A natural polysaccharide-based nanogel has been synthesized and characterized as pH-sensitive drug delivery system for poorly water-soluble anticancer drugs. In this work, methacrylated hyaluronic acid (MAHA) was used to prepared acid degradable nanogels by a surfactant-free polymerization method in water, where 2,2-dimethacroyloxy-1-ethoxypropane (DMAEP) served as a pH labile cross-linker. Nanogels of different cross-linking density were prepared and doxorubicin (DOX) was successfully encapsulated into the nanogels with drug-loading contents (DLC) ranging from 7.67 to 12.15%. An accelerated DOX release was found in acidic conditions. Cytotoxicity study showed that the DOX loaded nanogels have significantly enhanced cytotoxicity in vitro compared with the nonsensitive ones. Confocal microscopy revealed that there was more DOX in the nuclei of tumor cells when incubated with DOX-loaded pH sensitive nanogels for 3 to 12 h. The enhanced anticancer activity of DOX-loaded pH-sensitive nanogels was also verified by in vivo therapeutic study on mice, in which tumor volume evolution was measured and tumor tissues cell apoptosis and proliferation was examined.

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Biodegradable pH-sensitive amphiphilic block polymer (mPEG-Hyde-PLGA) was synthesized via ring-opening polymerization, initiated from a hydrazone-containing macro-initiator. In this way, a pH-sensitive hydrazone bond was inserted into the backbone of block copolymer, linking hydrophilic poly(ethylene glycol) segment and hydrophobic poly(lactic-co-glycolic acid) segment. The copolymer self-assembled to form stable micelles with mean diameters below 100 nm and served as a drug delivery system for doxorubicin, with drug loading content of 5.3%. pH sensitivity of the hydrazone-containing micelles was investigated by changes in diameter and size distribution observed by dynamic light scattering measurements when the micelles were encountered to acidic medium. Small pieces and larger aggregates were found by transmission electron microscopy resulting from the disassociation of the micelles in acidic conditions. It was also noted that doxorubicin release from the pH-sensitive micelles is significantly faster at pH 4.0 and pH 5.0 compared to pH 7.4, while almost no difference was detected in the case of pH non-sensitive micelles. MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assays on HepG-2 and MCF-7 cells revealed that doxorubicin-loaded pH-sensitive micelles had higher antitumor activity than pH-insensitive ones. This pH-sensitive drug delivery system based on hydrazonecontaining block copolymer has been proved as a promising drug formulation for cancer therapy.

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