GSH-responsive paclitaxel prodrug used in chemotherapy in combination with photodynamic therapy

Abstract

The lack of targeting and poor solubility of anti-tumor drugs are two major limitations to the outcome of tumor therapy. To address the inherent drawbacks, we designed a novel prodrug of paclitaxel (PTX), HP-PTX. This HP-PTX prodrug contains a PEGylated heptamethylene cyanine dye (PEG-IR808–1) that was conjugated to PTX via a redox-sensitive disulfide bond. The moiety of IR808–1 acts as a tumor-targeting ligand, enabling HP-PTX not only to target tumor cells, but also to localize to mitochondria and generate ROS under 808 nm laser irradiation to wound cellular mitochondria thus exerting cytotoxic effect. Meanwhile, in vitro cellular uptake assays showed that HP-PTX possesses MCF-7 cell tumor targeting specificity which was attributed to the preferential uptake of heptamethine cyanine dye mediated by the overexpressed organic anion-transporting polypeptides (OATP) on MCF-7 cell membrane. Near-infrared in vivo imaging showed that incorporation of polyethylene glycol effectively prolonged prodrug's half-life in vivo. In addition, in vivo experiments showed that with combinational therapy strategy HP-PTX was able to kill cancer cells with high efficiency (69.52 %) without notable toxic side effects compared to PTX. These results are evidence of the potential of the tumor-targeting prodrug HP-PTX for the treatment of breast cancer.