Stable synthetic bacteriochlorins overcome the resistance of melanoma to photodynamic therapy.
Cutaneous malignant melanoma remains a therapeutic challenge, and patients with advanced disease have limited survival. Photodynamic therapy (PDT) has been successfully used to treat many malignancies, and it may show promise as an antimelanoma modality. However, high melanin levels in melanomas can adversely affect PDT effectiveness. Herein the extent of melanin contribution to melanoma resistance to PDT was investigated in a set of melanoma cell lines that markedly differ in the levels of pigmentation; 3 new bacteriochlorins successfully overcame the resistance. Cell killing studies determined that bacteriochlorins are superior at (LD(50) approximately 0.1 microM) when compared with controls such as the FDA-approved Photofrin (LD(50) approximately 10 microM) and clinically tested LuTex (LD(50) approximately 1 microM). The melanin content affects PDT effectiveness, but the degree of reduction is significantly lower for bacteriochlorins than for Photofrin. Microscopy reveals that the least effective bacteriochlorin localizes predominantly in lysosomes, while the most effective one preferentially accumulates in mitochondria. Interestingly all bacteriochlorins accumulate in melanosomes, and subsequent illumination leads to melanosomal damage shown by electron microscopy. Fluorescent probes show that the most effective bacteriochlorin produces significantly higher levels of hydroxyl radicals, and this is consistent with the redox properties suggested by molecular-orbital calculations. The best in vitro performing bacteriochlorin was tested in vivo in a mouse melanoma model using spectrally resolved fluorescence imaging and provided significant survival advantage with 20% of cures (P<0.01).
Mroz
Pawel
P
Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom St., Boston, MA 02114, USA.
Huang
Ying-Ying
YY
Szokalska
Angelika
A
Zhiyentayev
Timur
T
Janjua
Sahar
S
Nifli
Artemissia-Phoebe
AP
Sherwood
Margaret E
ME
Ruzié
Christian
C
Borbas
K Eszter
KE
Fan
Dazhong
D
Krayer
Michael
M
Balasubramanian
Thiagarajan
T
Yang
Eunkyung
E
Kee
Hooi Ling
HL
Kirmaier
Christine
C
Diers
James R
JR
Bocian
David F
DF
Holten
Dewey
D
Lindsey
Jonathan S
JS
Hamblin
Michael R
MR
D000818:Animals; D045744:Cell Line, Tumor; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D010778:Photochemotherapy / Q000379:methods*; D011166:Porphyrins / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*
D011166:Porphyrins; C452433:bacteriochlorin
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