pH-responsive liposomes for enhanced drug delivery to the tumour.

The tumour tissue displays peculiar physiopathological features that can be exploited to yield site directed nanocarriers. Adequately designed drug nanocarriers can in fact respond to the lower pH of tumor environment with morphological changes. Here we present a novel class of pH-sensitive liposomes for anticancer drug delivery that can undergo structural modification when exposed to environmental alterations thus providing for site-selective delivery. pH sensitive liposomes were obtained by surface decoration with stearoyl-PEG-(poly-methacryloyl-sulfadimethoxine) stearoyl-PEG-poly(SDM) synthesized by ATRP polymerization. The unimer stearoyl-PEG-poly(SDM) was found to sense the pH decrease below 7.0 since sulfadimethoxine switches from a hydrophilic to hydrophobic state as consequence of protonation. Liposomes were assembled using a 6 mol % of stearoyl-PEG-poly(SDM) and 0.25 mol% of mPEG2kDa-DSPE. Dynamic light scattering analysis showed that the liposomes respond to the pH decrease by size increase. The incubation in PBS at pH 6.5 and 6.0 provokes the liposomes size increase from 183 nm ± 38 nm to 315 ± 125 nm and 449 ± 210 nm, respectively. Zeta-potential measurements revealed a ζ potential value of -13.3 ± 5.42 mV at pH 7.4. The negative charge was ascribed to the deprotonation of sulfadimethoxine at neutral pH. The liposomes were very stable in presence of fetal bovin serum for at least 14 hours at 37°C. The Liposomes were loaded with doxorubicin yielding a loading of 5% w/w. 50% of doxorubicin was released within 7 and 3 hours at pH 7.4 and 6.5, respectively, showing that the pH sensitiveness of the carrier modulates the drug release rate. Citofluorimetric analysis carried out by incubating MCF7 tumor cells with fluorescently labelled pH sensitive liposomes displayed that the carrier associates with cells 4.7 times more efficiently at pH 6.5 than at 7.4 while control liposomes negligibly associate with cells regardless of the pH of incubation. The study demonstrates that the physical response of the pH sensor stearoyl-PEG-polySDM to pH decrease is transferred to the surface properties of the liposomes, which may eventually promote the interaction of the carrier with tumor cells and trigger the drug release.