title: Novel water-soluble bacteriochlorophyll derivatives for vascular-targeted photodynamic therapy: synthesis, solubility, phototoxicity and the effect of serum proteins.
abstract: New negatively charged water-soluble bacteriochlorophyll (Bchl) derivatives were developed in our laboratory for vascular-targeted photodynamic therapy (VTP). Here we focused on the synthesis, characterization and interaction of the new candidates with serum proteins and particularly on the effect of serum albumin on the photocytotoxicity of WST11, a representative compound of the new derivatives. Using several approaches, we found that aminolysis of the isocyclic ring with negatively charged residues markedly increases the hydrophilicity of the Bchl sensitizers, decreases their self-association constant and selectively increases their affinity to serum albumin, compared with other serum proteins. The photocytotoxicity of the new candidates in endothelial cell culture largely depends on the concentration of the serum albumin. Importantly, after incubation with physiological concentrations of serum albumin (500-600 microM), WST11 was found to be poorly photocytotoxic (>80% endothelial cell survival in cell cultures). However, in a recent publication (Mazor, O. et al. [2005] Photochem. Photobiol. 81, 342-351) we showed that VTP of M2R melanoma xenografts with a similar WST11 concentration resulted in approximately 100% tumor flattening and >70% cure rate. We therefore propose that the two studies collectively suggest that the antitumor activity of WST11 and probably of other similar candidates does not depend on direct photointoxication of individual endothelial cells but on the vascular tissue response to the VTP insult.
authors.affiliation: Department of Plant Sciences, The Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Brandis
authors.forename: Ohad
authors.initials: O
authors.lastname: Mazor
authors.forename: Eran
authors.initials: E
authors.lastname: Neumark
authors.forename: Varda
authors.initials: V
authors.lastname: Rosenbach-Belkin
authors.forename: Yoram
authors.initials: Y
authors.lastname: Salomon
authors.forename: Avigdor
authors.initials: A
authors.lastname: Scherz
mesh_terms: D001429:Bacteriochlorophylls / Q000096:biosynthesis / Q000494:pharmacology* / Q000528:radiation effects; D001798:Blood Proteins / Q000502:physiology*; D002470:Cell Survival / Q000528:radiation effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000528:radiation effects; D010778:Photochemotherapy; D012710:Serum Albumin, Bovine / Q000528:radiation effects
chemical_list: D001429:Bacteriochlorophylls; D001798:Blood Proteins; D012710:Serum Albumin, Bovine