cellular photosensitizer and oxygen concentration. Taking into consideration cell size, ploidy and glutathione content, no significant difference in sensitivity to phototoxicity was observed between tumor and endothelial cells. Electron microscopy studies were also conducted to examine endothelial and tumor cells for differential cellular damage following interstitial PDT of rat prostate tumor. No evidence for selective damage to endothelial cells was demonstrated. Conclusions: Rodent tumor cells and endothelial cells are equally susceptible to Photofrinmediated PDT damage. Sufficient photosensitizer accumulated in solid tumor seems to be one of the key factors for PDT effectiveness. Crown
International journal of oncology, 2004
The aim of this study was to assess the anti-tumor effect of photodynamic therapy (PDT) using a novel bacteriochlorophyll derivative, palladium-bacteriopheophorbide (TOOKAD) on tumor growth, perfusion and oxygenation. Rat DS-sarcomas were treated with either TOOKAD-PDT (2 mg/kg, i.v., immediate illumination) or one of the control treatments (sham-treatment, illumination without photosensitizer, or photosensitizer without illumination). The light source was an infrared-A irradiator fitted with appropriate filters, so that the wavelengths applied (665-800 nm) included the absorption maximum of TOOKAD at 763 nm. Tumor volume was monitored for 90 days after treatment or until a target volume (3.5 ml) was reached. TOOKAD-PDT dramatically inhibited tumor growth with 92% of tumors not reaching the target volume within the observation period. In further experiments, tumor perfusion was assessed using laser Doppler flowmetry. Upon TOOKAD-PDT treatment, a rapid, pronounced decrease in perfusi...
Photochemistry and Photobiology, 2007
The phototoxic effect of meso-tetra-hydroxyphenyl-chlorin (mTHPC)-mediated photodynamic therapy (PDT) on human microvascular endothelial cells (hMVEC) was compared with that on human fibroblasts (BCT-27) and two human tumor cell lines (HMESO-1 and HNXOE). To examine the relationship between intrinsic phototoxicity and intracellular mTHPC content, we expressed cell survival as a function of cellular fluorescence. On the basis of total cell fluorescence, HNXOE tumor cells were the most sensitive and BCT-27 fibroblasts the most resistant, but these differences disappeared after correcting for cell volume. Endothelial cells were not intrinsically more sensitive to mTHPC-PDT than tumor cells or fibroblasts. Uptake of mTHPC in hMVEC increased linearly to at least 48 h, whereas drug uptake in the other cell lines reached a maximum by 24 h. No difference in drug uptake was seen between the cell lines during the first 24 h, but by 48 h hMVEC had a 1.8to 2.8fold higher uptake than other cell lines. Endothelial cells showed a rapid apoptotic response after mTHPC-mediated PDT, whereas similar protocols gave a delayed apoptotic or necrotic like response in HNXOE. We conclude that endothelial cells are not intrinsically more sensitive than other cell types to mTHPC-mediated PDT but that continued drug uptake beyond 24 h may lead to higher intracellular drug levels and increased photosensitivity under certain conditions.
Journal of Veterinary Medicine Series A, 2006
The aim of this study was to examine the pharmacokinetics of clinically applied benzoporphyrin derivative monoacid ring-A (BPD-MA; Verteporfin Ò ), a second-generation photosensitizer, during a trial of photodynamic therapy (PDT) in nine dogs having naturally occurring neoplasms. After injecting BPD-MA at 0.5 mg/kg intravenously, its mean half-life (t 1/2 ) was found to be 8.14 ± 5.34 h, mean clearance (Cl) 35.13 ± 9.62 ml/(h kg), the mean value of the volume of distribution (V c ) 0.08 ± 0.01 l/kg and the mean steady state volume of distribution (V ss ) 0.38 ± 0.31 l/kg respectively. With the exception of a transitional increase in serum alkaline phosphatase activity, no other clinical abnormalities were observed. The t 1/2 in dogs with naturally occurring tumours was longer than that in humans, but similar to that in rats. The values of Cl and V ss in dogs having naturally occurring neoplasms were lower than those in humans. It is suggested that the pharmacokinetics of BPD-MA in tumour-bearing dogs would be helpful in determining the protocol of a short druglight interval PDT with BPD-MA that mainly targets the tumour vasculature.
Journal of Biomedical Optics, 2020
Photodynamic therapy (PDT) is a well-established treatment modality for cancer and other malignant diseases; however, quantities such as light fluence and PDT dose do not fully account for all of the dynamic interactions between the key components involved. In particular, fluence rate (ϕ) effects, which impact the photochemical oxygen consumption rate, are not accounted for. In this preclinical study, reacted reactive oxygen species (½ROS rx) was investigated as a dosimetric quantity for PDT outcome. The ability of ½ROS rx to predict the cure index (CI) of tumor growth, CI ¼ 1 − k∕k ctr , where k and k ctr are the growth rate of tumor under PDT study and the control tumor without PDT, respectively, for benzoporphyrin derivative (BPD)mediated PDT, was examined. Mice bearing radiation-induced fibrosarcoma (RIF) tumors were treated with different in-air fluences (Φ ¼ 22.5 to 166.7 J∕cm 2) and in-air fluence rates (ϕ air ¼ 75 to 250 mW∕cm 2) with a BPD dose of 1 mg∕kg and a drug-light interval (DLI) of 15 min. Treatment was delivered with a collimated laser beam of 1-cm-diameter at 690 nm. Explicit measurements of in-air light fluence rate, tissue oxygen concentration, and BPD concentration were used to calculate for ½ROS rx. Light fluence rate at 3-mm depth (ϕ 3 mm), determined based on Monte-Carlo simulations, was used in the calculation of ½ROS rx at the base of tumor. CI was used as an endpoint for three dose metrics: light fluence, PDT dose, and ½ROS rx. PDT dose was defined as the product of the time-integral of photosensitizer concentration and ϕ 3 mm. Preliminary studies show that ½ROS rx best correlates with CI and is an effective dosimetric quantity that can predict treatment outcome. The threshold dose for ½ROS rx for vascular BPD-mediated PDT using DLI of 15 min is determined to be 0.26 mM and is about 3.8 times smaller than the corresponding value for conventional BPD-mediated PDT using DLI of 3 h. © The Authors. Published by SPIE under a Creative Commons Attribution 4.0 Unported License. Distribution or reproduction of this work in whole or in part requires full attribution of the original publication, including its DOI.
JNCI Journal of the National Cancer Institute, 1988
The effect of photodynamic therapy on the tumor microvasculature in the first few hours after treatment was studied, at the light and electron microscopy levels. BALB/c mice with EMT-6 tumor received ip injections of hematoporphyrin derivative, chlorin, or phthalocyanine, and 24 hours later, the tumors were treated with light at 100 J/cm 2 at the appropriate therapeutic wavelength for each photosensltizer. Animals were killed and their tumors removed at time 0, 30 minutes, 1 hour, and 2, 4, 6, 8, 12, 16, and 24 hours after treatment The results indicate that for all three sensitizers the effects of photodynamic therapy leading to rapid necrosis of tumor tissue are not the result of direct tumor cell kill but are secondary to destruction of the tumor microvasculature. The first observable signs of destruction occur in the subendothelial zone of the tumor capillary wall. This' zone, composed of dense collagen fibers and other connective tissue elements, is destroyed in the first few hours after phototherapy. However, the ultrastructural changes seen in this zone are different for the hematoporphyrin derivative, compared with chlorin and phthalocyanine. Binding of photosensitizers to the elements in this zone as well as altered permeability and transport through the endothelial cell layer because of the increased intraluminal pressure may be key features of tumor destruction. [