Neuropilin-1 Targeting Photosensitization-Induced Early Stages of Thrombosis via Tissue Factor Release
Neuropilin-1 Targeting Photosensitization-Induced Early Stages of Thrombosis via Tissue Factor Release
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DOI：
10.1007/s11095-009-0035-8
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发表时间：
2010-03-01
影响因子：
3.7
通讯作者：
Barberi-Heyob, Muriel
中科院分区：
文献类型：
--
作者：
Bechet, Denise;Tirand, Loraine;Barberi-Heyob, Muriel
本文描述了血管靶向光动力治疗后的血管效应，光敏剂积极靶向内皮细胞。在人类恶性胶质瘤裸鼠中，通过将氯偶联到靶向神经肽-1的七肽来考虑这一策略。采用激光多普勒微血管血流灌注监测仪监测肿瘤组织微血管血流灌注情况。透射电镜观察内皮细胞超微结构完整性。通过免疫组织化学染色研究光敏对肿瘤血管、组织因子表达、纤维蛋白原消耗和血栓形成效应的影响。用该缀合物治疗胶质瘤小鼠显示出统计学上显著的肿瘤生长延迟。血管效应的特点是在治疗期间肿瘤组织血流量减少约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。在没有超结构改变的情况下，靶向内皮细胞的促血栓行为导致治疗后最早时间组织因子表达的诱导。组织因子引发的血栓形成的表达也与纤维蛋白原消耗的增加有关。使用针对neuropilin-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效应的建立。
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.