Abstract
A facile strategy is developed to construct an ultrasensitive pH triggered charge/size dual-rebound gene delivery system for efficient tumor treatment. The therapeutic gene is complexed by polyethylenimine (PEI) and poly-l-glutamate (PLG), further in situ tightened by aldehyde modified polyethylene glycol (PEG) via Schiff base reaction. The generated Schiff base bonds are stable in neutral pH but cleavable in tumor extracellular pH. This gene delivery system possesses following favorable properties: (1) the tunable gene delivery system is constructed by chemical bench-free "green" and fast process which is favored by clinician, (2) PEG cross-linking shields the surface positive charges and tightens the complex particles, leading to decreased cytotoxicity, improved stability, and prolonged circulation, (3) PEG shielding can be rapidly peeled off by acidic pH as soon as arriving tumors, (4) dual charge/size ultrasensitively rebounding to higher positive potential and bigger size enhances tumor cell uptake efficiency. A series of experiments both in vitro and in vivo are carried out to investigate this gene delivery system in detail. An antiangiogenesis therapeutic gene is carried for the treatment of CT26 tumors in mice, achieving superior antitumor efficacy which is well proved by sufficient biological evidence. The system has great potentials for cancer therapy in the future.
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