title: Comparison of hexamethylhypericin and tetrabromohypericin to hypericin for their in vivo efficacy as PDT tools.
abstract: The present study was performed to evaluate the PDT efficacy, the singlet oxygen yield, and the plasma binding profile of the natural photosensitizer hypericin and two hypericin derivatives, hexamethylhypericin and tetrabromohypericin. All compounds exhibited an excellent 1O2 quantum yield, as documented by TEMP spin trapping experiments. The efficacy of PDT with the different compounds using a P388 lymphoma tumour model was clearly dependent on the interval between drug administration and light irradiation of the tumours. The most effective PDT treatment time was obtained with hypericin (5 mg/kg) using a 30-min drug-light interval, whereas a 24-h interval was optimal for a similar dose of tetrabromohypericin. No significant difference in survival between control animals and animals treated with PDT using tetrabromohypericin (5 mg/kg) was noted when a 30-min, 2- or 6-h interval was used. PDT with hexamethylhypericin (5 mg/kg) using different drug-light intervals was unable to prolong the life span of the tumour-bearing mice. In contrast, a dose of 20 mg/kg hexamethylhypericin, especially when administered 30 min prior to light exposure, produced a profound local reduction of tumour mass and a concomitant significant increase in survival time. The binding of the hypericins to human plasma was evaluated using density-gradient ultracentrifugation. It was found that tetrabromohypericin exhibits an affinity for plasma constituents almost similar to hypericin, in contrast to the more hydrophilic hexamethylhypericin that mainly binds to heavy proteins (e.g. albumin). Since the latter compound showed an efficacy profile similar to hypericin, no correlation could be found between the optimal drug-light interval and the plasma protein binding of the compounds.
authors.affiliation: Laboratorium voor Farmaceutische Biologie en Fytofarmacologie, Faculteit Farmaceutische Wetenschappen, K.U. Leuven, 3000 Leuven, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Delaey
authors.forename: István
authors.initials: I
authors.lastname: Zupko
authors.forename: Bin
authors.initials: B
authors.lastname: Chen
authors.forename: Annelies
authors.initials: A
authors.lastname: Derycke
authors.forename: Frederik
authors.initials: F
authors.lastname: van Laar
authors.forename: Dirk
authors.initials: D
authors.lastname: De Vos
authors.forename: Peter
authors.initials: P
authors.lastname: De Witte
mesh_terms: D000818:Animals; D000873:Anthracenes; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001798:Blood Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010569:Perylene / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D015996:Survival Rate; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000873:Anthracenes; D000970:Antineoplastic Agents; D001798:Blood Proteins; D017319:Photosensitizing Agents; D010569:Perylene; C004965:hypericin; D011493:Protein Kinase C