Reduction of vein graft disease using photodynamic therapy with motexafin lutetium in a rodent isograft model.
BACKGROUND
Motexafin lutetium (Lu-Tex) is a photosensitizer that targets atheromatous plaque. Subsequent photoactivation (photodynamic therapy [PDT]) induces local cytotoxic effects. The aim of the present study was to investigate whether Lu-Tex targets vein graft intimal hyperplasia and whether subsequent photoactivation attenuates the disease process.


RESULTS
The subcellular localization of Lu-Tex and postillumination viability were studied in cultured human vein graft smooth muscle cells. Inferior vena cava-grafted rats were injected with Lu-Tex (10 mg/kg) 4 or 12 weeks after grafting. Biodistribution was assessed in a subgroup 24 hours after administration. Light therapy (742 nm) was performed 24 hours after Lu-Tex injection by illuminating intraperitoneally placed isografts using a laparotomy. Animals were divided into the following 4 groups: PDT (n=15), Lu-Tex injection and laparotomy (n=13), light treatment (n=14), and laparotomy only (n=13). Grafts were harvested 14 days after treatment for histochemical analysis. Lu-Tex localized within subcellular organelles of smooth muscle cells, and subsequent photoactivation induced cell death via apoptosis. The Lu-Tex concentrations present in the vein grafts were 9.3 times higher than those in the normal inferior vena cava. Postoperative PDT at 4 weeks after surgery significantly reduced the intima/media ratio, whereas treatment at 12 weeks did not reduce the intima/media ratio. Activated macrophages were observed 4 weeks after grafting; however, a significant reduction occurred in these cells by 12 weeks. The mechanism by which PDT works may be related to the presence of activated macrophages.


CONCLUSIONS
PDT significantly reduces the intima/media ratio in the early phase of vein graft disease. Lu-Tex-mediated PDT may be a viable method for the attenuation of atherosclerotic disease in vein grafts.
Yamaguchi
A
A
Departments of Cardiothoracic Surgery and Cardiovascular Medicine, Stanford University, Stanford, CA, USA.
Woodburn
K W
KW
Hayase
M
M
Robbins
R C
RC
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D002478:Cells, Cultured; D006083:Graft Occlusion, Vascular / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D006965:Hyperplasia / Q000473:pathology / Q000517:prevention & control; D007813:Laparotomy; D008027:Light; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008665:Metalloporphyrins / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000648:ultrastructure; D010778:Photochemotherapy / Q000379:methods*; D017319:Photosensitizing Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D014018:Tissue Distribution; D014185:Transplantation, Isogeneic; D017539:Tunica Intima / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014682:Vena Cava, Inferior / Q000187:drug effects / Q000473:pathology / Q000637:transplantation
D000943:Antigens, Differentiation; D008665:Metalloporphyrins; D017319:Photosensitizing Agents; C102825:motexafin lutetium; C437683:motexafin gadolinium