Improved intestinal absorption of paclitaxel by mixed micelles self-assembled from vitamin E succinate-based amphiphilic polymers and their transcellular transport mechanism and intracellular trafficking routes

Abstract

To ensure that antitumor drugs can be effectively transported across intestinal barrier and then quickly released in tumor cells, mixed polymeric micelles (Mix-PMs) were designed and fabricated by combining poly(2-ethyl-2-oxazoline)-vitamin E succinate (PEOz-VES) with TPGS1000 for enhancing intestinal absorption of paclitaxel. PEOz-VES exhibited an extremely low critical micelle concentration and negligible cytotoxicity. The Mix-PMs were characterized to have about 20 nm in diameter, uniform spherical morphology, high drug-loading content and sustained drug release profile with a retained pH-sensitivity. The results of the transport through Caco-2 cell monolayers and intestinal absorption revealed that Mix-PMs displayed higher transcellular transport efficiency compared with PEOz-VES micelles and Taxol®. The possible mechanism of transcellular transport for Mix-PMs was elucidated to be mainly through clathrin- and caveolae/lipid rafts-mediated transcytosis. Confocal laser scanning micrographs revealed that late endosomes, lysosomes, endoplasmic reticulum, Golgi apparatus, and mitochondria were all involved in intracellular trafficking of Mix-PMs. The proteins involved in transcytosis of Mix-PMs and finally excreted were unraveled for the first time by the analysis of proteins in the basolateral media according to the proteomics method. Consequently, the fabricated mixed polymeric micelles may have great potential in enhancing intestinal absorption and accelerating drug release in tumor cells.

Enhanced Intestinal Absorption and Pharmacokinetic Modulation of Berberine and Its Metabolites through the Inhibition of P-Glycoprotein and Intestinal Metabolism in Rats Using a Berberine Mixed Micelle Formulation

“…Park et al [41] reported that surfactants with permeability-enhancing effects and a medium fatty acid chain length may penetrate the lipid bilayer easily because of their proper lipid solubility. Qu et al [42] reported the enhanced permeability of paclitaxel in Caco-2 cells using paclitaxel-loaded mixed polymeric micelles combining poly (2-ethyl-2-oxazoline)-vitamin E succinate with TPGS, in which the energy-dependent transmembrane transport of a mixed micelle formulation was involved via both clathrin-and caveolae-mediated micropinocytosis mechanisms. Taken together, a mixed micelle formulation consisting of a large mw surfactant could penetrate the intestinal lumen through its decreased cell integrity, which was evidenced by the decrease in the TEER values and/or micropinocytosis transmembrane mechanisms [27,39,42].…”

“…Qu et al [42] reported the enhanced permeability of paclitaxel in Caco-2 cells using paclitaxel-loaded mixed polymeric micelles combining poly (2-ethyl-2-oxazoline)-vitamin E succinate with TPGS, in which the energy-dependent transmembrane transport of a mixed micelle formulation was involved via both clathrin-and caveolae-mediated micropinocytosis mechanisms. Taken together, a mixed micelle formulation consisting of a large mw surfactant could penetrate the intestinal lumen through its decreased cell integrity, which was evidenced by the decrease in the TEER values and/or micropinocytosis transmembrane mechanisms [27,39,42]. Our berberine-loaded mixed micelle formulation could act as a P-gp modulator and CYP inhibitor in the enterocytes through the decreased cell membrane integrity by increasing the modulation of tight junctions in parts.…”

“…Caco-2 cells (passage number [38][39][40][41][42] were purchased from American Type Culture Collection (Rockville, MD, USA). LLC-PK1-P-gp cells (passage number 22-23), ultrapooled human liver microsomes, reduced nicotinamide adenine dinucleotide phosphate (NADPH) generating solution, and fetal bovine serum were purchased from BD-Corning (Corning, NY, USA).…”

A simple and versatile route to amphiphilic polymethacrylates: catalytic chain transfer polymerisation (CCTP) coupled with post-polymerisation modifications

“…The synthesis and behaviour of amphiphiles in solution has been the focus of numerous experimental [1][2][3][4] and theoretical [5][6][7] studies over the past few decades. Self-assembly, exemplified in nature with molecules such as phospholipids, cholesterol, or bile acids, occurs in order to reduce the overall free energy of a system by minimising interactions between water and hydrophobic moieties, 8 resulting in the formation of supramolecular structures of varying morphologies, such as spherical micelles, 9,10 worm-like micelles, 11 and vesicles.…”

Dipeptide-modified nanoparticles to facilitate oral docetaxel delivery: new insights into PepT1-mediated targeting strategy

“…Oral administration has been considered as a preferred route in clinical treatment due to its convenience, patient compliance, and lower-cost. Over the decades, enormous developments in nanotechnology have introduced new approaches to improve oral drug delivery (Shan et al., 2016 ; Fan et al., 2018 ; Qu et al., 2018 ). However, the ideal oral delivery efficacy still confronts great challenges, including the poor physicochemical properties of drugs, harsh gastrointestinal environment, the diffusion barrier of intestinal mucus layer, and the compromised enterocyte absorption before entering systemic circulation (Shan et al., 2015 ; Tang et al., 2018 ).…”