Microvascular biodistribution of L19-SIP in angiogenesis targeting strategies
Microvascular biodistribution of L19-SIP in angiogenesis targeting strategies
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DOI：
10.1016/j.ejca.2011.02.001
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发表时间：
2011-05-01
影响因子：
8.4
通讯作者：
Vajkoczy, Peter
中科院分区：
文献类型：
--
作者：
Czabanka, Marcus;Parmaksiz, Gueliz;Vajkoczy, Peter
引言：使用L19介导的纤连蛋白靶向的各种策略已成为抗肿瘤治疗和诊断中有用的临床工具。材料和方法：将SF 126胶质瘤细胞和F9畸胎瘤细胞植入背侧皮褶腔（SF 126：n = 4; F9：n = 6），观察肿瘤血管生成过程中微血管的生物分布和结合过程。使用荧光和共聚焦活体显微镜，在静脉内施用Cy 3-L19-SIP后t = 0 h、t = 4 h和t = 24 h评估生物分布过程。应用舒尼替尼治疗6天，并在治疗开始后2天和6天进行显微镜检查。分析的参数包括：血管和间质结合，L19-SIP的优先结合位点，微血管血流速率，微血管通透性。结果：L19-SIP具有特异性和时间依赖性的新生血管结合，并伴有二次外渗过程，在静脉给药后4 h达到最佳血管/间质结合比（F9：L19-SIP：血管结合：74.6 +/- 14.5;间质结合：46.8 +/- 12.1;对照血管：22，2 +/- 16.6）。血管生成芽是优选的结合位点（F9：L19-SIP：188 +/- 15.5; RTV：90.6 +/- 13.5）。抗血管生成治疗增加微血管血流动力学（SF 126：Su：106.6 +/- 13.3 μ l/sec;未处理：19.7 +/- 9.1 μ l/sec）并诱导L19-SIP积累增加（SF 126：t24; Su：92.6 +/- 2.7;未处理：71.9 +/- 5.9）。L19-SIP显示时间和血流依赖性微血管生物分布过程，血管生成芽作为优先结合位点，随后是抗体的二次外渗。抗血管生成治疗耐药肿瘤血管中的微血管生物分布增强。(C)2011爱思唯尔有限公司保留所有权利。
Introduction: Various strategies using L19-mediated fibronectin targeting have become useful clinical tools in anti-tumour therapy and diagnostics. The aim of our study was to characterise the microvascular biodistribution and binding process during tumour angiogenesis and after anti-angiogenic therapy.Materials and methods: SF126 glioma and F9 teratocarcinoma cells were implanted into dorsal skin fold chambers (SF126: n = 4; F9: n = 6). Using fluorescence and confocal intravital microscopy the biodistribution process was assessed at t = 0 h, t = 4 h and t = 24 h after intravenous application of Cy3-L19-SIP. Sunitinib treatment was applied for six days and microscopy was performed 2 and 6 days after treatment initiation. Analysed parameters included: vascular and interstitial binding, preferential binding sites of L19-SIP, microvascular blood flow rate, microvascular permeability. Histological analysis included CD31 and DAPI.Results: L19-SIP showed a specific and time-dependent neovascular binding with a secondary extravasation process reaching optimal vascular/interstitial binding ratio 4 hours after iv administration (F9: L19-SIP: vascular binding: 74.6 +/- 14.5; interstitial binding: 46.8 +/- 12.1; control vascular: 22,2 +/- 16.6). Angiogenic sprouts were preferred binding sites (F9: L19-SIP: 188 +/- 15.5; RTV: 90.6 +/- 13.5). Anti-angiogenic therapy increased microvascular hemodynamics (SF126: Su: 106.6 +/- 13.3 mu l/sec; Untreated: 19.7 +/- 9.1 mu l/sec) and induced increased L19-SIP accumulation (SF 126: t24; Su: 92.6 +/- 2.7; Untreated: 71.9 +/- 5.9) in therapy resistant tumour vessels.Conclusion: L19-SIP shows a time and blood-flow dependent microvascular biodistribution process with angiogenic sprouts as preferential binding sites followed by secondary extravasation of the antibody. Microvascular biodistribution is enhanced in anti-angiogenic-therapy resistant tumour vessels. (C) 2011 Elsevier Ltd. All rights reserved.