Doxorubicin-Loaded Nanogel Assemblies with pH/Thermo-triggered Payload Release for Intracellular Drug Delivery

For improving intracellular doxorubicin (DOX) delivery, DOX-encapsulated nanogel assemblies with pH/thermo-responsive drug release are developed. DOX and a graft copolymer comprising acrylic acid (AAc) and 2-methacryloyloxyethyl acrylate (MEA) units as the backbone and with poly(N -isopropylacrylamide) (PNIPAAm) and monomethoxy poly(ethylene glycol) as the grafts at pH 7.4 and 4 degrees C undergo electrostatically induced co-association into copolymer/DOX nanocomplexes. After being crosslinked by polymerization of the MEA moieties, the complex nanoconstructs exhibit a unique nanogel-like architecture. Taking advantage of the extensive electrostatic attraction of the DOX molecules with ionized AAc residues and pi-pi stacking among copolymer-bound DOX molecules, the DOX-loaded nanogels show a relatively high payload content. With the milieu pH being reduced from 7.4 to 4.7, the drug release is appreciably promoted due to the massive disruption of ionic AAc/DOX pairings. The thermo-evolved phase transition of the PNIPAAm grafts further accelerates drug elution, particularly at pH 4.7. In vitro characterization indicates that the DOX-embedded nanogels endocytosed by HeLa cells can progressively release DOX within acidic organelles. As a result, the viability of cancer cells treated with DOX-loaded nanoparticles can be further reduced by prolonging incubation time. This work demonstrates the great potential of the DOX-loaded nanogel assemblies for effective intracellular drug delivery