Photodynamic therapy of normal rat arteries after photosensitisation using disulphonated aluminium phthalocyanine and 5-aminolaevulinic acid

Abstract

S_m.ary Photodynamic therapy of cancer exposes adjacent arteries to the nsk of injury and the possibility of haemorrhage and thrombosis. The nature of photodynamic injury to normal arteries has not been satisfactorily defined, and the ability of arteries to recover with time is unclear. To clarify these issues, we have investigated the effects of PDT on rat femoral arteries, using a second-generation photosensitiser, disulphonated aluminium phthalocyanine, and a new method of photosensitisation, using endogenous synthesis of protoporphyrin IX following systemic administration of 5-aminolaevulinic acid (ALA). Pharmacokinetic studies of sensitiser fluorescence were carried out to determine peak levels of sensitiser. Subsequently photodynamic therapy at times corresponding to maximal fluorescence was performed using two light doses, 100 and 250 J cm-2. The nature of injury sustained and recovery over a 6 month period was investigated. Three days following PDT, all vessels treated showed complete loss of endothelium, with death of all medial smooth muscle cells, leaving an acellular flaccid artery wall. No vascular occlusion, haemorrhage or thrombosis was found. A striking feature was the lack of inflammatory response in the vessel wall at any time studied. Re-endothelialisation occurred in all vessels by 2 weeks. The phthalocyanine group showed repopulation of the media with smooth muscle cells to be almost complete by 3 months. However, the ALA group failed to redevelop a muscular wall and remained dilated at 6 months. Luminal cross-sectional area of the ALA-treated group was significantly greater than both control and phthalocyanine groups at 6 months. All vessels remained patent. This study indicates that arteries exposed to PDT are not at risk of catastrophic haemorrhage or occlusion, a finding that is of significance for both the local treatment of tumours and the use of PDT as an intraoperative adjunct to surgery for the ablation of microscopic residual malignant disease.

Photodynamic therapy with local photosensitizer delivery inhibits experimental intimal hyperplasia

“…Recent in vitro studies from this laboratory suggest that PDT alters extracellular matrix, probably by dosedependent growth factor inactivation and thus inhibits smooth muscle cell attachment, proliferation, and migration [34,35]. These in vitro findings correspond with previous in vivo studies [7,20,21,23] and observations of the present study, which reveal an acellular media even 21 days after PDT, whereas PR arteries, at the same time, display complete repopulation of the media with smooth muscle cells.…”

“…The simplicity of the rat model has facilitated kinetic analyses of the smooth muscle cell responses to injury and to the identification of molecules playing a role in the pathogenesis of IH [1,3,22]. Numerous vascular PDT studies have also applied this model, and a significant body of experience was acquired with regard to PDT dosimetry, histology, and healing responses [10,20,21,23]. However, local drug delivery to the rat artery has thus far not been attempted, because the small size of these vessels did not support the use of specialized delivery catheters such as double-balloon-, porous-, microporous-, channel-, iontophoresis, or hydrogel balloon catheters [11,17].…”

Photoangioplasty

“…7 However, there is demonstrable preservation of the intact elastic lamina and of normal collagen in the adventitia, suggesting that the functional integrity of the vessel is conserved. 22 The absence of mural inflammation, despite extensive cell death, is consistent with the regression of atherosclerotic plaque through a hypothesized mechanism of apoptosis, although this has not yet been conclusively demonstrated. Paradoxically, a so-called "dark effect," ie, a therapeutic response to the drug in the absence of light, has also been described for the inhibitory effect on restenosis of at least one photosensitizer, a benzoporphyrin derivative.…”

Interstitial photodynamic therapy in the canine prostate with disulfonated aluminum phthalocyanine and 5-aminolevulinic acid-induced protoporphyrin IX

“…It is also likely to make it safe to treat large areas of the gland, which is important as the disease is often multifocal and occurs in the peripheral zone close to surrounding vital structures such as the neurovascular bundle, rectum, and urethral sphincter. The prostate capsule seems unlikely to be significantly affected by PDT, but if PDT effects do extend to the rectum or major blood vessels, using AlS 2 Pc, it is welldocumented that the resultant lesions heal without any unacceptable effects on their structure or function [31,32]. There are no good experimental studies on the effect of PDT using AlS 2 Pc (or indeed any other photosensitizer) on peripheral nerves, although our own fluorescence microscopy data suggest that very little AlS 2 Pc is taken up in nerve bundles (unpublished data).…”