Structural factors and mechanisms underlying the improved photodynamic cell killing with silicon phthalocyanine photosensitizers directed to lysosomes versus mitochondria.
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.
Rodriguez
Myriam E
ME
Department of Radiation Oncology, Case Western Reserve University, Cleveland, OH, USA.
Zhang
Ping
P
Azizuddin
Kashif
K
Delos Santos
Grace B
GB
Chiu
Song-mao
SM
Xue
Liang-yan
LY
Berlin
Jeffery C
JC
Peng
Xinzhan
X
Wu
Hongqiao
H
Lam
Minh
M
Nieminen
Anna-Liisa
AL
Kenney
Malcolm E
ME
Oleinick
Nancy L
NL
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*
D007211:Indoles; D054833:Isoindoles; D017319:Photosensitizing Agents; C013647:phthalocyanine; D012825:Silicon