Characterization of a liposomal copper(II)-quercetin formulation suitable for parenteral use

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 AUC 0-24H 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 IC 50 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.

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Herbal Liposomes: Natural Network for Targeted Drug Delivery System

“…For liposome preparation, the following methods are used: [24]. Another approach used to prepare quercetin-loaded liposomes is the thin film hydration process.…”

Improvement in the Pharmacological Profile of Copper Biological Active Complexes by Their Incorporation into Organic or Inorganic Matrix

“…A liposomal formulation based on DSPC:CHOL containing a copper quercetin complex ( 15 ) with enhanced circulation longevity was recently developed and studied as system suitable for parenteral use in cancer treatment [ 52 ]. The vesicular assembly of metallosomes type developed by CHOL incorporation into cetylpyridinium chloride (CPC) surfactant in Cu(II) presence exhibits the ability to inhibit methicillin-resistant S. aureus (MRSA) strain [ 53 ].…”