A next-generation bifunctional photosensitizer with improved water-solubility for photodynamic therapy and diagnosis.
A next-generation bifunctional photosensitizer with improved water-solubility for photodynamic therapy and diagnosis.
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DOI：
10.18632/oncotarget.12366
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发表时间：
2016-11-08
期刊：
影响因子：
--
通讯作者：
Joh T
中科院分区：
文献类型：
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作者：
Nishie H;Kataoka H;Yano S;Kikuchi JI;Hayashi N;Narumi A;Nomoto A;Kubota E;Joh T
光动力疗法（PDT）利用光相互作用和光敏剂来诱导细胞毒性活性氧。光动力诊断（PDD）利用光敏剂发射荧光的现象来区分某些肿瘤与正常组织。用于PDD的标准光敏剂是5-氨基乙酰丙酸(5-ALA)，尽管它并不完全令人满意。我们之前报道过葡萄糖结合的二氢卟酚（G-二氢卟酚）是一种比另一种广泛使用的光敏剂他拉泊芬钠（TS）更有效的光敏剂；然而，G-二氢卟酚是疏水性的。我们合成了水溶性改善的寡糖缀合二氢卟酚（O-二氢卟酚）。我们在此报告其积累和细胞毒性。合成O-二氢卟酚并检查其溶解度。进行流式细胞术分析以评估癌细胞中 O-二氢卟酚的积累。为了评估光敏剂的细胞内定位，用 O-二氢卟酚和细胞器特异性荧光探针对细胞进行染色。然后，我们测量了各种光敏剂的体外荧光和半最大抑制浓度，以分别评估 PDD 和 PDT 的效果。建立异种移植肿瘤模型，并分析抗肿瘤和可视性效果。 O-二氢卟酚首先被证明是亲水性的。流式细胞术显示癌细胞中 O-二氢卟酚的积累量比 TS 高 20 至 40 倍，荧光强度比 5-ALA 高 7 至 23 倍。在体外，O-二氢卟酚 PDT 的细胞毒性强于 TS PDT，并且 O-二氢卟酚更容易在溶酶体中积累。在体内，与其他光敏剂相比，O-二氢卟酚在PDT和PDD中表现出最好的效果。 O-二氢卟酚具有亲水性，表现出优异的肿瘤聚集和荧光特性。 O-二氢卟酚有望成为 PDT 和 PDD 的下一代双功能光敏剂候选者。
Photodynamic therapy (PDT) exploits light interactions and photosensitizers to induce cytotoxic reactive oxygen species. Photodynamic diagnosis (PDD) uses the phenomenon of photosensitizer emitting fluorescence to distinguish some tumors from normal tissue. The standard photosensitizer used for PDD is 5-aminolevulinic acid (5-ALA), although it is not entirely satisfactory. We previously reported glucose-conjugated chlorin (G-chlorin) as a more effective photosensitizer than another widely used photosensitizer, talaporfin sodium (TS); however, G-chlorin is hydrophobic. We synthesized oligosaccharide-conjugated chlorin (O-chlorin) with improved water-solubility. We report herein on its accumulation and cytotoxicity. O-chlorin was synthesized and examined for solubility. Flow cytometric analysis was performed to evaluate O-chlorin accumulation in cancer cells. To evaluate the intracellular localization of photosensitizer, cells were stained with O-chlorin and organelle-specific fluorescent probes. We then measured the in vitro fluorescence of various photosensitizers and the half-maximal inhibitory concentrations to evaluate effects in PDD and PDT, respectively. Xenograft tumor models were established, and antitumor and visibility effects were analyzed. O-chlorin was first shown to be hydrophilic. Flow cytometry then revealed a 20- to 40-times higher accumulation of O-chlorin in cancer cells than of TS, and a 7- to 23-times greater fluorescence than 5-ALA. In vitro, the cytotoxicity of O-chlorin PDT was stronger than that of TS PDT, and O-chlorin tended to accumulate in lysosomes. In vivo, O-chlorin showed the best effect in PDT and PDD compared to other photosensitizers. O-chlorin was hydrophilic and showed excellent tumor accumulation and fluorescence. O-chlorin is promising as a next-generation bifunctional photosensitizer candidate for both PDT and PDD.