Abstract
PEGylated protein delivery systems that effectively improve the efficiency of protein delivery often suffer limitations of uncontrollable release and non-targeting. In this study, pH-responsive nanogels are developed by forming benzoic imine bonds between hyaluronic acid-graft-methoxy poly(ethylene glycol)-diethylenetriamine (HA-PEG-Diet) copolymers and terephthalaldehyde (TPA) crosslinkers for dual-targeting protein delivery. Cytochrome C (CC), a protein drug, could be facilely encapsulated into the nanogels with a high loading efficiency. Under a physiological environment, these nanogels exhibit excellent stability due to the presence of hydrophobic cores. However, under an acidic tumor microenvironment, the nanogels can undergo pH-induced cleavage of benzoic imines that initiates surface charge conversion from negative to positive, thus promoting cell uptake and protein release. Importantly, confocal images and cytotoxicity results confirm that CC-loaded nanogels can effectively target and eliminate CD44-positive cancer cells via pH-induced surface charge switching and CD44 receptors on cell surfaces. Thus, these pH-responsive dual-targeted nanogels prepared through a green method, have great potential for protein delivery and cancer therapy.
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