Homologous-targeting biomimetic nanoparticles for photothermal therapy and Nrf2-siRNA amplified photodynamic therapy against oral tongue squamous cell carcinoma
Homologous-targeting biomimetic nanoparticles for photothermal therapy and Nrf2-siRNA amplified photodynamic therapy against oral tongue squamous cell carcinoma
复制标题
同源靶向仿生纳米光热及Nrf 2-siRNA扩增光动力治疗口腔舌鳞癌
DOI：
10.1016/j.cej.2020.124268
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发表时间：
2020-05
影响因子：
15.1
通讯作者：
S. Shi;Yue Wang;Beibei Wang;Qian Chen;Guoyun Wan;Xiaoying Yang;Juan-juan Zhang;Lianyun Zhang;Changyi Li;Yinsong Wang
中科院分区：
文献类型：
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作者：
S. Shi;Yue Wang;Beibei Wang;Qian Chen;Guoyun Wan;Xiaoying Yang;Juan-juan Zhang;Lianyun Zhang;Changyi Li;Yinsong Wang
光热疗法（PTT）和光动力疗法（PDT）在治疗口腔舌鳞癌（OTSCC）中具有部位选择性、无或侵袭性小、耐药可忽略等优点。然而，细胞内抗氧化反应的激活将部分抵消PDT的抗癌作用。Nrf2是一种众所周知的氧化还原调控转录因子，已被发现参与肿瘤细胞对PDT的抗性。为此，设计了一种仿生纳米颗粒体系，将光敏剂吲哚青绿（ICG）与Nrf2-siRNA共载靶向递送，以期在OTSCC中实现PTT与扩增PDT的协同作用。制备了聚β-氨基酯(PBAE)/聚乳酸-羟基乙酸（PLGA）共载ICG和Nrf2-siRNA的混合纳米粒子，并将其包被在同源OTSCC特异性衍生的癌细胞膜（CCM）囊泡内，从而获得了仿生纳米粒子M@PPI-siRNA。在体外和体内，M@PPI-siRNA纳米颗粒由于同源CCM的肿瘤归巢作用而表现出较强的otscc靶向能力。在808 nm激光照射下，M@PPI-siRNA纳米颗粒显著下调在ROS解毒中起重要作用的Nrf2及其调控基因、谷氨酸-半胱氨酸连接酶催化亚基（GCLC）和修饰亚基（GCLM）的表达，并通过维持细胞内ROS的积累间接增强PDT抗癌作用。通过PTT和Nrf2-siRNA扩增的PDT协同作用，M@PPI-siRNA纳米颗粒显著抑制OTSCC细胞的增殖和诱导凋亡，并显著抑制OTSCC荷瘤小鼠的肿瘤生长和血管生成。综上所述，本研究提供了一种有前景的otscc靶向光敏剂和基因递送系统，也证实了Nrf2-siRNA是一种有效的PDT扩增增效剂。
Photothermal therapy (PTT) and photodynamic therapy (PDT) have some advantages such as site selectivity, non- or little-invasive property and negligible drug resistance for treatment of oral tongue squamous cell carcinoma (OTSCC). However, the activation of intracellular antioxidant responses will partly counteract anticancer effects of PDT. As a well-known redox-regulated transcription factor, Nrf2 has been found to participate in the resistance of tumor cells against PDT. Hereon, a biomimetic nanoparticle system was designed for co-loading and targeted delivery of photosensitizer indocyanine green (ICG) and Nrf2-siRNA, thus hope to achieve synergistic effects of PTT and amplified PDT in OTSCC. Poly(β-amino ester) (PBAE)/poly lactic-co-glycolic acid (PLGA) blended nanoparticles co-loaded with ICG and Nrf2-siRNA were prepared and then encapsulated within the vesicles of cancer cell membrane (CCM) specifically derived from homologous OTSCC, thus obtained biomimetic nanoparticles named as M@PPI-siRNA. Bothin vitroandin vivo, M@PPI-siRNA nanoparticles exhibited strong OTSCC-targeting ability due to tumor-homing effect of homologous CCM. Upon laser irradiation at 808 nm, M@PPI-siRNA nanoparticles significantly down-regulated the expressions of Nrf2 and its regulated genes, glutamate-cysteine ligase catalytic subunit (GCLC) and modifier subunit (GCLM) that play important roles in ROS detoxification, and subsequently indirectly enhanced PDT anticancer effects by maintaining the accumulation of intracellular ROS. Through cooperation of PTT and Nrf2-siRNA amplified PDT, M@PPI-siRNA nanoparticles significantly inhibited the proliferation and induced the apoptosis of OTSCC cells, and also notably suppressed tumor growth and angiogenesis in OTSCC tumor-bearing mice. In summary, this study provides a promising OTSCC-targeted delivery system for both photosensitizer and gene, and also confirms that Nrf2-siRNA is an efficient synergist for amplifying PDT.