Impact of molecular weight on the mechanism of cellular uptake of polyethylene glycols (PEGs) with particular reference to P-glycoprotein.
Polyethylene glycols (PEGs) in general use are polydisperse molecules with molecular weight (MW) distributed around an average value applied in their designation e.g., PEG 4000. Previous research has shown that PEGs can act as P-glycoprotein (P-gp) inhibitors with the potential to affect the absorption and efflux of concomitantly administered drugs. However, questions related to the mechanism of cellular uptake of PEGs and the exact role played by P-gp has not been addressed. In this study, we examined the mechanism of uptake of PEGs by MDCK-mock cells, in particular, the effect of MW and interaction with P-gp by MDCK-hMDR1 and A549 cells. The results show that: (a) the uptake of PEGs by MDCK-hMDR1 cells is enhanced by P-gp inhibitors; (b) PEGs stimulate P-gp ATPase activity but to a much lesser extent than verapamil; and (c) uptake of PEGs of low MW (<2000 Da) occurs by passive diffusion whereas uptake of PEGs of high MW (>5000 Da) occurs by a combination of passive diffusion and caveolae-mediated endocytosis. These findings suggest that PEGs can engage in P-gp-based drug interactions which we believe should be taken into account when using PEGs as excipients and in PEGylated drugs and drug delivery systems.
['Wang|Tingting|T|', 'Guo|Yingjie|Y|', 'He|Yang|Y|', 'Ren|Tianming|T|', 'Yin|Lei|L|', 'Fawcett|John Paul|JP|', 'Gu|Jingkai|J|', 'Sun|Huimin|H|']
PEGs P-gp Passive diffusion Endocytosis ACN, acetonitrile AUC, area under the plasma concentration-time curve CE, collision energy Cmax, maximum plasma concentration CsA, cyclosporine A DBD, drug-binding domain DDS, drug delivery system DMEM, Dulbecco's modified Eagle's medium DMSO, dimethyl sulfoxide DP, declustering potential FBS, fetal bovine serum HBSS, Hanks' balanced salt solution HEPES, 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid IS, internal standard LC−HRMS/MS, liquid chromatography−high resolution tandem mass spectrometry MW, molecular weight NBD, nucleotide binding domain P-gp, P-glycoprotein P-gp-substrate PAC, paclitaxel PEG, polyethylene glycol VER, verapamil