The pH and reduction dual-responsive
polypeptide nanogels with self-reinforced endocytoses were prepared through ring-opening polymerization of
l-glutamate N-carboxyanhydrides, deprotection of benzyl group and subsequent quaternization reaction between γ-2-chloroethyl-l-glutamate unit in
polypeptide block and 2,2'-dithiobis(N,N-dimethylethylamine). The
nanogels were revealed to exhibit smart pH and reduction dual-responsiveness, and excellent biocompatibilities, which expressed great potential as
antitumor drug nanocarriers.
Doxorubicin (DOX) as a model
antitumor drug was loaded into
nanogels through dispersion. DOX-loaded
nanogels displayed a stable core-cross-linked structure under normal physiological condition (pH7.4), while rapidly releasing the payloads in the mimicking endosomal (pH5.3),
tumor tissular (pH6.8) or intracellular reductive microenvironments (10.0mM
glutathione). Confocal fluorescence microscopy demonstrated that DOX-loaded
nanogels could deliver DOX into HepG2 cells (a human
hepatoma cell line) more efficiently than the parent DOX-loaded
micelle and free DOX. The enhanced cellular internalizations of DOX-loaded
nanogels were more significant under
tumor tissular acidic condition (pH6.8) ascribed to the quaternary
ammonium groups in the cores. In addition, DOX-loaded
nanogels exhibited improved in vitro and in vivo antitumor activities, and in vivo securities compared with DOX-loaded
micelle and free DOX. These excellent features of the smart
nanogels with quaternary
ammonium groups were endowed with a bright prospect for intracellular targeting
antitumor drug delivery.