Mild hyperthermia enhances drug accumulation and photodynamic therapy efficacy

摘要

Photodynamic therapy (PDT) of tumors relies on the delivery of a photosensitizer to the tumor site followed by externallaser activation. The effectiveness of the therapy is determined by the fluence and irradiation of the laser, intratumoralphotosensitizer retention, and availability of molecular oxygen. We hypothesized that retention and resulting therapeuticresponse may be improved with local hyperthermia. Tumors were grown in the rear limb then locally heated for 1 hourat 42.5°C immediately following i.v. injection of the photosensitizer in an immunocompetent murine model. Laserexposure was applied at 2 h or 24 h after the heating session. Administration of heating caused a significant growthdelay when a single laser treatment was applied only 2 hours following injection. However, in animals givenphotosensitizer only and irradiated 2 h later there was no measurable anti-tumor effect observed. The marked anti-tumoreffects obtained with prior local hyperthermia were observed even as the dose was lowered from 10 mg/kg to 1.3 mg/kg.Additionally, histological analysis of our intial studies revealed that the majority of the tumor tissue (～75%) was necroticafter two days when heat was combined with PDT, while PDT alone resulted in only ～25% necrotic tissue.Additionally, a significant, though less notable, increase in the efficacy was observed if the laser treatment was applied24 hours after hyperthermia and photosensitizer administration. This increase is in part ascribed to the increasedretention of the photosensitizer in the tumor tissue and likely lasting effects on tumor blood flow and oxygenation in theheated vs. control groups.