Construction of carboxymethyl chitosan-based nanoparticles of hypoxia response for co-loading doxorubicin and tanshinone IIA.

As a first-line drug for breast cancer chemotherapy, the effectiveness of doxorubicin (DOX) is challenged by high doses and high toxicity. Studies showed the combination of Tanshinone IIA (TSIIA) and DOX could enhance the efficacy of DOX for cancer and reduce the toxic effects to normal tissues. Unfortunately, free drugs are easily metabolized in the systemic circulation, which are less prone to aggregation at the tumor site to exert anticancer efficacy. In present study, we prepared a carboxymethyl chitosan-based hypoxia-responsive nanoparticles loaded with DOX and TSIIA for the treatment of breast cancer. The results demonstrated that these hypoxia-responsive nanoparticles not only improved the delivery efficiency of the drugs but also enhanced the therapeutic efficacy of DOX. The average size of nanoparticles was about 200-220 nm, the optimal drug loading and encapsulation efficiency of TSIIA in DOX/TSIIA NPs were 9.06 % and 73.59 %, respectively. Hypoxia-responsive behavior were recorded in vitro, while the synergistic efficacy is significantly exhibited in vivo and the tumor inhibitory rate was 85.87 %. Notably, TUNEL assay and immunofluorescence staining verified that the combined nanoparticles exerted a synergistic anti-tumor effect by inhibiting tumor fibrosis, decreasing the expression of HIF-1α and inducing tumor cell apoptosis. Collectively, this carboxymethyl chitosan-based hypoxia-responsive nanoparticles could have promising application prospect for effective breast cancer therapy.