A smart drug delivery system is prepared by citraconylated polyaspartic acid (PASP) derivate-drug conjugate. The conjugate contains two pH-sensitive groups: citraconic amide and hydrazone linker. Citraconic amide group can enhance tumor therapy efficiency by the extracellular pH-sensitive charge-conversion property. Hydrazone linker between polymer and drug can cleave efficiently in the intracellular pH environment. The resulting conjugate shows dual-pH sensitive properties: extracellular pH-triggered enhanced tumor targeting and intracellular pH-triggered drug release. The results of physicochemical properties, intracellular location, and cytotoxicity of conjugate micelles demonstrate that this novel smart drug delivery system can enhance intracellular delivery of drug at a low pH and then release drug rapidly.

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Efficient delivery of anticancer drugs into tumor cells to increase the intracellular drug concentration is a major challenge for cancer therapy due to drug resistance and inefficient cellular uptake. pH-Sensitive intracellular tumor targeting is increasingly investigated as a pathway to trigger the release of drugs once the drug carrier reached the unique acidic environment of the solid tumors, resulting in the localization of the polymer in the acidic endosomes and lysosomes. Herein, we report a novel pH-responsive amphiphilic polymer poly (itaconic acid)-poly(ethylene glycol)-poly(L-histidine) (PIA-PEG-PHIS) for use as an anticancer drug carrier. The product was found to form homogeneous and spherical micelles in aqueous media due to its amphiphilic nature measured by dynamic light scattering (DLS) and Transmission electron microscopy (TEM) imaging. In vitro drug release study demonstrated that doxorubicin (DOX) was released in a sustained manner in response to endosome pH conditions (pH 4-6) while inhibited at normal physiological pH. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide MTT assays demonstrated that PIA-PEG-PHIS were nontoxic and biocompatible. These favorable properties suggested PIA-PEG-PHIS micelles have great potential for targeted cancer chemotherapy.

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