Delivery of benzoporphyrin derivative, a photosensitizer, into atherosclerotic plaque of Watanabe heritable hyperlipidemic rabbits and balloon-injured New Zealand rabbits.
In this study we compared the plasma distribution and arterial accumulation of a photosensitizer, benzoporphyrin derivative (BPD), in two models of atherosclerosis: the spontaneous lesions of the Watanabe heritable hyperlipidemic (WHHL) rabbit and induced lesions of the balloon-injured, cholesterol-fed New Zealand white (NZW) rabbit. Selective uptake and retention of a photosensitizer by the abnormal portion of a vessel is a necessity in order for photodynamic therapy to become a successful modality for inhibition of intimal hyperplasia, selective removal of atherosclerotic tissue or imaging of diseased arteries. Liposome-based formulations were compared to freshly isolated native low density lipoprotein (LDL) and acetylated-LDL (Ac-LDL) as delivery vehicles for BPD. Plasma distribution of the photosensitizer was analyzed by KBr density gradient ultracentrifugation. Although the delivery vehicle influenced plasma distribution immediately postinjection, BPD subsequently partitioned according to the plasma concentration of the lipoproteins. Photosensitizer level in plaque and normal artery specimens was determined by ethyl acetate extraction and spectrofluorometric measurement. The measurement of BPD in normal and atherosclerotic arterial tissue demonstrated a selective accumulation in atherosclerotic tissue. Preassociation with LDL and Ac-LDL enhanced accumulation of BPD in atherosclerotic tissue when compared with normal artery (mean ratios of 2.8 and 4.1 were achieved, respectively). These results indicate that the preferential uptake of BPD by atherosclerotic plaque can be enhanced by preassociation with plasma lipoproteins, suggesting that light activation could lead to a highly selective destruction of diseased vascular tissue.
Allison
B A
BA
Department of Surgery, University of British Columbia, Vancouver, Canada. betha@interchange.ubc.ca
Crespo
M T
MT
Jain
A K
AK
Richter
A M
AM
Hsiang
Y N
YN
Levy
J G
JG
D017130:Angioplasty; D000818:Animals; D001161:Arteriosclerosis / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D002791:Cholesterol, Dietary / Q000009:adverse effects; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D006949:Hyperlipidemias / Q000097:blood / Q000378:metabolism / Q000473:pathology*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008081:Liposomes; D017319:Photosensitizing Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010789:Phototherapy / Q000379:methods; D011166:Porphyrins / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011817:Rabbits
D002791:Cholesterol, Dietary; D004791:Enzyme Inhibitors; D008077:Lipoproteins, LDL; D008081:Liposomes; D017319:Photosensitizing Agents; D011166:Porphyrins; C032629:acetyl-LDL; C504224:benzoporphyrin D