Metabolic fate of poly-(lactic-co-glycolic acid)-based curcumin nanoparticles following oral administration

Abstract

Purpose

Curcumin (CUR), the main polyphenol in turmeric, is poorly absorbed and rapidly metabolized following oral administration, which severely curtails its bioavailability. Poly-(lactic-co-glycolic acid)-based CUR nanoparticles (CUR-NP) have recently been suggested to improve CUR bioavailability, but this has not been fully verified. Specifically, no data are available about curcumin glucuronide (CURG), the major metabolite of CUR found in the plasma following oral administration of CUR-NP. Herein, we investigated the absorption and metabolism of CUR-NP and evaluated whether CUR-NP improves CUR bioavailability.

Methods

Following oral administration of CUR-NP in rats, we analyzed the plasma and organ distribution of CUR and its metabolites using high-performance liquid chromatography-tandem mass spectrometry. To elucidate the mechanism of increased intestinal absorption of CUR-NP, we prepared mixed micelles comprised of phosphatidylcholine and bile salts and examined the micellar solubility of CUR-NP. Additionally, we investigated the cellular incorporation of the resultant micelles into differentiated Caco-2 human intestinal cells.

Results

Following in vivo administration of CUR-NP, CUR was effectively absorbed and present mainly as CURG in the plasma which contained significant amounts of the metabolite compared with other organs. Thus, CUR-NP increased intestinal absorption of CUR rather than decreasing metabolic degradation and conversion to other metabolites. In vitro, CUR encapsulated in CUR-NP was solubilized in mixed micelles; however, whether the micelles contained CUR or CUR-NP had little influence on cellular uptake efficiency. Therefore, we suggest that the high solubilization capacity of CUR-NP in mixed micelles, rather than cellular uptake efficiency, explains the high intestinal absorption of CUR-NP in vivo.

Conclusion

These findings provide a better understanding of the bioavailability of CUR and CUR-NP following oral administration. To improve the bioavailability of CUR, future studies should focus on enhancing the resistance to metabolic degradation and conversion of CUR to other metabolites, which may lead to novel discoveries regarding food function and disease prevention.

Keywords:

• absorption
• metabolism
• bioavailability
• mixed micelles
• Caco-2
• HPLC-MS/MS

Supplementary material

Figure S1 Representative chromatogram of OHCS.

Notes: Representative chromatogram of OHCS in rat liver at 1.5 hours following oral administration of CUR-NP. The homogenized organ (100 μL) was extracted in 1 mL of methanol and 10 μL of it was analyzed by HPLC-MS/MS with MRM.

Abbreviations: OHCS, octahydrocurcumin sulfate; cps, centipoise; CUR-NP, curcumin nanoparticles; HPLC-MS/MS, high-performance liquid chromatography-tandem mass spectrometry; MRM, multiple-reaction monitoring.

Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Research (KAKENHI, 15K14725) of the Japan Society for the Promotion of Science (JSPS), Japan. Taiki Miyazawa was supported by the Japan Society for the Promotion of Science Postdoctoral Fellowships for Research Abroad (https://www.jsps.go.jp/). We thank Myles Migneault (Vascular Biology Laboratory, Jean Mayer Human Nutrition Research Center on Aging (HNRCA) at Tufts University) and Mayuko Itaya, Reina Kamiyoshihara, Yasuhiko Hanzawa and, Saki Hayasaka (Food and Biodynamic Chemistry Laboratory, Graduate School of Agricultural Science at Tohoku University) for their assistance in the preparation of the manuscript.

Disclosure

The authors report no conflicts of interest in this work.