Resveratrol-piperine loaded mixed micelles: formulation, characterization, bioavailability, safety and in vitro anticancer activity

Abstract

Resveratrol (RES) is a natural lipophilic, useful anticancer molecule. However, due to its low aqueous solubility and extensive metabolism in the intestine and liver, RES shows poor oral bioavailability. The aim of this study was to develop a novel method to deliver RES, using piperine-loaded mixed micelles (RES-P-MM) composed of Poloxamer 407 and D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), in order to enhance its solubility, oral bioavailability and anticancer potency in comparison with RES loaded mixed micelles (RES-MM) and pure RES. RES-P-MM exhibited small particle size, good encapsulation efficiency, good stability in media simulating the physiological conditions of the gastrointestinal tract, and biocompatibility with no sign of tissue toxicity. Oral bioavailability of RES from RES-P-MM and RES-MM was increased by 5.7 and 2 fold compared to pure RES, respectively, while long circulation time and slow plasma elimination were observed, due to the metabolism inhibition effect of piperine. Moreover, RES-P-MM demonstrated higher in vitro anticancer activity in human breast cancer MCF-7 cells. The concentration of the drug needed for the growth inhibition of 50% of cells in a designated time period (GI₅₀) was 7.97 ± 0.56 μg mL⁻¹ for pure RES, while this was decreased by 79.42% for the RES-MM. Remarkably, the GI₅₀ value for the RES-P-MM was 0.55 ± 0.29 μg mL⁻¹, i.e., a 93.09% decrease compared with pure RES. Therefore, the developed mixed micelles containing piperine can act as a promising carrier system for hydrophobic anticancer drugs that have poor oral absorption and extensive metabolism such as RES, and can offer significant improvement in their oral bioavailability.