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

Abstract

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.

Chemophototherapy: An Emerging Treatment Option for Solid Tumors

“…TSL + GNR + TSK was significantly different from all other groups. Reproduced with permission . Copyright 2011 American Chemical Society.…”

“…Lei et al developed thermosensitive liposomes based on a copper–Dox complex that were responsive to both pH and heat . Synergistic application of GNRs and dual pH/thermal sensitive liposomes with NIR light produced a precise and localized temperature which remotely controlled Dox release and efficiently inhibited tumor growth.…”

Remote loading paclitaxel–doxorubicin prodrug into liposomes for cancer combination therapy

“…Thus, this limits the combination of PTX and DOX utilizing a remote loading liposomal formulation. It is reported that copper ions (Cu 2+ ) could bind with the anthracene nucleus of DOX to form a stable complex (Cu–DOX), and DOX could be loaded into liposomes using a Cu 2+ gradient 22 , 23 , 24 . Furthermore, there has been reported that the formation of Cu–DOX complexation could induce the death of tumor cells, which is mediated by the generation of reactive oxygen species (ROS), the damage of DNA strand, and lipid peroxidation 25 , 26 , 27 .…”

Normalization of doxorubicin release from graphene oxide: New approach for optimization of effective parameters on drug loading

“…An important issue in new DDS is proper release of loaded drug . pH sensitivity of carrier is an applicable feature for cancer therapy, which leads to less harm to normal tissues . The complex of carrier–drug (e.g.…”