Fluorocoxib A loaded nanoparticles enable targeted visualization of cyclooxygenase-2 in inflammation and cancer.
Fluorocoxib A loaded nanoparticles enable targeted visualization of cyclooxygenase-2 in inflammation and cancer.
复制标题
氟昔伯A负载的纳米颗粒可以在炎症和癌症中靶向可视化环氧酶-2。
DOI：
10.1016/j.biomaterials.2016.03.028
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发表时间：
2016-06
期刊：
影响因子：
14
通讯作者：
Duvall CL
中科院分区：
文献类型：
--
作者：
Uddin MJ;Werfel TA;Crews BC;Gupta MK;Kavanaugh TE;Kingsley PJ;Boyd K;Marnett LJ;Duvall CL
环氧合酶-2(COX-2)在几乎所有实体瘤中都有表达，其过度表达是炎症的标志。因此，它是一个潜在的强大的生物标志物，用于炎症性疾病和人类癌症的早期临床检测。我们报道了一种活性氧物种(ROS)响应的胶束纳米粒子，PPS-b-POEGA，它溶解了第一个荧光COX-2选择性抑制物氟柯昔布A(FA)，用于体内COX-2的可视化。研究了FA-PPS-b-POEGA纳米粒(FA-NPs)静脉注射后的药代动力学和生物分布。在野生型小鼠中给药，发现注射后4-8h是最佳的荧光成像窗口。用FA-NPs成功地显示了角叉菜胶诱导的大鼠和小鼠足垫炎症以及1483只HNSCC移植瘤，其荧光强度比正常组织高出10倍。用COX-2抑制剂吲哚美辛阻断FA的靶向结合，证实了COX-2的特异性结合和FA在病变部位的局部滞留。我们的集体数据表明，FA-NPs是第一个静脉注射就绪的FA制剂，在炎症、癌前和恶性组织中提供高信噪比，并将独特地使难溶FA化合物的临床翻译成为可能。
Cyclooxygenase-2 (COX-2) is expressed in virtually all solid tumors and its overexpression is a hallmark of inflammation. Thus, it is a potentially powerful biomarker for the early clinical detection of inflammatory disease and human cancers. We report a reactive oxygen species (ROS) responsive micellar nanoparticle, PPS-b-POEGA, that solubilizes the first fluorescent COX-2-selective inhibitor fluorocoxib A (FA) for COX-2 visualization in vivo. Pharmacokinetics and biodistribution of FA-PPS-b-POEGA nanoparticles (FA-NPs) were assessed after a fully-aqueous intravenous (i.v.) administration in wild-type mice and revealed 4 – 8 h post-injection as an optimal fluorescent imaging window. Carrageenan-induced inflammation in the rat and mouse footpads and 1483 HNSCC tumor xenografts were successfully visualized by FA-NPs with fluorescence up to 10-fold higher than that of normal tissues. The targeted binding of the FA cargo was blocked by pretreatment with the COX-2 inhibitor indomethacin, confirming COX-2-specific binding and local retention of FA at pathological sites. Our collective data indicate that FA-NPs are the first i.v.-ready FA formulation, provide high signal-to-noise in inflamed, premalignant, and malignant tissues, and will uniquely enable clinical translation of the poorly water-soluble FA compound.