Redox dual-responsive dendrimeric nanoparticles for mutually synergistic chemo-photodynamic therapy to overcome drug resistance.
Redox dual-responsive dendrimeric nanoparticles for mutually synergistic chemo-photodynamic therapy to overcome drug resistance.
复制标题
DOI：
10.1016/j.jconrel.2020.10.048
复制
发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Dan Zhong;Huayu Wu;Yahui Wu;Yunkun Li;Jun Yang;Qiyong Gong;Kui Luo;Z. Gu
中科院分区：
文献类型：
--
作者：
Dan Zhong;Huayu Wu;Yahui Wu;Yunkun Li;Jun Yang;Qiyong Gong;Kui Luo;Z. Gu
联合疗法在治疗癌症，特别是耐药性癌症中表现出至关重要的潜力。在这项工作中，开发了一种基于多功能树枝状聚合物和香菇多糖的新型肿瘤靶向、氧化还原双重响应且负载紫杉醇（紫杉醇）的纳米颗粒，用于紫杉醇耐药癌症的化学-光动力学联合治疗。纳米颗粒表现出增强的细胞摄取和肿瘤渗透的基础上苯硼酸-唾液酸的相互作用，并有能力控制药物释放响应细胞内高浓度的谷胱甘肽和过氧化氢。具体而言，光照射不仅触发纳米颗粒的光动力效应以产生显著的光动力细胞毒性，而且还导致PTX通过溶酶体破坏增加内化并加速释放到细胞质中，以及对微管和肌动蛋白微丝的明显损伤，从而逆转A549/T细胞的耐药性。同时，PTX处理可使细胞阻滞于G2/M期，从而延长核膜破裂的时间，进一步促进光敏剂在细胞核内的积聚，提高DNA损伤反应。因此，紫杉醇与光动力学联合应用对耐药的A549/T细胞具有良好的体外和体内抗肿瘤作用，这为克服耐药的共递送系统的设计提供了新的策略。
Combination therapy has exhibited crucial potential in the treatment of cancers, especially in drug-resistant cancers. In this work, a novel tumor-targeted, redox dual-responsive and paclitaxel (PTX) loaded nanoparticle based on multifunctional dendrimer and lentinan was developed for combinational chemo-photodynamic therapy of PTX-resistant cancers. The nanoparticles exhibited enhanced cellular uptake and tumor penetration based on phenylboronic acid-sialic acid interactions, and had the ability to control drug release in response to intracellular high concentration of glutathione and H2O2. Specifically, light irradiation not only triggered the photodynamic effect of the nanoparticles for prominent photodynamic cytotoxicity, but also resulted in increased internalization and accelerated release of PTX into cytoplasm through the lysosome disruption, as well as the obvious damage to microtubules and actin microfilaments, for drug resistance reversal of A549/T cells. Meanwhile, PTX treatment would arrest cells in G2/M phase, thereby prolonging the period when nuclear membrane is broken down, which further facilitated photosensitizer accumulation in nuclei and improved DNA damage response. Consequently, the combination of PTX and photodynamic treatment lead to excellent antitumor effects to drug-resistant A549/T cellsin vitroandin vivo, which provides a new strategy for the design of co-delivery system to overcome drug resistance.