Tetra(3,4-pyrido)porphyrazines Caught in the Cationic Cage: Toward Nanomolar Active Photosensitizers

Investigation of a series of tetra­(3,4-pyrido)­porphyrazines
(TPyPzs)
substituted with hydrophilic substituents revealed important structure–activity
relationships for their use in photodynamic therapy (PDT). Among them,
a cationic TPyPz derivative with total of 12 cationic charges above,
below and in the plane of the core featured a unique spatial arrangement
that caught the hydrophobic core in a cage, thereby protecting it
fully from aggregation in water. This derivative exhibited exceptionally
effective photodynamic activity on a number of tumor cell lines (HeLa,
SK-MEL-28, A549, MCF-7) with effective concentrations (EC50) typically below 5 nM, at least an order of magnitude better than
the EC50 values obtained for the clinically approved photosensitizers
verteporfin, temoporfin, protoporphyrin IX, and trisulfonated hydroxyaluminum
phthalocyanine. Its very low dark toxicity (TC50 > 400
μM) and high ability to induce photodamage to endothelial cells
(EA.hy926) without preincubation suggest the high potential of this
cationic TPyPz derivative in vascular-targeted PDT.