Stable synthetic bacteriochlorins overcome the resistance of melanoma to photodynamic therapy
Stable synthetic bacteriochlorins overcome the resistance of melanoma to photodynamic therapy
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DOI：
10.1096/fj.09-152587
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发表时间：
2010-09-01
期刊：
影响因子：
4.8
通讯作者：
Hamblin, Michael R.
中科院分区：
文献类型：
--
作者：
Mroz, Pawel;Huang, Ying-Ying;Hamblin, Michael R.
皮肤恶性黑色素瘤仍然是一个治疗挑战，晚期患者的生存率有限。光动力疗法（PDT）已经成功地用于治疗许多恶性肿瘤，它可能显示出希望作为一种抗黑色素瘤的方式。然而，黑色素瘤中的高黑色素水平会对PDT的效果产生不利影响。本文在一组色素沉着水平明显不同的黑色素瘤细胞系中研究了黑色素对黑色素瘤抗PDT的贡献程度；3种新的细菌氯成功地克服了耐药性。细胞杀伤研究确定，与fda批准的Photofrin （LD50约为10 μ M）和临床测试的LuTex （LD50约为1 μ M）等对照品相比，细菌氯的LD50（约为0.1 μ M）更优越。黑色素含量影响PDT效果，但细菌氯的降低程度明显低于Photofrin。镜检显示，最无效的细菌氯主要集中在溶酶体中，而最有效的细菌氯优先积聚在线粒体中。有趣的是，所有的细菌氯都聚集在黑素小体中，随后的光照导致电子显微镜显示的黑素小体损伤。荧光探针显示，最有效的细菌氯产生明显更高水平的羟基自由基，这与分子轨道计算表明的氧化还原性质一致。体外表现最好的细菌氯在小鼠黑色素瘤模型中进行了体内测试，使用光谱分辨荧光成像，具有显着的生存优势，治愈率为20% (P
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 approximate to 0.1 mu M) when compared with controls such as the FDA-approved Photofrin (LD50 approximate to 10 mu M) and clinically tested LuTex (LD50 approximate to 1 mu M). 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