Background: In specific conditions, photodynamic therapy (PDT) can enhance the distribution of macromolecules across the endothelial barrier in solid tumors. It was recently postulated that tumor neovessels were more responsive to PDT than the normal vasculature. We hypothesized that Visudyne (R)-mediated PDT could selectively increase liposomal doxorubicin (Liporubicin (TM)) uptake in sarcoma tumors to rodent lungs while sparing the normal surrounding tissue. Materials and Methods: Sarcoma tumors were generated subpleurally in the left lower lung lobe of 66 Fischer rats. Ten days following sarcoma implantation, tumors underwent different pre-treatment schemes: no PDT (controls), low-dose PDT (0.0625 mg/kg Visudyne (R), 10 J/cm(2) and 35 mW/cm(2)) and high-dose PDT (0.125 mg/kg Visudyne (R), 10 J/cm(2) and 35 mW/cm(2)). Liporubicin (TM) was then administered and allowed to circulate for 1, 3, or 6 hours. At the end of each treatment scheme, we assessed the uptake of Liporubicin (TM) in tumor and lung tissues by high-performance liquid chromatography and fluorescence microscopy. Results: In all PDT-treated groups, there was a significant enhancement of Liporubicin (TM) uptake in tumors compared to controls after 3 and 6 hours of drug circulation. In addition, Liporubicin (TM) distribution within the normal lung tissue was not affected by PDT. Thus, PDT pretreatment significantly enhanced the ratio of tumor-to-lung drug uptake compared to controls. Finally, fluorescence microscopy revealed a well-detectable Liporubicin (TM) signaling throughout PDT-treated tumors but not in controls. Conclusions: PDT is a tumor-specific enhancer of Liporubicin (TM) distribution in sarcoma lung tumors which may find a translation in clinics. Lasers Surg. Med. 42:391-399, 2010. (C) 2010 Wiley-Liss, Inc.