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

Abstract

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.

• Authors: Md Jashim Uddin, Thomas A Werfel, Brenda C Crews, Mukesh K Gupta, Taylor E Kavanaugh, Philip J Kingsley, Kelli Boyd, Lawrence J Marnett, Craig L Duvall
• Journal: Biomaterials (Biomaterials) Vol. 92 Pg. 71-80 (Jun 2016) ISSN: 1878-5905 [Electronic] Netherlands
• PMID: 27043768 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Indoles
• Polymers
• Rhodamines
• fluorocoxib A
• Cyclooxygenase 2

Topics

• Animals
• Cell Line, Tumor
• Cyclooxygenase 2 (metabolism)
• Dynamic Light Scattering
• Female
• Humans
• Indoles (administration & dosage, pharmacokinetics, pharmacology, toxicity)
• Inflammation (enzymology)
• Injections, Intraperitoneal
• Mice, Inbred C57BL
• Mice, Nude
• Molecular Imaging
• Nanoparticles (chemistry, toxicity, ultrastructure)
• Neoplasms (enzymology)
• Polymers (chemical synthesis, chemistry)
• Rhodamines (administration & dosage, pharmacokinetics, pharmacology, toxicity)
• Tissue Distribution (drug effects)