Molecular imaging of cell death in tumors. Increasing annexin A5 size reduces contribution of phosphatidylserine-targeting function to tumor uptake.
Molecular imaging of cell death in tumors. Increasing annexin A5 size reduces contribution of phosphatidylserine-targeting function to tumor uptake.
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DOI：
10.1371/journal.pone.0096749
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Reutelingsperger CP
中科院分区：
文献类型：
--
作者：
Ungethüm L;Chatrou M;Kusters D;Schurgers L;Reutelingsperger CP
膜联蛋白A5是一种磷脂酰丝氨酸结合蛋白，在体内与垂死细胞结合。膜联蛋白A5是一种潜在的分子显像剂，可用于确定患者抗癌治疗的疗效。它从循环中的快速清除限制了肿瘤的摄取，因此也限制了它的敏感性。本研究的目的是确定通过增加膜联蛋白A5的大小来增加循环时间是否有利于肿瘤细胞死亡的非侵入性成像。生物素化膜联蛋白A5与alexa - fluor680标记的链亲和素络合后膜联蛋白A5的大小增加。以膜联蛋白A5的非结合变异体M1234为阴性对照。采用NMRI裸鼠HT29结肠癌异种移植模型测定肿瘤在体内的摄取情况。采用非侵入性光学成像测量荧光膜联蛋白a5变异的肿瘤摄取。膜联蛋白A5-链亲和素复合物（4∶1，摩尔：摩尔，Mw ~ 200 kDa）结合磷脂酰丝氨酸表达膜，Ca2+结合的hill系数为5.7±0.5，EC50为0.9±0.1 mM Ca2+ （EC50为最大结合一半所需的Ca2+浓度）（膜联蛋白A5: hill系数3.9±0.2，EC50为1.5±0.2 mM Ca2+）。膜联蛋白A5-链亲和素循环半衰期为±21分钟（膜联蛋白A5循环半衰期为±4分钟）。肿瘤对膜联蛋白a5 -链亲和素的摄取比膜联蛋白a5的摄取更高，持续时间更长，但对磷脂酰丝氨酸结合的依赖较小。膜联蛋白A5大小的增加延长了循环时间，增加了肿瘤摄取，但降低了ps靶向对肿瘤摄取的贡献，并取消了报告治疗效果的能力。
Annexin A5 is a phosphatidylserine binding protein that binds dying cells in vivo. Annexin A5 is a potential molecular imaging agent to determine efficacy of anti-cancer therapy in patients. Its rapid clearance from circulation limits tumor uptake and, hence, its sensitivity. The aim of this study is to determine if non-invasive imaging of cell death in tumors will benefit from increasing circulation time of annexin A5 by increasing its size. Annexin A5 size was increased by complexation of biotinylated annexin A5 with Alexa-Fluor680-labeled streptavidin. The non-binding variant of annexin A5, M1234, was used as negative control. The HT29 colon carcinoma xenograft model in NMRI nude mice was used to measure tumor uptake in vivo. Tumor uptake of fluorescent annexin A5-variants was measured using non-invasive optical imaging. The annexin A5-streptavidin complex (4∶1, moles:moles, Mw ∼200 kDa) binds phosphatidylserine-expressing membranes with a Hill-coefficient of 5.7±0.5 for Ca2+-binding and an EC50 of 0.9±0.1 mM Ca2+ (EC50 is the Ca2+ concentration required for half maximal binding)(annexin A5: Hill-coefficient 3.9±0.2, EC50 1.5±0.2 mM Ca2+). Circulation half-life of annexin A5-streptavidin is ±21 minutes (circulation half-life of annexin A5 is ±4 min.). Tumor uptake of annexin A5-streptavidin was higher and persisted longer than annexin A5-uptake but depended less on phosphatidylserine binding. Increasing annexin A5 size prolongs circulation times and increases tumor uptake, but decreases contribution of PS-targeting to tumor uptake and abolishes power to report efficacy of therapy.
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影响因子：
5.2
作者：
Schaper FL;Reutelingsperger CP
通讯作者：
Reutelingsperger CP
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作者：
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作者：
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