A DM1-doped porous gold nanoshell system for NIR accelerated redox-responsive release and triple modal imaging guided photothermal synergistic chemotherapy

Abstract BackgroundAlthough many treatments are available for breast cancer, poor tumor targeting limits the effectiveness of most approaches and a monotherapy will yield satisfactory results difficultly. Furthermore, the lack of accurate diagnostic and tumor monitoring methods also limit the benefits of treatment. This study aimed to design a nanocarrier based on porous gold nanoshell (PGNSs) co-decorated with methoxy polyethylene glycol (mPEG) and trastuzumab (Herceptin®, HER) which can specifically bind to human epidermal receptor-2 (Her-2) over-expressed breast cancer cells and was incorporated with a derivative of the microtubule-targeting drug maytansine (DM1). PGNSs were prepared and then covered by the mPEG, DM1 and HER via the electrostatic interactions and Au-S bonds. The cytotoxicity of DM1-mPEG/HER-PGNSs on SK-BR-3 and MCF-7 cancer cells was evaluated in terms of cell viability and apoptosis analysis. The selective cancer cell uptake and accumulation were studied via ICP-MS and fluorescence imaging in vitro and in vivo. The multimodal imaging and synergistic chemo-photothermal therapeutic efficacy was investigated in breast cancer tumor-bearing mice. Then the molecular mechanism of the nanoparticles in anti-tumor applications were also elucidated.ResultThe as-prepared DM1-mPEG/HER-PGNSs with a size of 78.6 nm displayed excellent colloidal stability, photothermal conversion ability, and redox-sensitive drug release. These DM1-mPEG/HER-PGNSs exhibited selectively uptake by cancer cells in vitro and accumulation to tumor sites in vivo. Moreover, the DM1-mPEG/HER-PGNSs showed enhanced multimodal computed tomography (CT), photoacoustic (PA) and photothermal (PT) imaging and chemo-thermal combination therapy. The therapeutic mechanism involved the induction of tumor cell apoptosis via the activation of tubulin, caspase-3 and the HSP70 pathway. Meanwhile, the suppression of M2 macrophages and anti-metastatic functions were observed.ConclusionThese DM1-mPEG/HER-PGNSs would display nanodart-like targeting CT/PA/PT imaging in vivo and powerful tumor inhibition mediated by chemo-thermal combination therapy suggest that these unique gold nanocarriers are potential theranostic nanoagents that can serve both as a probe for enhanced multimodal imaging and as a novel targeted antitumor drug delivery system to achieve precision nanomedicine for cancer.