Tumor vascular permeabilization by vascular-targeting photosensitization: Effects, mechanism, and therapeutic implications
Tumor vascular permeabilization by vascular-targeting photosensitization: Effects, mechanism, and therapeutic implications
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DOI：
10.1158/1078-0432.ccr-05-1673
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发表时间：
2006-02-01
影响因子：
11.5
通讯作者：
Hasan, T
中科院分区：
文献类型：
--
作者：
Chen, B;Pogue, BW;Hasan, T
目的：血管靶向光动力治疗后不久就观察到血管屏障功能丧失。然而，该事件涉及的机制仍不清楚，与该病理生理变化相关的治疗意义尚未得到充分探索。 实验设计：在皮下和皮下检查中检查了血管靶向光动力疗法对血管屏障功能的影响。和原位MatLyLu大鼠前列腺肿瘤模型和体外内皮细胞，使用光敏剂维替泊芬。通过染料提取（离体）和活体显微镜（体内）方法评估血管对大分子（伊文思蓝白蛋白和高分子量右旋糖酐）的渗透性。活体显微镜还用于监测血管靶向光动力治疗后肿瘤血管功能的变化。采用免疫荧光染色研究光敏化对单层内皮细胞形态和细胞骨架结构的影响。结果：血管靶向光动力治疗导致MatLyLu肿瘤血管屏障功能障碍。因此，光动力疗法治疗后肿瘤对大分子的摄取显着增加。除了血管通透性增加之外，治疗后不久还观察到血细胞粘附在血管壁上，进一步表明内皮完整性的丧失。血细胞粘附导致血栓形成，血栓可阻塞血管，导致血管关闭。然而，血管靶向光动力治疗后，经常在肿瘤周围检测到存活的肿瘤细胞。通过在 Transwell 插入物上培养单层内皮细胞，还可以在体外观察到光动力疗法治疗后的内皮细胞屏障功能障碍。免疫荧光研究显示光敏处理后不久微管解聚，随后形成应激肌动蛋白纤维。结果，发现内皮细胞收缩，这种内皮形态变化导致细胞间间隙的形成。结论：血管靶向光动力疗法通过内皮细胞间间隙的形成使血管通透，这可能是通过血管光敏后内皮细胞微管解聚诱导的。内皮屏障功能的丧失最终会导致肿瘤血管关闭，并对药物转运和肿瘤细胞转移产生重大影响。
Purpose: Loss of vascular barrier function has been observed shortly following vascular-targeting photodynamic therapy. However, the mechanism involved in this event is still not clear, and the therapeutic implications associated with this pathophysiologic change have not been fully explored.Experimental Design: The effect of vascular-targeting photodynamic therapy on vascular barrier function was examined in both s.c. and orthotopic MatLyLu rat prostate tumor models and endothelial cells in vitro, using photosensitizer verteporfin. Vascular permeability to macromolecules (Evans blue-albumin and high molecular weight dextran) was assessed with dye extraction (ex vivo) and intravital microscopy (in vivo) methods. Intravital microscopy was also used to monitor tumor vascular functional changes after vascular-targeting photodynamic therapy. The effects of photosensitization on monolayer endothelial cell morphology and cytoskeleton structures were studied with immunofluorescence staining.Results: Vascular-targeting photodynamic therapy induced vascular barrier dysfunction in the MatLyLu tumors. Thus, tumor uptake of macromolecules was significantly increased following photodynamic therapy treatments. In addition to vascular permeability increase, blood cell adherence to vessel wall was observed shortly after treatment, further suggesting the loss of endothelial integrity. Blood cell adhesion led to the formation of thrombi that can occlude blood vessels, causing vascular shutdown. However, viable tumor cells were often detected at tumor periphery after vascular-targeting photodynamic therapy. Endothelial cell barrier dysfunction following photodynamic therapy treatment was also observed in vitro by culturing monolayer endothelial cells on Transwell inserts. Immunofluorescence study revealed microtubule depolymerization shortly after photosensitization treatment and stress actin fiber formation thereafter. Consequently, endothelial cells were found to retract, and this endothelial morphologic change led to the formation of intercellular gaps.Conclusions: Vascular-targeting photodynamic therapy permeabilizes blood vessels through the formation of endothelial intercellular gaps, which are likely induced via endothelial cell microtubule depolymerization following vascular photosensitization. Loss of endothelial barrier function can ultimately lead to tumor vascular shutdown and has significant implications in drug transport and tumor cell metastasis.