Cyclooxgenase-2 Inhibiting Perfluoropoly (Ethylene Glycol) Ether Theranostic Nanoemulsions—In Vitro Study

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.

Development and Characterization of Resveratrol Nanoemulsions Carrying Dual-Imaging Agents

“…Nanoemulsions were prepared using premade aqueous solution of two nonionic surfactants, Pluronic P105 (P105) and Cremophor EL as published previously with modifications [35]. Resveratrol in PG solution was prepared by dissolving 42.6 mg resveratrol in 2 ml PG stirring at 350 rpm overnight at room temperature, protected from light.…”

“…Hence, we have replaced it for the purpose of this experiment with DiD. DiD dye is chemically similar to DiR and can be used in these formulations interchangeably with DiR as reported previously [35]. Macrophages exposed to treatment received 2 ml fresh media at nanoemulsion concentration of 19.58 μl/ml.…”

“…The theranostic resveratrol nanoemulsions presented here are new formulations based on our earlier reported complex triphasic systems [23,[35][36]. Triphasic nanoemulsions contain a PFPE core that can be imaged with 19 F MRI.…”

“…The organic phase is stabilized with a nonionic surfactant mixture of Pluronic P105 and Cremophor EL. Previous work has shown that celecoxib-loaded nanoemulsions could be designed to target macrophages, immune cells that are involved in inflammation and pain [22][23][35][36]. Resveratrol is known to inhibit TNF-α-induced activation of nuclear factor-κB (NF-κB), a transcription factor responsible for the regulation of inflammatory signaling pathways in macrophages [37].…”

“…The first strategy uses phospholipids in the surfactant layer of the nanoemulsion as the main carrier for the drug [33,34], while the second strategy, developed earlier by our group, uses the formulation of triphasic nanoemulsions, where PFPE and hydrocarbon oils are future science group Development & characterization of resveratrol nanoemulsions carrying dual-imaging agents Preliminary Communication combined into a nanoemulsion internal phase. In these formulations, the hydrocarbon oil represents the key drug carrying excipient while PFPE is passive in this regard [22,35]. The impact of the incorporation of perfluorocarbons such as PFPE on nanoemulsion colloidal behavior and drug carrying capacity has not been reported.…”