Therefore, ATP depletion caused by the inhibition of the ATPase activity induced by the Pluronic copolymers has been proposed to be a reason for chemosensitization of these cells [165, 166]. Figure 4 Pluronic block copolymers
available from BASF (Wyandotte, MI, USA) contain two hydrophilic EO blocks and a hydrophobic PO block [167]. D-a-tocopheryl polyethylene glycol succinate (Vitamin E TPGS or simply TPGS) Inhibitors,research,lifescience,medical (see Figure 5) is a water-soluble derivative of natural Vitamin E, which is formed by esterification of Vitamin E succinate with polyethylene glycol (PEG) [168]. Therefore, it has advantages over PEG and Vitamin E in application of various drug delivery device, including extending the half-life of the drug in plasma and enhancing the especially cellular uptake [169]. TPGS has amphiphilic structure of lipophilic alkyl tail and hydrophilic polar head with an HLB value of 13.2 and a low CMC value
[170]. Figure 5 Structure of Inhibitors,research,lifescience,medical D-a-tocopheryl polyethylene glycol succinate (TPGS). The effect of TPGS on the bioavailability of a P-gp substrate was first reported in enhancing CyA absorption. It was initially postulated that the improvement in oral availability was due solely to micelle formation and increased drug solubility. Subsequently, Inhibitors,research,lifescience,medical Chang and coworkers demonstrated an increased CyA absorption at TPGS concentrations below the CMC [171]. Since CyA is a known P-gp substrate, the authors hinted at a possible mechanism implicating the efflux transporter, a premise which was later confirmed. Dabholkar and his coworkers made use of PEG-PE/TPGS mixed micelles as drug carrier Inhibitors,research,lifescience,medical and investigated some properties of the efficiency in solubilizing PTX and the ability to bypass the P-gp-mediated drug efflux [172]. It was shown that PTX was efficiently solubilized in the nontoxic PEG-PE/TPGS micelles,
and the entrapment was quite stable with only about 20% of the incorporated drug released from micelles after 48h at 37°C. In addition, PTX-containing PEG-PE/TPGS Inhibitors,research,lifescience,medical micelles were stable in vitro under various conditions, in particular, Entinostat at low pH values and in the presence of bile acids, which is especially important for oral administration. Contrary to other surfactants, TPGS seems to have only a minor effect on membrane fluidity [173], challenging earlier reports [159]. Indeed, it was speculated that the inhibition of P-gp resulted from a decrease in ATPase activity following substrate binding [173]. Further in vitro studies were carried out to investigate the mechanisms of P-gp inhibition using Caco-2 cells model [174]. The data suggest that TPGS is neither a P-gp substrate nor a trigger of intracellular ATP depletion. Instead, TPGS might act as an allosteric modulator not involving the Cis(Z)-flupentixol binding site.