Photodynamic therapy (PDT), which is based on the activation of photosensitizers with light, can be used to reduce plaque burden. We hypothesized that intra-arterial photosensitizer administration and photo-activation will lead to high and rapid accumulation within the plaque with reduced systemic adverse effects. Thus, this intra-arterial PDT would be expected to have less side effects and due to the short time involved would be compatible with percutaneous coronary interventions. Aim: We characterized the dose-dependent uptake and efficacy of intra-arterial PDT using Liposomal Verteporfin (Visudyne (R)), efficient for cancer-PDT but not tested before for PDT of atherosclerosis. Methods and Results: Visudyne (R) (100, 200, and 500 ng/ml) was perfused for 530 min in atherosclerotic aorta isolated from ApoE(-/-) mice. The fluorescence Intensity (FI) after 15 min of Visudyne (R) perfusion increased with doses of 100 (FI-5.5 +/- 1.8), 200 (FI-31.9 +/- 1.9) or 500 ng/ml (FI-42.9 +/- 1.2). Visudyne (R) (500 ng/ml) uptake also increased with the administration time from 5 min (FI-9.8 +/- 2.5) to 10 min (FI-23.3 +/- 3.0) and 15 min (FI-42.9 +/- 3.4) before reaching saturation at 30 min (FI-39.3 +/- 2.4) contact. Intra-arterial PDT (Fluence: 100 and 200 J/cm(2), irradiance-334 mW/cm(2)) was applied immediately after Visudyne (R) perfusion (500 ng/ml for 15 min) using a cylindrical light diffuser coupled to a diode laser (690 nm). PDT led to an increase of ROS (Dihydroethidium; FI-6.9 +/- 1.8, 25.3 +/- 5.5, 43.4 +/- 13.9) and apoptotic cells (TUNEL; 2.5 +/- 1.6, 41.3 +/- 15.3, 58.9 +/- 6%), mainly plaque macrophages (immunostaining; 0.3 +/- 0.2, 37.6 +/- 6.4, 45.3 +/- 5.4%) respectively without laser irradiation, or at 100 and 200 J/cm2. Limited apoptosis was observed in the medial wall (0.5 +/- 0.2, 8.5 +/- 4.7, 15.3 +/- 12.7%). Finally, Visudyne (R)-PDT was found to be associated with reduced vessel functionality (Myogram). Conclusion: We demonstrated that sufficient accumulation of Visudyne (R) within plaque could be achieved in short-time and therefore validated the feasibility of local intravascular administration of photosensitizer. Intra-arterial Visudyne (R)-PDT preferentially affected plaque macrophages and may therefore alter the dynamic progression of plaque development.