Zheng Xiang, Morgan Janet, Pandey Suresh K, Chen Yihui, Tracy Erin, Baumann Heinz, Missert Joseph R, Batt Carrie, Jackson Jennifer, Bellnier David A, Henderson Barbara W, Pandey Ravindra K
PDT Center, Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
J Med Chem. 2009 Jul 23;52(14):4306-18. doi: 10.1021/jm9001617.
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.
与3-(1'-己氧基乙基)-3-去乙烯基焦脱镁叶绿酸-a（HPPH）共轭的碳水化合物部分改变了摄取过程以及从线粒体到溶酶体的细胞内定位。在体外，通过非磷酸化STAT3的氧化交联以及在表达ABCG2的RIF细胞而非ABCG2阴性的Colon26细胞中的细胞杀伤作用检测到，HPPH-Gal 9光动力疗法（PDT）相较于HPPH-PDT显示出更高的PDT疗效。RIF细胞中这种疗效的提高至少部分归因于9的细胞内积累增加，这表明ABCG2转运蛋白发挥了作用，而HPPH是该转运蛋白的底物。虽然在体内未检测到肿瘤组织对HPPH衍生物积累的此类差异，但在携带RIF以及Colon26肿瘤的小鼠中，与HPPH相比，9仍显示出更高的光剂量依赖性活性。目前正在对体内不同治疗参数下的碳水化合物共轭物进行进一步优化。
