Doxorubicin (DOX), one of the most widely used anticancer drugs, is restricted in clinical application due to its severe side effects and inefficient cellular uptake. To overcome the drawbacks, herein, an endosomal pH-activated prodrug was designed and fabricated by conjugating DOX with chitosan via an acid-cleavable hydrazone bond. The resulting DOX conjugates can self-assemble into nano-sized particles, which were very stable and presented no burst release of DOX at a neutral pH condition. Notably, the nanoparticles exhibited excellent cell uptake properties and a remarkable drug accumulation in tumor cells. Once internalized into the cells, moreover, DOX can be fast released from the nanoparticles, and the release mechanism changed from the anomalous transport at pH 7.4 to the combination pattern of diffusion- and erosion-controlled release at pH 6.0 or 5.0. The prodrugs showed obvious cytotoxicity for HeLa cells with fairly low IC50 values, offering a new platform for targeted cancer therapy.

The development of environmentally responsive drug delivery systems for the treatment of cancer has attracted particular interest in recent years. However, the enhancement of drug loading capacity and realization of pH-responsive drug delivery remain challenging. Herein, we employ carboxymethyl curdlan as a hydrophilic carrier to wrap doxorubicin (DOX) directly via electrostatic interaction. The sizes of the formed nanoparticles can be simply tuned by changing their feeding ratios. In particular, the nanoparticles are highly stable in aqueous solution without size variation. In vitro drug release and cytotoxicity assays illustrate that this delivery system can release DOX differentially under various environmental conditions and transport it into cell nuclei efficiently, with comparable therapeutic effect to the free drug. These results suggest that the carrying of antitumor drugs by polysaccharide via electrostatic interaction is a simple but effective way to construct a pH-dependent drug delivery platform.

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