Centre de Recherche en Automatique de Nancy (CRAN), Nancy-University, CNRS, Centre Alexis Vautrin, Avenue de Bourgogne, Brabois, 54511, Vandoeuvre-lès-Nancy, France.
Pharm Res. 2010 Mar;27(3):468-79. doi: 10.1007/s11095-009-0035-8. Epub 2010 Jan 20.
This article characterizes the vascular effects following vascular-targeted photodynamic therapy with a photosensitizer which actively targets endothelial cells.
This strategy was considered by coupling a chlorin to a heptapeptide targeting neuropilin-1 in human malignant glioma-bearing nude mice. A laser Doppler microvascular perfusion monitor was used to monitor microvascular blood perfusion in tumor tissue. Endothelial cells' ultra structural integrity was observed by transmission electron microscopy. The consequences of photosensitization on tumor vessels, tissue factor expression, fibrinogen consumption, and thrombogenic effects were studied by immunohistochemical staining.
Treatment of glioma-bearing mice with the conjugate showed a statistically significant tumor growth delay. Vascular effect was characterized by a decrease in tumor tissue blood flow at about 50% baseline during treatment not related to variations in temperature. This vascular shutdown was mediated by tumor blood vessels' congestion. A pro-thrombotic behavior of targeted endothelial cells in the absence of ultra structural changes led to the induction of tissue factor expression from the earliest times post-treatment. Expression of tissue factor-initiated thrombi formation was also related to an increase in fibrinogen consumption.
Using a peptide-conjugated photosensitizer targeting neuropilin-1, induction of tissue factor expression immediately post-treatment, led to the establishment of thrombogenic effects within the vessel lumen.
本文描述了一种针对内皮细胞的血管靶向光动力疗法的血管效应。
该策略是通过将叶绿素与靶向人恶性神经胶质瘤的神经纤毛蛋白-1的七肽偶联来实现的。使用激光多普勒微血管灌注监测仪监测肿瘤组织中的微血管血流灌注。通过透射电子显微镜观察内皮细胞的超微结构完整性。通过免疫组织化学染色研究光敏化对肿瘤血管、组织因子表达、纤维蛋白原消耗和血栓形成作用的影响。
用缀合物治疗荷瘤小鼠可显著延缓肿瘤生长。血管效应的特征是在治疗过程中肿瘤组织血流下降约 50%，与温度变化无关。这种血管关闭是由肿瘤血管充血介导的。靶向内皮细胞的促血栓形成行为在没有超微结构变化的情况下导致组织因子表达的诱导，这发生在治疗后最早的时间。纤维蛋白原消耗的增加也与组织因子诱导的血栓形成有关。
使用靶向神经纤毛蛋白-1的肽偶联光敏剂，在治疗后立即诱导组织因子表达，导致血管腔内血栓形成作用的建立。
