Systematic Evaluation of Light-Activatable Biohybrids for Anti-Glioma Photodynamic Therapy
Systematic Evaluation of Light-Activatable Biohybrids for Anti-Glioma Photodynamic Therapy
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DOI：
10.3390/jcm8091269
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发表时间：
2019-09-01
影响因子：
3.9
通讯作者：
Huang, Huang-Chiao
中科院分区：
文献类型：
--
作者：
Inglut, Collin T.;Baglo, Yan;Huang, Huang-Chiao
光敏化生物分子(PSBM)代表了新一代的光吸收化合物，具有更好的光学和物理化学性能，可用于生物医学。尽管基于脂质、聚合物和蛋白质的PSBM取得了许多进展，但它们的有效使用需要从根本上了解大分子结构如何影响光敏剂的物理化学和生物学特性。在这里，我们基于一种临床使用的光敏剂，苯并卟啉衍生物(BPD)，制备并表征了三种定义良好的PSBM。PSBM包括16：0溶血磷胆碱-BPD(16：0lyso PC-BPD)、distearoyl-phosphoethanolamine-polyethylene-glycol-BPD(DSPE-PEG-BPD)和抗EGFR西妥昔单抗(CET-BPD)。在两个胶质瘤细胞系中，DSPE-PEG-BPD显示出最高的单线态氧产量，但由于细胞摄取较低，其光毒性最小。16：0lyso PC-BPD在促进细胞摄取方面最有效，但将BPD的亚细胞定位从线粒体重定向到溶酶体。孵育24 h后，蛋白水解物cet-bpd定位于线粒体，并在光激活时有效地破坏线粒体膜电位。我们的结果揭示了PSBM的可变转运和末端效应，为PSBM的评估方法以及基于亚细胞靶点和细胞毒机制选择PSBM的策略提供了有价值的见解。我们证明，结合生物信息的PSBms同时靶向溶酶体和线粒体，可能会增强对胶质瘤的治疗效果。
Photosensitizing biomolecules (PSBM) represent a new generation of light-absorbing compounds with improved optical and physicochemical properties for biomedical applications. Despite numerous advances in lipid-, polymer-, and protein-based PSBMs, their effective use requires a fundamental understanding of how macromolecular structure influences the physicochemical and biological properties of the photosensitizer. Here, we prepared and characterized three well-defined PSBMs based on a clinically used photosensitizer, benzoporphyrin derivative (BPD). The PSBMs include 16:0 lysophosphocholine-BPD (16:0 Lyso PC-BPD), distearoyl-phosphoethanolamine-polyethylene-glycol-BPD (DSPE-PEG-BPD), and anti-EGFR cetuximab-BPD (Cet-BPD). In two glioma cell lines, DSPE-PEG-BPD exhibited the highest singlet oxygen yield but was the least phototoxic due to low cellular uptake. The 16:0 Lyso PC-BPD was most efficient in promoting cellular uptake but redirected BPD's subcellular localization from mitochondria to lysosomes. At 24 h after incubation, proteolyzed Cet-BPD was localized to mitochondria and effectively disrupted the mitochondrial membrane potential upon light activation. Our results revealed the variable trafficking and end effects of PSBMs, providing valuable insights into methods of PSBM evaluation, as well as strategies to select PSBMs based on subcellular targets and cytotoxic mechanisms. We demonstrated that biologically informed combinations of PSBMs to target lysosomes and mitochondria, concurrently, may lead to enhanced therapeutic effects against gliomas.