title: Stable synthetic bacteriochlorins overcome the resistance of melanoma to photodynamic therapy.
abstract: 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).
authors.affiliation: Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom St., Boston, MA 02114, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Mroz
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Huang
authors.forename: Angelika
authors.initials: A
authors.lastname: Szokalska
authors.forename: Timur
authors.initials: T
authors.lastname: Zhiyentayev
authors.forename: Sahar
authors.initials: S
authors.lastname: Janjua
authors.forename: Artemissia-Phoebe
authors.initials: AP
authors.lastname: Nifli
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Sherwood
authors.forename: Christian
authors.initials: C
authors.lastname: Ruzié
authors.forename: K Eszter
authors.initials: KE
authors.lastname: Borbas
authors.forename: Dazhong
authors.initials: D
authors.lastname: Fan
authors.forename: Michael
authors.initials: M
authors.lastname: Krayer
authors.forename: Thiagarajan
authors.initials: T
authors.lastname: Balasubramanian
authors.forename: Eunkyung
authors.initials: E
authors.lastname: Yang
authors.forename: Hooi Ling
authors.initials: HL
authors.lastname: Kee
authors.forename: Christine
authors.initials: C
authors.lastname: Kirmaier
authors.forename: James R
authors.initials: JR
authors.lastname: Diers
authors.forename: David F
authors.initials: DF
authors.lastname: Bocian
authors.forename: Dewey
authors.initials: D
authors.lastname: Holten
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Lindsey
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hamblin
mesh_terms: 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*
chemical_list: D011166:Porphyrins; C452433:bacteriochlorin
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