Multi-functional D-alpha-tocopheryl polyethylene glycol succinate surface modified nanocrystals improve the stability and oral bioavailability of pueraria flavonoids

Abstract

Pueraria flavonoids (PF), the main component of “Getong Tongluo capsule”, were applied in the clinical treatment of cardiovascular diseases. However, the complex nature of multiple-components, along with poor stability and low oral bioavailability of PF, hinders its widespread clinical use. This study aimed to develop D-alpha-tocopheryl polyethylene glycol succinate (TPGS) surface-modified PF-loaded nanocrystals (PF–NCs)，and investigate their physico-chemical properties and oral absorption mechanism. The prepared PF-NCs showed as rod shape crystal with an average particle size and polydispersity index of 259.0 ± 7.80 nm and 0.195 ± 0.046. Compared with PF, the stability of PF-NCs was significantly improved. Furthermore, the transport of PF-NCs in Madin-Darby canine kidney (MDCK) monolayers was time-, concentration- and energy-dependent. The endocytosis of PF-NCs was mediated mainly through macropinocytosis, caveolin, clathrin and lipid rafts/caveolae. The involvement of multidrug resistance-associated protein 2 (MRP2) transporter and P-gp in the transmembrane transport of PF-NCs was also significant. Pharmacokinetic studies demonstrated that PF-NCs exhibited a substantial enhancement of PF's oral bioavailability. Overall, the prepared PF-NCs demonstrated enhanced stability and bioavailability, offering valuable insights for the development of multi-component nanocrystals and investigation into their mechanisms of oral absorption.