Circulation kinetics and biodistribution of dual-labeled polymersomes with modulated surface charge in tumor-bearing mice: comparison with stealth liposomes.

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 (tau(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 tau(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.