Selective targeting and photodynamic destruction of intimal hyperplasia by scavenger-receptor mediated protein-chlorin e6 conjugates.
BACKGROUND
Photosensitizers, such as Photofrin II or Chloroaluminum-sulfonated phthalocyanine accumulate at sites of arterial injury. We have exploited this property to develop a model of photodynamic therapy (PDT) for intimal hyperplasia. The fluorescent probe [maleylated-bovine serum albumin (mal-BSA) conjugated with Texas-red] can be selectively targeted to intimal macrophages and smooth muscle cells recruited during formation of hyperplasia via a receptor-mediated mechanism.


METHODS
In this study, the photosensitizer chlorin e6 (Cle6) was conjugated to mal-BSA in a rat model of intimal hyperplasia, then tested the efficacy of the ligand conjugation to photosensitizer (mal-BSA/Cle6) in PDT of intimal hyperplasia. Arterial wall injury was produced by a balloon catheter pulled through the abdominal aorta of the rat to create a model of intimal hyperplasia. Fluorescent compounds were injected two weeks after injury.


RESULTS
Four hours after injection, the intensity of fluorescence achieved with injection of mal-BSA/Cle6 was higher for intimal hyperplastic lesions as compared to control areas. BSA-Cle6 unconjugated did not demonstrate such delivery. Two weeks after balloon injury, the injured aorta was irradiated externally with an argon pumped dye laser four hours following the photosensitizer injection. We employed two total radiant exposures: 20 J/cm2 and 40 J/cm2. Forty-eight hours after PDT, the arteries were examined histologically. Intimal hyperplastic cells were significantly reduced by PDT in the mal-BSA/Cle6 injected group (40-100%) versus the Cle6 group (0-20%).


CONCLUSIONS
Mal-BSA/Cle6 is taken up efficiently by a scavenger pathway, localizes in areas of intimal hyperplasia, and functions as a photosensitizer for PDT.
Nagae
T
T
Department of Surgery, Tokyo Medical College Hospital, Japan.
Louie
A Y
AY
Aizawa
K
K
Ishimaru
S
S
Wilson
S E
SE
D000818:Animals; D001012:Aorta, Abdominal; D001013:Aorta, Thoracic; D001018:Aortic Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001667:Binding, Competitive; D002735:Chlorophyllides; D004195:Disease Models, Animal; D004337:Drug Carriers; D005500:Follow-Up Studies; D006965:Hyperplasia; D007275:Injections, Intravenous; D008297:Male; D008856:Microscopy, Fluorescence; D010778:Photochemotherapy; D011166:Porphyrins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology