Conjugation of 2-(1'-hexyloxyethyl)-2-devinylpyropheophorbide-a (HPPH) to carbohydrates changes its subcellular distribution and enhances photodynamic activity in vivo.
The carbohydrate moieties on conjugating with 3-(1'-hexyloxyethyl)-3-devinyl pyropeophorbide-a (HPPH) altered the uptake and intracellular localization from mitochondria to lysosomes. In vitro, HPPH-Gal 9 PDT showed increased PDT efficacy over HPPH-PDT as detectable by the oxidative cross-linking of nonphosphorylated STAT3 and cell killing in ABCG2-expressing RIF cells but not in ABCG2-negative Colon26 cells. This increased efficacy in RIF cells could at least partially be attributed to increased cellular accumulation of 9, suggesting a role of the ABCG2 transporter for which HPPH is a substrate. While such differences in the accumulation in HPPH derivatives by tumor tissue in vivo were not detectable, 9 still showed an elevated light dose-dependent activity compared to HPPH in mice bearing RIF as well as Colon26 tumors. Further optimization of the carbohydrate conjugates at variable treatment parameters in vivo is currently underway.
Zheng
Xiang
X
PDT Center, Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Morgan
Janet
J
Pandey
Suresh K
SK
Chen
Yihui
Y
Tracy
Erin
E
Baumann
Heinz
H
Missert
Joseph R
JR
Batt
Carrie
C
Jackson
Jennifer
J
Bellnier
David A
DA
Henderson
Barbara W
BW
Pandey
Ravindra K
RK
D000818:Animals; D001692:Biological Transport; D002241:Carbohydrates / Q000737:chemistry*; D045744:Cell Line, Tumor; D002734:Chlorophyll / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002986:Clinical Trials as Topic; D005690:Galactose / Q000737:chemistry; D057927:Hydrophobic and Hydrophilic Interactions; D042541:Intracellular Space / Q000378:metabolism*; D051379:Mice; D010778:Photochemotherapy; D017319:Photosensitizing Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D050796:STAT3 Transcription Factor / Q000737:chemistry / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000528:radiation effects; D014018:Tissue Distribution
D002241:Carbohydrates; D017319:Photosensitizing Agents; D050796:STAT3 Transcription Factor; D002734:Chlorophyll; C083998:2-(1-hexyloxyethyl)-2-devinyl pyropheophorbide-a; D005690:Galactose