Excogitation and Assessment of Curcumin-Vitamin E Self-assembly PEGylated Nanoparticles by the Route of Oral Administration

Abstract

Curcumin (CUR) has attracted wide research interests due to its abundant bioactivities and potential advantages in cancer treatment. But the poor water solubility, instability, and quick metabolization and elimination after oral administration severely restrict the efficacy and further clinical application of CUR. Derivation is an approach often used to improve the druggability of active ingredients, so the study aim to prepare a CUR derivate with better stability, satisfactory pharmacokinetics, and inherent self-assembled ability in contrast with CUR. The derivate was designed and evaluated in vitro and in vivo. Vitamin E (VE) was used to perform the esterification reaction with CUR, and the cytotoxicity of derivative CUR-VE ester on MCF-7 tumor cells was similar to CUR. Besides the better stability in simulated gastric and intestinal fluid, plasma and liver homogenate, the self-assembly CUR-VE nanoparticles were fabricated by feasible and controllable nanoprecipitation method. The Transmission Electron Microscope (TEM) showed CUR-VE NPs were spherical with an average particle size of 172.9 nm, and drug loading was up to 93%. CUR-VE NPs exhibited a sustained-release behavior and fitted to Fick's diffusion mechanism. Differential Scanning Calorimeter (DSC), X-ray Powder Diffractometer (XRPD) and Fourier Transform Infrared Spectrometer (FTIR) declared no crystalline substances were formed, and the self-assembly process of CUR-VE relied on driving forces including van der Waals forces, hydrogen bonding forces, intermolecular forces. In pharmacokinetics, C_max and AUC_0-∞ of CUR-VE NPs by the route of oral administration were (104.69 ± 40.72) ng/mL and (3496.92 ± 1088.93) ng/mL∗h, which were about three times and 18 times more compared with CUR. The eliminated half-time of CUR-VE extended to 28 h ascribed to the outstanding stability and surface PEGylation of NPs. It prompted that appropriately PEGylated NPs via oral administration was beneficial to prolong systemic circulation similar to intravenous PEGylated NPs. In summary, the study provides a convenient way to fabricate the self-assembled CUR-VE NPs qualified with high drug loading, satisfactory stability and desired pharmacokinetics. CUR-VE has the potent advantage to be an ideal substitute for CUR in the future of healthcare and clinical application.

Keywords: Curcumin-vitamin E; Pharmacokinetics; Self-assembly nanoparticles; Stability.