Delivery of Benzoporphyrin Derivative, a Photosensitizer, into Atherosclerotic Plaque of Watanabe Heritable Hyperlipidemic Rabbits and Balloon‐Injured New Zealand Rabbits

Abstract

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.

Photosensitizer delivery to vulnerable atherosclerotic plaque: comparison of macrophage-targeted conjugate versus free chlorine(e6)

“…This is even more necessary in the case of targeted delivery of a PS to atherosclerotic plaques, as there have been several reports of free PS alone localizing in various atherosclerotic lesions in diverse animal models of atherosclerosis. [19][20][21][22] The findings in the present study are highly supportive of the hypothesis that scavengerreceptor targeting of ce6 can indeed provide an advantage over the accumulation of free ce6 in plaques that appears to occur by an unknown mechanism. When MA-ce6 is used with a 24-h time interval, there is significantly more ce6 in plaques than free ce6 at either time point, without a corresponding increase in accumulation in normal rabbit arteries.…”

“…This model, involving endothelial injury to the abdominal aorta followed by four months of an atherogenic diet, has been shown to lead to the development of inflamed atherosclerotic plaques with many characteristics of human vulnerable plaques including high levels of macrophage infiltration. 33,34 While unconjugated molecules closely related to ce6 have been reported to localize in atherosclerotic plaques, [19][20][21][22] it was not known if MA-ce6 would localize in the same manner as free ce6 under the same conditions. We also decided to investigate the relative fluorescence accumulation at two different time points.…”

“…18 There have been several reports that PS developed for treatment of other diseases such as cancer can localize in atherosclerotic lesions. [18][19][20][21][22] The reason for this selective localization is poorly understood, but may be related to their chemical structure being lipophilic and the plaques having high amounts of lipid accumulation. The fact that most PS that have been investigated for PDT are also fluorescent when excited with visible light, together with their ability to selectively accumulate in diseased tissue, has led to the administration of various PS being used for fluorescent diagnosis or detection of disease.…”

Analysis of acute vascular damage after photodynamic therapy using benzoporphyrin derivative (BPD)

“…This selectivity may be related to the increased accumulation of BPD by tumour endothelial cells with high levels of low-density lipoprotein (LDL) receptors (Allison et al, 1994) or the rapid internalization of agents bound to the LDL receptor on proliferating endothelial cells compared to quiescent endothelial cells (Fielding et al, 1979). Cells with increased phagocytotic activity, such as injured vessel wall in atherosclerotic vessels, have been shown to accumulate BPD at levels in excess of surrounding microvasculature (Allison et al, 1997) and this may play a role in tumour microvasculature as well. Similarly, macrophages show pronounced levels of BPD uptake compared to other cells and this may also contribute to the observed effect (Korbelik and Krosl, 1995).…”

Photodynamic Therapy of Atherosclerosis Using YAG-OPO Laser and Porfimer Sodium, and Comparison With Using Argon-Dye Laser

“…[24][25][26] The pattern of accumulation of HpD in atherosclerotic tissue has been reported to show the greatest red fluorescence in the lumenal side of the intima, then gradually decrease towards the media, with no medial accumulation. 8,9 The mechanisms of HpD accumulation in atherosclerotic tissue include: (1) porphyrin accumulates in response to rapidly proliferating tissues such as malignancies; (2) vascular endothelial permeability is increased in atherosclerotic areas; (3) porphyrin possesses affinity for fibrinogen and platelets; and (4) porphyrin bound to lipoproteins is phagocytosed by macrophages.…”