Photodynamic therapy with mTHPC and polyethylene glycol-derived mTHPC: a comparative study on human tumour xenografts

Abstract

SummaryThe photosensitizing properties of m-tetrahydroxyphenylchlorin (mTHPC) and polyethylene glycol-derivatized mTHPC (pegylated mTHPC) were compared in nude mice bearing human malignant mesothelioma, squamous cell carcinoma and adenocarcinoma xenografts. Laser light (20 J/cm 2 ) at 652 nm was delivered to the tumour (surface irradiance) and to an equal-sized area of the hind leg of the animals after i.p. administration of 0.1 mg/kg body weight mTHPC and an equimolar dose of pegylated mTHPC, respectively. The extent of tumour necrosis and normal tissue injury was assessed by histology. Both mTHPC and pegylated mTHPC catalyse photosensitized necrosis in mesothelioma xenografts at drug-light intervals of 1-4 days. The onset of action of pegylated mTHPC seemed slower but significantly exceeds that of mTHPC by days 3 and 4 with the greatest difference being noted at day 4. Pegylated mTHPC also induced significantly larger photonecrosis than mTHPC in squamous cell xenografts but not in adenocarcinoma at day 4, where mTHPC showed greatest activity. The degree of necrosis induced by pegylated mTHPC was the same for all three xenografts. mTHPC led to necrosis of skin and underlying muscle at a drug-light interval of 1 day but minor histological changes only at drug-light intervals from 2-4 days. In contrast, pegylated mTHPC did not result in histologically detectable changes in normal tissues under the same treatment conditions at any drug-light interval assessed. In this study, pegylated mTHPC had advantages as a photosensitizer compared to mTHPC.Tissue concentrations of mTHPC and pegylated mTHPC were measured by high-performance liquid chromatography in non-irradiated animals 4 days after administration. There was no significant difference in tumour uptake between the two sensitizers in mesothelioma, adenocarcinoma and squamous cell carcinoma xenografts. Tissue concentration measurements were of limited use for predicting photosensitization in this model.

Optimizing Photodynamic Therapy:In vivoPharmacokinetics of Liposomalmeta-(Tetrahydroxyphenyl)Chlorin in Feline Squamous Cell Carcinoma

“…In previously published work using m-THPC, a drug-light interval of 4 to 12 hours resulted in extensive skin and muscle necrosis (20,21), indicating a low tumor-to-normal tissue ratio at this early time point. In contrary, no obvious changes in normal tissues were observed at any drug-light interval when pegylated m-THPC was used (22). Results of our study clearly show much higher tumor-toskin ratios in spontaneous feline squamous cell carcinoma with the liposomal drug.…”

Preclinical Comparison of mTHPC and Verteporfin for Intracavitary Photodynamic Therapy of Malignant Pleural Mesothelioma

“…Its feasibility in association with cytoreductive surgery has been shown in several clinical studies in this respect. However, the efficiency and tumour selectivity of PDT for MPM depends on the choice of the sensitizer and on the treatment conditions applied [4][5][6][7][9][10][11][12][13] . Photofrin and mTHPC were the sensitizers used for intracavitary PDT after resection in patients with MPM [4][5][6][7] .…”

“…Most of these experiments were performed on nude mice bearing human mesothelioma xenografts [8][9][10]14] or on tumour-free minipigs [13] and canines [11] . However, none of these models allows the assessment of PDT on MPM growing within the pleural cavity in an experimental setting.…”

Correlation of photodynamic activity and fluorescence signaling for free and pegylated mTHPC in mesothelioma xenografts

“…This has led to relevant morbidity after PDT of the chest cavity after surgery for pleural mesothelioma [1][2][3][4][5][6], even in the presence of new second generation sensitizers [7][8][9][10][11][12][13]. Several experimental studies focusing on PDT for mesothelioma have shown that enhanced tumor selectivity may be obtained by modulating treatment conditions [14][15][16][17][18] and by pegylation of the sensitizer [19,20].…”

“…Since previous work has shown that tissue concentration measurements of free and pegylated mTHPC performed by HPLC were of limited use for predicting the photodynamic activity in this model [15,19], we hypothesized that fluorescence signaling measurements by fluorescence microscopy might be well suited in this respect. Fluorescence signaling of free and pegylated mTHPC was analyzed in tumors and skin by use of fluorescence microscopy in order to assess the photosensitizer distribution in tumors and to measure the tumor to skin fluorescence intensity ratio for both mTHPC formulations.…”