NIR-triggered DOX/ICG Co-delivered Gold Nanocages For Multidrug Resistant Cancer Treatment Though Chemo/Photothermal/Photodynamic Therapy

It is a great challenge to combat multidrug resistant?MDR?cancer effectively.During the last decades,many efforts have been made to develop targeted delivery and stimuli-responsive release systems to combine multi-model synergistic effect for combating multidrug resistant treatments.Firstly,gold nanocages?AuNCs?,with localized surface plasmon resonance peaks?LSPR?in the NIR region was prepared and used as nanocarrier for cancer therapy because of their properties of porous walls and hollow interiors.AuNC showed great property of photothermal effect.Then a NIR triggered drug delivery system based on biotin-PEG modified AuNC,which interiorly filled with temperature sensitive phase-change 1-tetradecanol?PCM?and photosensitizer indocyanine green?ICG?was prepared,ICG@biotin-PEG-AuNC-PCM,for combined therapy to enhance cancer treatment.The research prepared nanomedicine which is consist of indocyanine green,1-tetradecanol and biotin-PEG modified gold nanocages.The nanomedicine was characterized by TEM and DLS,and the photothermal effect was also examined.Confocal laser scanning microscopy?CLSM?was used to investigate the intracellular localization of ICG within MCF-7/ADR cells.MTT method and Annexin-V/propidium iodide?PI?double staining were used to calculate the cytotoxicity and cell apoptosis of nanomedicine.The results showed that the size of gold nanocages is 75nm and it has outstanding photothermal effect.The ICG-loading weight efficiency of nanomedicine was determined as1.34×10⁸ g/mol AuNC.Compared with free ICG,the nanomedicine showed a higher uptake by biotin receptor-mediated internalization,and thus it significantly increased the cytotoxicity and apoptosis to MCF-7/ADR.Lastly,we developed a NIR triggered chemotherapeutic agent doxorubicin?DOX?and ICG co-release system by aid of NIR induced photothermal effect of AuNCs and temperature sensitive phase-change property of 1-tetradecanol at its melting point of 39?,which could simultaneously exerted chemo/photothermal/photodynamic treatment on MDR human breast cancer MCF-7/ADR cells.This nano-sized system was constructed by filling the interior of AuNCs with DOX,ICG and1-tetradecanol,and modifying the surface with biotinylated poly?ethylene glycol?via Au-S bonds,termed as DOX/ICG@biotin-PEG-AuNC-PCM.The DOX and ICG co-release from DOX/ICG@biotin-PEG-AuNC-PCM was much faster in PBS at 40?or under 808 nm NIR irradiation at 2.5W/cm² than at 37??e.g.67.27%or 80.31%vs.5.57%of DOX,76.08%vs.3.83%of ICG for 20 min?.The flow cytometry and confocal laser scanning microscopy?CLSM?results showed,the AuNCs were taken up by MCF-7/ADR cells via endocytosis,thus enhancing DOX uptake;the biotin on AuNCs facilitated this endocytosis;NIR irradiation caused the heating of the AuNCs,triggering the DOX and ICG co-release and enhancing the distribution of DOX in nuclei,the released ICG generated ROS to take photodynamic therapy.Due to the above unique properties,DOX/ICG@biotin-PEG-AuNC-PCM exerted excellent anti-tumour effects under NIR irradiation,its IC₅₀ against MCF-7/ADR cells was very low,only 0.48?g/mL,much smaller than that of free DOX?74.51?g/mL?.Therefore,this new NIR-triggered DDS demonstrates potential for synergistic effect of chemo-,photothermal and photodynamic therapy to MDR cancer cells.