title: Circulation kinetics and biodistribution of dual-labeled polymersomes with modulated surface charge in tumor-bearing mice: comparison with stealth liposomes.
abstract: Polymersomes (Ps) based on poly(ethylene glycol)-b-poly(D,L-lactide) (PEG-PDLLA), with similar sizes (90-100 nm), but different zeta potentials (-7.6 to -38.7 mV) were prepared to investigate the effect of surface charge on blood circulation time and tissue distribution in tumor-bearing mice. For the in vivo studies dual labeled Ps were applied, which were obtained by encapsulating (3)H-dextran 70k in the aqueous core of Ps and by post-coupling of (14)C-thioglycolic acid onto acrylated PEG chains of the Ps. Stealth liposomes (103 nm, -6 mV) were used as a control. A substantial longer half lifetime (τ(1/2)) (47.3h) and a reduced liver uptake (27.9% of injected dose (% ID)) of Ps with a zeta potential of -7.6 mV were observed as compared to those of stealth liposomes (10.6h, 39.8% ID) most probably due to the presence of a relatively thicker and denser PEG brush of the Ps as compared to the liposomes. As a result of their longer circulation times a high tumor accumulation of 18.6% ID was obtained for these Ps after 3d circulation in mice while only 11.2% ID of stealth liposomes accumulated in the tumors as a result of their relatively short τ(1/2) in blood. By increasing the zeta potential on Ps, more rapid clearance of Ps from the blood circulation was found due to an enhanced uptake by the liver. Importantly, co-localization of the two labels of Ps was observed during circulation indicating that dual labeled Ps were colloidally stable in blood without leakage of (3)H-dextran. In conclusion, the results show that Ps with a slightly negative surface charge (zeta potential -7.6 mV) are stable in the circulation and have longer circulation times and a higher tumor accumulation in mice than Ps with more negative zeta potentials or the stealth liposomes used as a control.
authors.affiliation: Department of Polymer Chemistry and Biomaterials, Institute for Biomedical Technology and Technical Medicine, MIRA, Faculty of Science and Technology, University of Twente, Enschede, The Netherlands.
authors.forename: Jung Seok
authors.initials: JS
authors.lastname: Lee
authors.forename: Marc
authors.initials: M
authors.lastname: Ankone
authors.forename: Ebel
authors.initials: E
authors.lastname: Pieters
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Schiffelers
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
authors.forename: Jan
authors.initials: J
authors.lastname: Feijen
mesh_terms: D000818:Animals; D001775:Blood Circulation; D002250:Carbon Radioisotopes; D002470:Cell Survival / Q000187:drug effects; D003911:Dextrans / Q000737:chemistry; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D005260:Female; D006367:HeLa Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007700:Kinetics; D008081:Liposomes; D008099:Liver / Q000378:metabolism; D008546:Melanoma, Experimental / Q000097:blood / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010316:Particle Size; D011091:Polyesters / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013499:Surface Properties; D013864:Thioglycolates / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D002250:Carbon Radioisotopes; D003911:Dextrans; D004337:Drug Carriers; D008081:Liposomes; D011091:Polyesters; D013864:Thioglycolates; C561465:methoxy poly(ethylene glycol)-block-poly(lactic acid); D011092:Polyethylene Glycols; C017487:2-mercaptoacetate