Structural and Epimeric Isomers of HPPH [3-Devinyl 3-{1-(1-hexyloxy) ethyl}pyropheophorbide-a]: Effects on Uptake and Photodynamic Therapy of Cancer.
The tetrapyrrole structure of porphyrins used as photosentizing agents is thought to determine uptake and retention by malignant epithelial cancer cells. To assess the contribution of the oxidized state of individual rings to these cellular processes, bacteriochlorophyll a was converted into the ring "D" reduced 3-devinyl-3-[1-(1-hexyloxy)ethyl]pyropheophorbide-a (HPPH) and the corresponding ring "B" reduced isomer (iso-HPPH). The carboxylic acid analogs of both ring "B" and ring "D" reduced isomers showed several-fold higher accumulation into the mitochondria and endoplasmic reticulum by primary culture of human lung and head and neck cancer cells than the corresponding methyl ester analogs that localize primarily to granular vesicles and to a lesser extent to mitochondria. However, long-term cellular retention of these compounds exhibited an inverse relationship with tumor cells generally retaining better the methyl-ester derivatives. In vivo distribution and tumor uptake was evaluated in the isogenic model of BALB/c mice bearing Colon26 tumors using the respective14C-labeled analogs. Both carboxylic acid derivatives demonstrated similar intracellular localization and long-term tumor cure with no significant skin phototoxicity. PDT-mediated tumor action involved vascular damage, which was confirmed by a reduction in blood flow and immunohistochemical assessment of damage to the vascular endothelium. The HPPH stereoisomers (epimers) showed identical uptake (in vitro & in vivo), intracellular retention and photoreaction.
Courtney
C
Saenz
Ravindra R
RR
Cheruku
College of Optoelectronic Engineering, Shenzhen University , Shenzhen, Guangdong, China 518060.|Institute for Lasers, Photonics and Biophotonics, SUNY at Buffalo , Buffalo, New York 14260, United States.
Tymish Y
TY
Ohulchanskyy
Penny
P
Joshi
Walter A
WA
Tabaczynski
Joseph R
JR
Missert
Yihui
Y
Chen
Paula
P
Pera
Erin
E
Tracy
Aimee
A
Marko
Daniel
D
Rohrbach
Ulas
U
Sunar
Heinz
H
Baumann
Ravindra K
0000-0002-9889-4860
RK
Pandey
D000818:Animals; D045744:Cell Line, Tumor; D002734:Chlorophyll / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007536:Isomerism; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000378:metabolism / Q000494:pharmacology*
D017319:Photosensitizing Agents; D002734:Chlorophyll; C083998:2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a