Abstract 2178: A novel injectable formulation of quercetin reliant on the ability of the drug to complex copper
Authors: Chen Kent T. , Anantha Malathi , Leung Ada W.Y. , Wehbe Mohamed , Sutherland Brent , Bally Marcel B. 
Published: July 2016

Low levels of fruit and vegetable consumptions have been linked to increased risk of cancer. Quercetin is one of the most ubiquitous flavanoids found in fruits and vegetables and there is increasing evidence that points to the anti-cancer potential of quercetin. This flavanoid acts as a promoter of apoptosis by modulating apoptosis through Bcl-2, Akt-1, and/or NF-κB. In addition, quercetin also demonstrated promise when used in combination with approved chemotherapeutic agents such as cisplatin and irinotecan. However, quercetin has remained largely clinically irrelevant despite all the potential anti-cancer benefits noted in in vitro assays. This is due in part to the low bioavailability of the compound and its poor aqueous solubility (solubility &lt;100μg/mL). In order to realize the full therapeutic potential of quercetin, we have developed an injectable quercetin formulation prepared using a method that relies on its ability to bind copper. Quercetin was added to pre-formed copper-containing liposomes (,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol (CHOL) (55:45 molar ratio)); a strategy that involved addition of quercetin powder directly to the liposomes at 60°C. In vivo pharmacokinetics of the liposomal quercetin formulation was assessed by injecting the product intravenously at a dose of 50mg/kg into RAG2m mice. Plasma samples were taken at 0.5, 1, 4, 8, and 24 hours post-injection. Quercetin concentration in plasma was analyzed via HPLC and lipid concentrations were determined using liquid scintillation counting. The plasma copper concentration was determined using atomic absorbance spectrometry. All data were plotted in Prism 6.0 (mean ± SEM). Quercetin encapsulation into copper liposomes resulted in a final drug-to-lipid ratio (mol:mol) of 0.2. The encapsulation process was copper-dependent. The formulation is stable at 4°C for at least three weeks, maintaining a particle size of approximately 135nm and &gt;98% encapsulation efficiency. Compared to previous data on free quercetin, the liposomal formulation of quercetin shows a markedly improved pharmacokinetic profile. The formulation demonstrated a 10-fold increase in elimination half life and a 7-fold increase in AUC when compared to previously published studies with free quercetin. A novel liposomal formulation of quercetin has been generated and the resulting formulation resolved the solubility issues faced when considering the use of quercetin for studies attempting to define its therapeutic activity in various cancer models.

Citation Format: Kent T. Chen, Malathi Anantha, Ada W.Y. Leung, Mohamed Wehbe, Brent Sutherland, Marcel B. Bally. A novel injectable formulation of quercetin reliant on the ability of the drug to complex copper. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2178.