title: Structural factors and mechanisms underlying the improved photodynamic cell killing with silicon phthalocyanine photosensitizers directed to lysosomes versus mitochondria.
abstract: The phthalocyanine photosensitizer Pc 4 has been shown to bind preferentially to mitochondrial and endoplasmic reticulum membranes. Upon photoirradiation of Pc 4-loaded cells, membrane components, especially Bcl-2, are photodamaged and apoptosis, as indicated by activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase, is triggered. A series of analogs of Pc 4 were synthesized, and the results demonstrate that Pcs with the aminopropylsiloxy ligand of Pc 4 or a similar one on one side of the Pc ring and a second large axial ligand on the other side of the ring have unexpected properties, including enhanced cell uptake, greater monomerization resulting in greater intracellular fluorescence and three-fold higher affinity constants for liposomes. The hydroxyl-bearing axial ligands tend to reduce aggregation of the Pc and direct it to lysosomes, resulting in four to six times more killing of cells, as defined by loss of clonogenicity, than with Pc 4. Whereas Pc 4-PDT photodamages Bcl-2 and Bcl-xL, Pc 181-PDT causes much less photodamage to Bcl-2 over the same dose-response range relative to cell killing, with earlier cleavage of Bid and slower caspase-3-dependent apoptosis. Therefore, within this series of photosensitizers, these hydroxyl-bearing axial ligands are less aggregated than is Pc 4, tend to localize to lysosomes and are more effective in overall cell killing than is Pc 4, but induce apoptosis more slowly and by a modified pathway.
authors.affiliation: Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Myriam E
authors.initials: ME
authors.lastname: Rodriguez
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.forename: Kashif
authors.initials: K
authors.lastname: Azizuddin
authors.forename: Grace B
authors.initials: GB
authors.lastname: Delos Santos
authors.forename: Song-mao
authors.initials: SM
authors.lastname: Chiu
authors.forename: Liang-yan
authors.initials: LY
authors.lastname: Xue
authors.forename: Jeffery C
authors.initials: JC
authors.lastname: Berlin
authors.forename: Xinzhan
authors.initials: X
authors.lastname: Peng
authors.forename: Hongqiao
authors.initials: H
authors.lastname: Wu
authors.forename: Minh
authors.initials: M
authors.lastname: Lam
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Nieminen
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Kenney
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Oleinick
mesh_terms: D007211:Indoles / Q000494:pharmacology*; D054833:Isoindoles; D008247:Lysosomes / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D008928:Mitochondria / Q000187:drug effects*; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000494:pharmacology*; D012825:Silicon / Q000737:chemistry*
chemical_list: D007211:Indoles; D054833:Isoindoles; D017319:Photosensitizing Agents; C013647:phthalocyanine; D012825:Silicon