Compartmental targeting for mTHPC-based photodynamic treatment in vivo: Correlation of efficiency, pharmacokinetics, and regional distribution of apoptosis.
OBJECTIVE
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
Mice bearing EMT6 tumors were subjected to a single irradiation (10 J/cm(2)) 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.
Garrier
Julie
J
Centre de Recherche en Automatique de Nancy, CRAN-UMR, Nancy-University, CNRS, Centre Alexis Vautrin, Vandœuvre-lès-Nancy, France.
Bressenot
Aude
A
Gräfe
Susanna
S
Marchal
Sophie
S
Mitra
Soumya
S
Foster
Thomas H
TH
Guillemin
François
F
Bezdetnaya
Lina
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000032:analysis / Q000276:immunology; D024141:Collagen Type IV / Q000032:analysis / Q000276:immunology; D005260:Female; D007150:Immunohistochemistry / Q000379:methods; D008652:Mesoporphyrins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D009363:Neoplasm Proteins / Q000032:analysis / Q000276:immunology; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D024141:Collagen Type IV; D008652:Mesoporphyrins; D009363:Neoplasm Proteins; D017319:Photosensitizing Agents; C505409:Casp3 protein, mouse; D053148:Caspase 3; C072269:temoporfin