title: Cycloimide bacteriochlorin p derivatives: photodynamic properties and cellular and tissue distribution.
abstract: Reactive oxygen species generated by photosensitizers are efficacious remedy for tumor eradication. Eleven cycloimide derivatives of bacteriochlorin p (CIBCs) with different N-substituents at the fused imide ring and various substituents replacing the 3-acetyl group were evaluated as photosensitizers with special emphasis on structure-activity relationships. The studied CIBCs absorb light within a tissue transparency window (780-830 nm) and possess high photostability at prolonged light irradiation. The most active derivatives are 300-fold more phototoxic toward HeLa and A549 cells than the clinically used photosensitizer Photogem due to the substituents that improve intracellular accumulation (distribution ratio of 8-13) and provide efficient photoinduced singlet oxygen generation (quantum yields of 0.54-0.57). The substituents predefine selective CIBC targeting to lipid droplets, Golgi apparatus, and lysosomes or provide mixed lipid droplets and Golgi apparatus localization in cancer cells. Lipid droplets and Golgi apparatus are critically sensitive to photoinduced damage. The average lethal dose of CIBC-generated singlet oxygen per volume unit of cell was estimated to be 0.22 mM. Confocal fluorescence analysis of tissue sections of tumor-bearing mice revealed the features of tissue distribution of selected CIBCs and, in particular, their ability to accumulate in tumor nodules and surrounding connective tissues. Considering the short-range action of singlet oxygen, these properties of CIBCs are prerequisite to efficient antitumor photodynamic therapy.
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, 117997 Moscow, Russia.
authors.forename: George V
authors.initials: GV
authors.lastname: Sharonov
authors.forename: Tatyana A
authors.initials: TA
authors.lastname: Karmakova
authors.forename: Roel
authors.initials: R
authors.lastname: Kassies
authors.forename: Anna D
authors.initials: AD
authors.lastname: Pljutinskaya
authors.forename: Michael A
authors.initials: MA
authors.lastname: Grin
authors.forename: Matthieu
authors.initials: M
authors.lastname: Refregiers
authors.forename: Raisa I
authors.initials: RI
authors.lastname: Yakubovskaya
authors.forename: Andrey F
authors.initials: AF
authors.lastname: Mironov
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Maurizot
authors.forename: Paul
authors.initials: P
authors.lastname: Vigny
authors.forename: Cees
authors.initials: C
authors.lastname: Otto
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Feofanov
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007928:Lethal Dose 50; D007941:Leukemia P388 / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008055:Lipids; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000493:pharmacokinetics* / Q000494:pharmacology; D011166:Porphyrins / Q000493:pharmacokinetics* / Q000494:pharmacology; D026082:Singlet Oxygen / Q000378:metabolism; D014018:Tissue Distribution
chemical_list: D008055:Lipids; D017319:Photosensitizing Agents; D011166:Porphyrins; C452433:bacteriochlorin; D026082:Singlet Oxygen