Fluorocoxib A loaded nanoparticles enable targeted visualization of cyclooxygenase-2 in inflammation and cancer

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• 作者：Md. Jashim Uddin^a ; ¹ ; Thomas A. Werfel^b ; ¹ ; Brenda C. Crews^a ; Mukesh K. Gupta^b ; Taylor E. Kavanaugh^b ; Philip J. Kingsley^a ; Kelli Boyd^c ; Lawrence J. Marnett^a ; ^{larry.marnett@vanderbilt.edu" class="auth_mail" title="E-mail the corresponding author} ; Craig L. Duvall^b ; ^{craig.duvall@vanderbilt.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cancer ; Inflammation ; COX-2 ; Molecular imaging ; Nanoparticles ; Reactive oxygen species
• 刊名：Biomaterials
• 出版年：2016
• 出版时间：June 2016
• 年：2016
• 卷：92
• 期：Complete
• 页码：71-80
• 全文大小：2542 K

文摘

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.