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 EC50values 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.
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague , Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
Miloslav
M
Machacek
Department of Biophysics and Physical Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague , Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
Jiri
J
Demuth
Department of Biophysics and Physical Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague , Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
Pavel
P
Cermak
Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague , Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
Magda
M
Vavreckova
Department of Biophysics and Physical Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague , Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
Lenka
L
Hruba
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague , Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
Adela
A
Jedlickova
J. Heyrovský Institute of Physical Chemistry, v.v.i., Academy of Sciences of the Czech Republic , Dolejškova 3, 182 23 Praha 8, Czech Republic.
Pavel
P
Kubat
Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague , Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
Tomas
T
Simunek
Department of Biophysics and Physical Chemistry, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague , Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
Veronika
V
Novakova
Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague , Heyrovskeho 1203, Hradec Kralove, 500 05, Czech Republic.
Petr
P
Zimcik
D016475:3T3 Cells; D000818:Animals; D002412:Cations / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D008665:Metalloporphyrins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D015394:Molecular Structure; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D002412:Cations; D008665:Metalloporphyrins; D017319:Photosensitizing Agents; D011725:Pyridines