ABSTRACT
Vascular-targeted photodynamic therapy (vPDT) is a novel vascular targeting modality based on site-directed delivery of a photosensitizer to tumor vasculature, which induces reactive oxygen species (ROS)-mediated vascular effects upon light activation. To enhance the therapeutic outcome of vPDT, we combined proteasomal inhibitor bortezomib and vPDT using photosensitizer verteporfin in the present study. We found that bortezomib in combination with verteporfin-PDT induced more accumulation of ubiquitinated proteins and apoptosis in endothelial cells than each individual treatment. The combination therapy also enhanced vPDT-induced inhibition in tumor growth. These results indicate that bortezomib can be used together with verteporfin-PDT for enhanced treatment outcome.
Subject(s)
Blood Vessels/drug effects , Photosensitizing Agents/pharmacology , Proteasome Endopeptidase Complex/metabolism , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Disease Models, Animal , Drug Synergism , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Humans , Male , Mice , Photochemotherapy , Photosensitizing Agents/administration & dosage , Porphyrins/administration & dosage , Porphyrins/pharmacology , Prostatic Neoplasms/blood supply , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/metabolism , Proteasome Inhibitors/pharmacology , Reactive Oxygen Species/metabolism , Transplantation, Heterologous , Ubiquitination/drug effects , VerteporfinABSTRACT
Photodynamic therapy (PDT) is a light-based cancer treatment modality. Here we employed both in vivo and ex vivo fluorescence imaging to visualize vascular response and tumor cell survival after verteporfin-mediated PDT designed to target tumor vasculature. EGFP-MatLyLu prostate tumor cells, transduced with EGFP using lentivirus vectors, were implanted in athymic nude mice. Immediately after PDT with different doses of verteporfin, tumor-bearing animals were injected with a fluorochrome-labeled albumin. The extravasation of fluorescent albumin along with tumor EGFP fluorescence was monitored noninvasively with a whole-body fluorescence imaging system. Ex vivo fluorescence microscopy was performed on frozen sections of tumor tissues taken at different times after treatment. Both in vivo and ex vivo imaging demonstrated that vascular-targeting PDT with verteporfin significantly increased the extravasation of fluorochrome-labeled albumin in the tumor tissue, especially in the tumor periphery. Although PDT induced substantial vascular shutdown in interior blood vessels, some peripheral tumor vessels were able to maintain perfusion function up to 24 hr after treatment. As a result, viable tumor cells were typically detected in the tumor periphery in spite of extensive tumor cell death. Our results demonstrate that vascular-targeting PDT with verteporfin causes a dose- and time-dependent increase in vascular permeability and decrease in blood perfusion. However, compared to the interior blood vessels, peripheral tumor blood vessels were found less sensitive to PDT-induced vascular shutdown, which was associated with subsequent tumor recurrence in the tumor periphery.
Subject(s)
Angiogenesis Inhibitors/pharmacology , Neovascularization, Pathologic/drug therapy , Photochemotherapy , Photosensitizing Agents/pharmacology , Porphyrins/pharmacology , Prostatic Neoplasms/blood supply , Prostatic Neoplasms/drug therapy , Animals , Antineoplastic Agents/pharmacology , Capillary Permeability/drug effects , Cell Survival , Disease Models, Animal , Dose-Response Relationship, Drug , Fluorescent Dyes , Green Fluorescent Proteins , Lentivirus , Male , Mice , Mice, Nude , Microscopy, Fluorescence/methods , Neoplasm Recurrence, Local/prevention & control , Photochemotherapy/methods , Rats , Time Factors , Treatment Failure , Treatment Outcome , VerteporfinABSTRACT
PURPOSE: Photodynamic therapy (PDT), involving the combination of a photosensitizer and light, is being evaluated as a vascular disrupting therapy and drug delivery enhancement modality based on its effects on vascular perfusion and barrier function. Since tumor vasculature is the common route for the delivery of both blood and therapeutic agents, it is important to compare the effects of PDT on blood perfusion and substance transport. MATERIALS AND METHODS: Tumor blood cell velocity and the extravasation of high molecular weight dextran molecules were continuously monitored by intravital fluorescence microscopy for up to 60 min after PDT using three doses of verteporfin in the MatLyLu prostate tumor model. RESULTS: PDT induced tumor perfusion disruption via thrombus formation. PDT using a higher dose of verteporfin was more effective in inhibiting blood perfusion while a lower dose verteporfin-PDT was more potent in enhancing dextran extravasation. The increase in dextran extravasation induced by PDT was dependent upon dextran molecular weight. A lower molecular weight dextran obtained a higher tumor accumulation after PDT than a higher molecular weight dextran. CONCLUSIONS: PDT with verteporfin had different effects on tumor vascular perfusion versus the extravasation of macromolecules. Optimal PDT conditions should be adjusted based on the therapeutic application.
