# PolySorbate-Based Drug Formulations for Brain-Targeted Drug Delivery and Anticancer Therapy
## 2 Basic Characteristics of PSs
### P-glycoprotein (P-gp) Inhibitory Property of PS  
P-gp is a membrane transport protein present in normal tissues, such as the intestine, brain, liver, placenta, kidney, and cancer cells [45]. The crucial role of P-gp is to maintain intracellular drug concentrations via influx and efflux pumps. Therefore, P-gp plays a key role in the absorption, localization, and elimination of various drugs. Drug-resistant tumors overexpress P-gp, which can eliminate cancer chemotherapeutic agents. Multidrug resistance (MDR) is a major issue in cancer treatment [46]. The inhibition of P-gp is one of the ideal steps to reverse MDR.  
Recently, nonionic surfactants were found to be effective P-gp inhibitors to overcome P-gp-mediated MDR in various types of cancer cells [47]. Working mechanisms of P-gp inhibition by PSs have been investigated using fluorescence polarization techniques [47]. The results indicated that PSs can alter the membrane fluidity of cells, thereby changing the conformation of transporters in the membranes [47]. Effects of nonionic surfactants such as PS 20 and Cremophor EL on breast cancer resistance protein (BCRP) transporters in Caco-2 cell monolayers were analyzed [48]. PS 20 increased the membrane fluidity of the inner lipid bilayers of the intestine. Therefore, PS 20 effectively improved the intestinal absorption of drugs topotecan in rats via the transcellular pathway by inhibiting the function of BCRP.  
The effects of PS as a pharmaceutical excipient on the intracellular localization, transport kinetics, and intestinal absorption of epirubicin were evaluated in both human colon adenocarcinoma (Caco-2) cells and rat jejunum and ileum [49]. PS 20 and PS 80 substantially increased apical to basolateral absorption and reduced the basolateral to apical efflux of epirubicin across Caco-2 cell monolayers [49]. In addition, PS drastically enhanced the mucosal to serosal absorption of epirubicin in the rat jejunum and ileum. These results suggest that the inhibition of intestinal P-gp by PSs significantly improves the oral absorption of drugs in multidrug-resistant cancer cells.  
The effect of PS 80 on the absorption of lipophilic digoxin was also investigated in vitro and in vivo. PS 80 enhanced the bioavailability of digoxin by modulating P-gp systems in cancer cells [29]. When rats were orally administered digoxin (0.2 mg/kg) containing 1% (\(v/v\)) and 10% (\(v/v\)) PS 80, the in vivo oral absorption of digoxin increased by 30% and 61%, respectively, compared to the control groups [26]. The significantly increased absorption of digoxin after oral administration was attributed to the inhibition of P-gp in the gut.  
To inhibit the effect of P-gp, a clay-based nanocomposite using montmorillonite and PS 20 was developed [50]. The particles consisted of montmorillonite, the nonionic surfactant PS 20, and the P-gp substrate digoxin. In vivo results showed that compared to administration of free digoxin, administration of montmorillonite-surfactant hybrid particles resulted in an increased digoxin concentration in the plasma. This increase in digoxin concentration might be attributed to the increase in mucosa-localized concentrations of both digoxin and PS 20.