An innovative pH-switchable colloidal system that can be exploited for site-selective anticancer drug delivery has been generated by
liposome decoration with a new novel synthetic non-peptidic oligo-
arginine cell-penetration enhancer (CPE) and a quenching PEGylated counterpart that detaches from the vesicle surface under the acidic conditions of
tumors. The CPE module ( Arg4- DAG) is formed by four
arginine units conjugated to a first-generation (G1) 2,2-bis(hydroxymethyl)propionic
acid (bis-MPA)/2,2-bis(aminomethyl)
propionic acid (bis-
AMPA)
polyester dendron terminating with 1,2-distearoyl-3-azidopropane for
liposome bilayer insertion. The zeta potential of the Arg4- DAG-decorated
liposomes increased up to +32 mV as the Arg4- DAG/
lipids molar ratio increased. The Arg4- DAG
liposome shielding at pH 7.4 was provided by methoxy-PEG5 kDa-polymethacryloyl
sulfadimethoxine (mPEG5 kDa-SDM8) with 7.1 apparent p Ka. Zeta potential, surface plasmon resonance and
synchrotron small-angle X-ray scattering analyses showed that at pH 7.4 mPEG5 kDa-SDM8 associates with polycationic Arg4- DAG-decorated
liposomes yielding
liposomes with neutral zeta potential. At pH 6.5, which mimics the
tumor environment, mPEG5 kDa-SDM8 detaches from the
liposome surface yielding Arg4- DAG exposure. Flow cytometry and confocal microscopy showed a 30-fold higher HeLa
cancer cell association of the Arg4- DAG-decorated
liposomes compared to non-decorated
liposomes. At pH 7.4, the mPEG5 kDa-SDM8-coated
liposomes undergo low cell association while remarkable cell association occurred at pH 6.5, which allowed for the controlled intracellular delivery of model macromolecules and small molecules loaded in the
liposome under
tumor conditions.