A dual pH/thermal responsive nanocarrier for combined chemo-thermotherapy based on a copper-doxorubicin complex and...

The development of treatment protocols that results in a complete response to chemotherapy has been hampered by low efficacy and systemic toxicity. Here, we created a pH sensitive copper-doxorubicin complex within the core of temperature-sensitive liposomes to maintain the stability during blood circulation and trigger Dox release in the tumor site. Synergistically, we also rationally applied gold nanorods (AuNRs) coupled with near-infrared (NIR) field strength to produce a precise and localized temperature, which not only remotely controlled the drug release but also directly destroyed the tumor, to enhance the therapeutic efficacy. As expected, the in vitro release studies showed that the drug release from CuDox-TSLs (Copper ion mediated Doxorubicin loading-Temperature Sensitive Liposomes) was both pH-dependent and temperature-dependent. Furthermore, MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide) assays showed that CuDox-TSLs combined with AuNRs exhibited a closer antiproliferative activity to free Dox in MCF-7 cells. The efficient intracellular Dox release from CuDox-TSLs toward the tumor cells further confirmed the anti-tumor effect. Moreover, the in vivo imaging and biodistribution studies revealed that CuDox-TSLs combined with AuNRs could actively target the tumor site. In addition, the therapeutic studies in MCF-7 nude mice exhibited CuDox-TSLs plus AuNRs in combination with NIR irradiation inhibited tumor growth to a great extent and possessed much lower side effects, which were further confirmed by systemic histological analyses. All detailed evidence suggested a considerable potential of CuDox-TSLs combined with AuNRs for treatment of metastatic cancer.