Abstract
Cylcooxgenase-2 (COX-2) expressing macrophages, constituting a major portion of tumor mass, are involved in several pro-tumorigenic mechanisms. In addition, macrophages are actively recruited by the tumor and represent a viable target for anticancer therapy. COX-2 specific inhibitor, celecoxib, apart from its anticancer properties was shown to switch macrophage phenotype from tumor promoting to tumor suppressing. Celecoxib has low aqueous solubility, which may limit its tumor inhibiting effect. As opposed to oral administration, we propose that maximum anticancer effect may be achieved by nanoemulsion mediated intravenous delivery. Here we report multifunctional celecoxib nanoemulsions that can be imaged by both near-infrared fluorescence (NIRF) and 19F magnetic resonance. Celecoxib loaded nanoemulsions showed a dose dependent uptake in mouse macrophages as measured by 19F NMR and NIRF signal intensities of labeled cells. Dramatic inhibition of intracellular COX-2 enzyme was observed in activated macrophages upon nanoemulsion uptake. COX-2 enzyme inhibition was statistically equivalent between free drug and drug loaded nanoemulsion. However, nanoemulsion mediated drug delivery may be advantageous, helping to avoid systemic exposure to celecoxib and related side effects. Dual molecular imaging signatures of the presented nanoemulsions allow for future in vivo monitoring of the labeled macrophages and may help in examining the role of macrophage COX-2 inhibition in inflammation-cancer interactions. These features strongly support the future use of the presented nanoemulsions as anti-COX-2 theranostic nanomedicine with possible anticancer applications.
Highlights
Inflammation processes are involved in all stages of cancer development [1]
COX-2 is involved in the synthesis of prostaglandin E2 (PGE2) which is necessary for the development of immunosuppressive cells [6]
We propose that the celecoxib loaded theranostic nanomedicine can suppress COX-2 activity in the circulating macrophages and allow us to track the macrophages tumor infiltration dynamics by molecular imaging (19F magnetic resonance and near-infrared fluorescence)
Summary
The tumor environment contains a wide variety of inflammatory cells such as mast cells, dendritic cells, natural killer cells and macrophages [2]. Macrophages, constituting up to 50% of tumor mass, are actively recruited during cancer development and play an important role in tumor angiogenesis and metastasis [3]. Cyclooxygenase-2 (COX-2) is an inducible pro-inflammatory enzyme implicated in tumor development and progression [4]. Recruitment of COX-2 expressing macrophages can create an inflammatory environment that strongly promotes tumor growth and angiogenesis [5]. COX-2 is involved in the synthesis of prostaglandin E2 (PGE2) which is necessary for the development of immunosuppressive cells (tumor associated suppressive macrophages and myeloid-derived suppressor cells) [6]. We hypothesize that inhibiting COX-2 in tumor recruited macrophages can be a viable anticancer strategy
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