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.

ATG7 deficiency suppresses apoptosis and cell death induced by lysosomal photodamage

“…WST11 was prepared from WST9 as described previously. 43 NPe6 was provided by Prof. Kevin M. Smith, Louisiana State University. MEM-Eagle α modification, (M0894) and HO33342 (B2261) were provided by Sigma-Aldrich.…”

Porphyrin-based cationic amphiphilic photosensitisers as potential anticancer, antimicrobial and immunosuppressive agents

“…Hydrophobic PSs are more likely to bind to the low-density lipoproteins (LDL), while more hydrophilic ones bind albumin fractions (Bonneau and Vever-Bizet 2008). For example, it was found that bacteriochlorophyll derivatives with improved amphiphilic properties had an increased affinity to serum albumin, and this was shown to be beneficial for the vascular targeted PDT (Brandis et al 2005). Asymmetric and amphiphilic PSs can be associated with both albumin and high-density lipoproteins (HDL) (Bonneau and Vever-Bizet 2008).…”

Modifications of Porphyrins and Hydroporphyrins for their Solubilization in Aqueous Media

“…The attachment of sulfonated groups to the β-positions of a tetrapyrrolic macrocycle is an alternative method toward the generation of hydrophilic sulfonated derivatives. This approach was applied to the generation of alkylsulfonated bacteriochlorins [120]. For example, sulfonated bacteriochlorophyll derivatives were prepared by reaction of Pd-bacteriopheophorbide (108) with homotaurine (Scheme 31) [120].…”

“…This approach was applied to the generation of alkylsulfonated bacteriochlorins [120]. For example, sulfonated bacteriochlorophyll derivatives were prepared by reaction of Pd-bacteriopheophorbide (108) with homotaurine (Scheme 31) [120]. Treatment of either 109 or the sulfo-NHS ester 110 with a second equivalent of homotaurine also yielded the bis-sulfonated product 111 (with the trisulfonated compound arising from imine formation with the β-acetyl group as a minor product).…”