Tumour localisation kinetics of photofrin and three synthetic porphyrinoids in an amelanotic melanoma of the hamster

Abstract

Summary In this study the localisation of porphyrinoid photosensitisers in tumours was investigated. To determine if tumour selectivity results from a preferential uptake or prolonged retention of photosensitisers, intravital fluorescence microscopy and chemical extraction were used. Amelanotic melanoma (A-Mel-3) were implanted in a skin fold chamber in Syrian Golden hamsters. Distribution of the porphyrin mixture Photofrin and three porphycenes, pure porphyrinoid model compounds, was studied quantitatively by intravital fluorescence microscopy. Extraction of tissue and blood samples was performed to verify and supplement intravital microscopic results. Photofrin accumulated in melanomas reaching a maximum tumour:skin tissue ratio of 1.7:1. Localisation of the different porphycenes was found to be highly tumour selective (3.2:1), anti-tumour selective (0.2:1), and non-selective (1:1) with increasing polarity of the porphycenes. The two non-tumour selective porphycenes had distinctly accelerated serum and tissue kinetics; serum halflife times being as short as 1 min. The specific localisation of the slowly distributed, tumour selective photosensitisers, occurred exclusively during the distribution from serum and uptake into tissues. For the most selective porphycene, the tumour selection process had a halflife of 260 ± 150 min and led to a strongly fluorescent tumour edge edema. Accumulation of porphyrines by the amelanotic melanoma (A-Mel-3) can be attributed to an enhanced uptake rate for lipophilic molecules in this subcutaneously growing neoplasm. The slow distribution of the two tumour specific photosensitisers and the strong fluorescence of these hydrophobic molecules in the tumour compartment with a high water content indicate a carrier role of serum proteins in the selection process. Enhanced permeability of the tumour vasculature to macromolecules appears to be the most probable reason for the tumour selectivity of these two sensitisers.In the first half of this century it was shown that systemically administered porphyrines preferentially localise in neoplasms of tumour-bearing animals (Policard, 1924;Auler et al., 1942). This phenomenon found diagnostic application as a method for tumour detection utilising the red fluorescence of the porphyrines (Lipson et al., 1961a,b;Baumgartner et al., 1987). The photosensitising properties of these molecules (Meyer-Betz, 1913) were exploited for therapeutic purposes and allowed the establishment of photodynamic therapy (PDT) as a new treatment modality for tumours (Dougherty et al., 1978).The mechanisms leading to the tumour specific localisation of the porphyrines are still under investigation (Moan et al., 1992). Experimental progress has been complicated by the fact that even the most purified photosensitiser, Photofrin (Pf), is a complex mixture of molecular species with very similar spectral characteristics (Dougherty, 1987;Pandey et al., 1990).In the present investigation, the localisation of three chemically pure synthetic porphyrinoids in an amelanotic mel...

Photofrin Uptake in the Tumor and Normal Tissues of Patients Receiving Intraperitoneal Photodynamic Therapy

“…* P < 0.01. c P < 0.001. b P < 0.0001. x P < 0.05. The presence of low Photofrin content in the skin and muscle of these patients is consistent with that found in other animal and clinical investigations (2,19,20). Muscle and skin Photofrin content in the present study, i.e., 0.71 F 0.63 and 1.20 F 0.62 ng/mg, respectively, are in general agreement with mean values of 2.24 ng/mg (range 0.69-3.86 ng/mg) in muscle and 2.19 ng/mg (range 0.67-3.16 ng/mg) in skin, reported in patients exposed to the same photosensitizing conditions as used in our trial (20).…”

Modular nanotransporters: a multipurpose in vivo working platform for targeted drug delivery

“…39 In comparison, the molecular weight of our MNT is approximately 70 kDa, and that of low-density lipoprotein is about 3000 kDa. 40 Leunig et al, 41 who investigated tumor accumulation of different porphyrin-like photosensitizers, showed that the enhanced permeability and retention effect appears to be the most probable reason for the tumor selectivity of this type of photosensitizer. Therefore, qualitatively, free photosensitizer in tumor vessels and photosensitizer transported by MNT may be considered as similar in terms of enhanced permeability and retention effect, and perhaps even more favorable for the free photosensitizer.…”

Porphycenes: Facts and Prospects in Photodynamic Therapy of Cancer

“…chemical design and prediction of biological activity, only few QSAR studies on pharmacokinetics, subcellular localization, and tumor photosensitization of new PSs have been published [42, [227][228][229][230][231][232][233], and also very limited information about QSAR of porphycene PSs is available [234][235][236].…”

“…The tumor uptake of porphycenes is mainly related to their lipophilic character [234], non-ionic polar sidechains such as alkoxy-alkyl groups (ether-porphycenes) producing accelerated cell uptake of the corresponding derivarives [334,335]. The targeting efficiency and selectivity of several TPrPo and TMPo derivatives on the mouse MS-2 fibrosarcoma have been studied as a function of the type of substituents linked to the C9 position of the macrocycle by amide, ester or ether functional groups.…”