Compartmental Targeting for mTHPC-based Photodynamic Treatment In Vivo: Correlation of Efficiency, Pharmacokinetics, and Regional Distribution of Apoptosis
Received 12 October 2009; received in revised form 12 April 2010; accepted 14 April 2010. published online 26 July 2010. Corrected Proof
Purpose
The present study investigates the efficacy of compartmental targeting in xenografted tumors treated by meta-tetra(hydroxyphenyl)chlorin (mTHPC)-mediated photodynamic therapy (PDT). The therapeutic efficacy was, furthermore, related to a regional photoinduced distribution of apoptosis and an mTHPC biodistribution profile.
Methods and Materials
Mice bearing EMT6 tumors were subjected to a single irradiation (10 J/cm2) of red laser light (652 nm) at different intervals after a single- (0.3 mg/kg or 0.15 mg/kg) or double-intravenous (2 × 0.15 mg/kg) injection(s) of mTHPC. Efficiency of the treatment was evaluated by monitoring tumor regrowth. mTHPC pharmacokinetics were assessed by high-performance liquid chromatography analysis of excised organs. The regional distribution of apoptosis in tumor sections was investigated with a newly developed colabelling immunohistochemistry technique.
Results
A fractionated double-injection protocol of mTHPC with 24-h and 3-h drug-light intervals (DLI) yielded 100% tumor cure, with tumors presenting a massive apoptosis of neoplastic cells along with a distortion of vessels. The best efficiency for a single injection (0.3 mg/kg) was about 54% tumor cure and corresponded to a DLI of 3 h. At this DLI, tumors showed apoptosis of endothelial cells in residual vessels. Concentrations of mTHPC observed in plasma and tumor for the fractionated injection were not statistically different and were less than the total drug dose in each compartment.
Conclusions
The present work suggests that clinical PDT protocols with mTHPC could be greatly improved by fractionation of the drug administration. Time points should be chosen based on the intratumoral spatiotemporal drug distribution.
∗Centre de Recherche en Automatique de Nancy (CRAN-UMR 7039), Nancy-University, CNRS, Centre Alexis Vautrin, Vandœuvre-lès-Nancy, France
†Service d'Anatomie et de Cytologie Pathologiques, CHU de Brabois, Vandœuvre-lès-Nancy, France
‡Research and Development, Biolitec AG, Jena, Germany
¶Department of Imaging Sciences, University of Rochester, Rochester, New York
Reprint requests to: Lina Bezdetnaya, M.D., Ph.D., CRAN-UMR 7039, Nancy-University, CNRS, Centre Alexis Vautrin, Avenue de Bourgogne, F-54511 Vandœuvre-lès-Nancy, France. Tel: 33 (0)3 83 59 83 06; Fax: 33 (0)3 83 59 83 78
This research was supported by the Alexis Vautrin Cancer Center and the French Ligue Nationale contre le Cancer and by U.S. National Institutes of Health grant CA68409 (to S.M. and T.H.F.).
This work was presented at the 13th Congress of the European Society of Pathology, Wroclaw, Poland, Sept 5-10, 2009.
ABSTRACT