Stable synthetic bacteriochlorins overcome the resistance of melanoma to photodynamic therapy

Pawel Mroz, Ying Ying Huang, Angelika Szokalska, Timur Zhiyentayev, Sahar Janjua, Artemissia Phoebe Nifli, Margaret E. Sherwood, Christian Ruzié, K. Eszter Borbas, Dazhong Fan, Michael Krayer, Thiagarajan Balasubramanian, Eunkyung Yang, Hooi Ling Kee, Christine Kirmaier, James R. Diers, David F. Bocian, Dewey Holten, Jonathan S. Lindsey, Michael R. Hamblin

Research output: Contribution to journalArticlepeer-review

73 Scopus citations

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 (LD50≈0.1 μM) when compared with controls such as the FDA-approved Photofrin (LD50≈10 μM) and clinically tested LuTex (LD50≈1 μM). 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).

Original languageEnglish (US)
Pages (from-to)3160-3170
Number of pages11
JournalFASEB Journal
Volume24
Issue number9
DOIs
StatePublished - Sep 2010

Keywords

  • Electron microscopy
  • Melanosomes
  • Multidrug resistance

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