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Abstract
Quercetin (3,3′,4′,5,7-pentahydroxyflavone) is a naturally derived flavonoid that is commonly found in fruits and vegetables. There is mounting evidence to suggest that quercetin has potential anticancer effects and appears to interact synergistically when used in combination with approved chemotherapeutic agents such as irinotecan and cisplatin. Unfortunately, quercetin has shown limited clinical utility, partly due to low bioavailability related to its poor aqueous solutions (< 10 μg/mL). In this study, liposomal formulations of quercetin were developed by exploiting quercetin’s ability to bind copper. Quercetin powder was added directly to pre-formed copper-containing liposomes (2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol (CHOL) (55:45 M ratio)). As a function of time and temperature, the formation of copper-quercetin was measured. Using this methodology, a final quercetin-to-lipid (mol:mol) ratio of 0.2 was achievable and solutions containing quercetin at concentrations of > 5 mg/mL were attained, representing at least a > 100-fold increase in apparent solubility. The resulting formulation was suitable for intravenous dosing with no overt toxicities when administered at doses of 50 mg/kg in mice. Pharmacokinetic studies demonstrated that the copper-quercetin formulations had an AUC0-24H of 8382.1 μg h/mL when administered to mice at 50 mg/kg. These studies suggested that quercetin (not copper-quercetin) dissociates from the liposomes after administration. The resulting formulation is suitable for further development and also serves as a proof-of-concept for formulating other flavonoids and flavonoid-like compounds. Given that quercetin exhibits an IC50 of >10 μM when tested against cancer cell lines, we believe that the utility of this novel quercetin formulation for cancer indications will ultimately be as a component of a combination product.
Highlights
One of the most common phenolics found in fruits and vegetables are the flavonoids
Quercetin is a triple-ringed flavonoid with capacity to coordinate copper at three domains: 3′,4′-dihydroxy group on the B ring, 3-hydroxy and 4-carbonyl group in the C ring, and the 5hydroxy and 4-carbonyl group that spans across the A and C rings (Fig. 1a)
The ability to form copper-quercetin within copper-containing liposomes is dependent on quercetin permeation across the liposomal lipid bilayer and this process is influenced by temperature
Summary
One of the most common phenolics found in fruits and vegetables are the flavonoids. These phenolic compounds are believed to be one reason why fruit- and vegetable-rich diets are commonly associated with lowered risk for cancer [1]. The most common, naturally occurring flavonoid is quercetin (3,3′,4′,5,7-pentahydroxyflavone) and it has garnered much attention as a potential anticancer agent [2, 3]. Quercetin is well-established as an effective antioxidant, protecting against. Quercetin’s antioxidant activity may be due to catalase’s ability to protect cells from oxidative stress and damage by scavenging H2O2 [4,5,6]. It has been suggested that quercetin exhibits anticancer activity through mechanisms that involve induction of apoptosis. Studies with A549 lung cancer cells, human glioma cells, and human hepatoma cells (HepG2) have shown that treatment with quercetin can concurrently downregulate anti-apoptotic proteins such as Bcl-2, AKT, and metallopeptidase 9 and upregulate pro-apoptotic proteins such as Bax [3, 7, 8]
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