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  • br Corresponding authors br E mail addresses jmqian mail xjt

    2019-10-22


    Corresponding authors.
    E-mail addresses: [email protected] (J. Qian), [email protected] (A. Suo).
    are usually loaded on the GNR surface via physical adsorption or en-capsulation. Such drug loading methods often lead to undesired drug release behavior, with the uncertainty about cancer treatment (Chen et al., 2014). Therefore, it is still necessary to explore novel GNR-based drug delivery systems with enhanced cellular uptake and stimulus-re-sponsive drug release abilities to achieve more efficient and precise cancer treatment.
    Hydroxyethyl chitosan (HECS), a water-soluble chitosan derivative, is being actively studied in biomedical field due to its excellent bio-compatibility and biodegradability (Qin et al., 2015; Wang, Liu et al., 2017, 2017b). More importantly, the abundant pendant functional groups of HECS provide the possibility for chemical modification, drug loading and stimulus-responsive release. In addition, positively-charged HECS-based nano drug delivery systems can actively interact with ne-gatively-charged plasma membranes, resulting in effective cellular in-ternalization of nanoparticles (Deng et al., 2016). Therefore, HECS is a promising polymer candidate to modify GNR and deliver chemother-apeutic drug. Encouragingly, it is reported that the nanoparticles formed from cationic polymer and anionic polymer exhibit a pH-sen-sitive surface charge reversal behavior, which may prolong blood cir-culation time, reduce side effects and improve cellular uptake (Deng et al., 2016; Hu et al., 2017). Hyaluronic Coelenterazine (HA) is a negatively charge hydrophilic polysaccharide (2013b, Hong, Lin, & Torchilin, 2013). HA can effectively improve the stability of nanoparticles and mediate active targeting via specifically interacting with CD44 re-ceptors overexpressed in tumor cells (Zhong et al., 2016). Hence, the integration of cationic HECS, anionic HA and GNR may be an attractive strategy to prepare the combined photothermal-chemotherapy system having tumor microenvironment-responsiveness. This stimulus-sensi-tive system is expected to provide effective drug delivery, enhanced cellular uptake, and stimulus-response drug release. To the best of our knowledge, such a smart stimuli-responsive combined photothermal-chemotherapy system has not been reported. The successful construc-tion of this nanosystem may provide new ideas for combined photo-thermal-chemotherapy of cancer.
    Herein, we are committed to developing a novel GNR-based con-jugate (namely DOX-DHHC-GNRAH) which is expected to exhibit im-proved stability, pH-responsive surface charge reversal and drug release behaviors, and excellent therapeutic effect of breast cancer. To obtain the conjugate, HECS was dihydroxyphenylated with 3,4-dihydrox-yphenylacetic acid (DA) via carbodiimide reaction and subsequently hydrazidated with 6-maleimidocaproic acid (MA)/mercaptopropio-nylhydrazide (MPH) through click chemistry, yielding dihydrox-yphenyl/hydrazide bifunctionalized HECS (DHHC). DHHC was con-jugated onto the GNR surface via biomimmetic adhesive catechol groups. Chemotherapeutic drug DOX was loaded onto the conjugate through an acid-labile hydrazone linkage. Finally, oxidized hyaluronic acid (AHA), as active targeting molecule and anionic hydrophilic layer, was decorated onto the DOX-loaded conjugate through Schiff base chemistry and electrostatic interaction. The DOX-DHHC-GNRAH con-jugate was designed to integrate the photothermal property of GNR, the excellent properties of HECS and HA and the superior cytotoxicity of DOX into one nanoplatform. To verify the availability of the conjugate for breast cancer therapy, the physico-chemical properties of DOX-DHHC-GNRAH were investigated systemically, including size, zeta po-tential, morphology, stability, photothermal conversion capability, drug release profile and surface charge-reversal behavior. After that, the cytocompatibility, cellular uptake and combined chemo-photo-thermal anticancer efficiency of the conjugate were evaluated with breast cancer MCF-7 cells in vitro. The results suggested that our con-jugate had desired physico-chemical properties and exhibited great potential for synergistic photothermal-chemotherapy of breast cancer.