carbocyanines and hypericin

Hypericin, a potent necrosis avid agent, features a peculiar affinity for necrotic tissue. Necrosis avid contrast agents have been investigated as markers for non-invasive imaging of different disorders. In view of the promising clinical applications, a more complete knowledge of the mechanism of action is important for the future development of new chemical structures with improved characteristics. To study whether a compound-specific or non-specific mechanism based on plasma lipoprotein transport is involved in the accumulation of hypericin in intratumoral necrosis, we performed a visual and quantitative fluoromicroscopic analysis of the colocalization of hypericin and DiOC18-labeled lipoproteins in subcutaneous murine radiation-induced fibrosarcoma tumors. Microscopic fluorescent overlay images of necrotic tumors demonstrated that hypericin already showed clear necrosis avid characteristics 4 h after injection, whereas a similar outstanding accumulation in necrosis was not demonstrated for the labeled lipoproteins. Moreover, a quantitative analysis of fluoromicroscopic images of tumor necrosis at 24 h after injection showed differences in normalized fluorescence intensities between hypericin and labeled lipoproteins of 50-100%, reflecting a shifted pattern in localization. We conclude that our results are indicative of a release of hypericin from the lipoprotein complex at some point along its way through the peri-necrotic tumor area and the necrotic tissue debris, which is in line with the hypothesis of a compound-specific mechanism.

Topics: Animals; Anthracenes; Carbocyanines; Female; Fibrosarcoma; Lipoproteins; Mice; Mice, Inbred C3H; Necrosis; Perylene; Sarcoma, Experimental; Xanthones

Hypericin is a potent agent in the photodynamic therapy of cancers. To better understand its tumoritropic behaviour, we evaluated the major determinants of the accumulation and dispersion of hypericin in subcutaneously growing mouse tumours. A rapid exponential decay in tumour accumulation of hypericin as a function of tumour weight was observed for each of the six tumour models investigated, and a similar relationship was found between tumour blood flow and tumour weight. Moreover, there was a close correlation between the higher hypericin uptake in RIF-1 tumours compared to R1 tumours and tumour vessel permeability. To define the role of lipoproteins in the transport of hypericin through the interstitial space, we performed a visual and quantitative analysis of the colocalization of hypericin and DiOC18-labelled lipoproteins in microscopic fluorescent overlay images. A coupled dynamic behaviour was found early after injection (normalised fluorescence intensity differences were on the whole less than 10%), while a shifted pattern in localisation of hypericin and DiOC18 was seen after 24 h, suggesting that during its migration through the tumour mass, hypericin is released from the lipoprotein complex. In conclusion, we were able to show that the tumour accumulation of hypericin is critically determined by a combination of biological (blood flow, vessel permeability) and physicochemical elements (affinity for interstitial constituents).

Topics: Animals; Anthracenes; Antineoplastic Agents; Caco-2 Cells; Carbocyanines; Carbon Radioisotopes; Female; Humans; Lipoproteins; Mice; Microscopy, Fluorescence; Neoplasm Transplantation; Neoplasms, Experimental; Perylene; Photosensitizing Agents; Rats; Tissue Distribution