Self-Assembled and Self-Monitored Sorafenib/Indocyanine Green Nanodrug with Synergistic Antitumor Activity Mediated by Hyperthermia and Reactive Oxygen Species-Induced Apoptosis
Self-Assembled and Self-Monitored Sorafenib/Indocyanine Green Nanodrug with Synergistic Antitumor Activity Mediated by Hyperthermia and Reactive Oxygen Species-Induced Apoptosis
复制标题
自组装和自监测的索拉非尼/吲哚菁绿纳米药物具有热疗和活性氧诱导细胞凋亡介导的协同抗肿瘤活性
DOI：
10.1021/acsami.9b18086
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发表时间：
2019-11-27
影响因子：
9.5
通讯作者：
Jin, Haojie
中科院分区：
文献类型：
--
作者：
Wu, Haiqiu;Wang, Cun;Jin, Haojie
肝癌是世界范围内癌症发病率和死亡率的主要原因，特别是在中国。索拉非尼（SRF）是目前最常用的全身性药物，用于治疗晚期肝细胞癌（HCC），这是最常见的肝癌类型。然而，肝细胞癌患者的获益有限，并且会遭受SRF的严重副作用。因此，迫切需要新的方法来提高SRF的治疗效果，减少其副作用。在我们目前的研究中，我们开发了一种自成像和自递送的纳米药物与SRF和吲哚菁（ICG），以提高索拉非尼对肝癌的治疗效果。利用SRF和ICG之间的π-π堆积效应，设计了一步纳米沉淀法，通过自组装得到SRF/ICG纳米粒子（SINP）。使用Pluronic F127来屏蔽SINP以进一步改善在水性环境中的稳定性。采用肝癌细胞系Huh 7及其异种移植瘤模型，对SINP的稳定性、光热效应、细胞摄取、活性氧产生、细胞毒性、肿瘤成像、肿瘤靶向和杀伤效果进行了体内外评价。我们发现，我们设计的SINP在体外和体内均表现出单分散稳定性和有效的光热效应。SINP在近红外（NIR）激光照射下能迅速进入Huh 7细胞并产生大量活性氧（ROS），从而产生较强的细胞毒性。SINP具有明显的稳定性和血液半衰期，并可通过增强的渗透性和滞留（EPR）效应特异性靶向肿瘤。此外，SINP在体内皮下和原位HCC植入模型中均显示出改善的细胞毒性。总体而言，这种合理设计的索拉非尼递送系统具有非常高的载量（33%），在体外具有显著提高的抗肿瘤效率，并且可以完全消除皮下肿瘤而在体内没有任何再生长。总之，我们的自成像和自递送纳米药物可以提高SRF的疗效，并可能成为HCC患者的潜在治疗方法。
Liver cancer is a leading cause of cancer morbidity and mortality worldwide, especially in China. Sorafenib (SRF) is currently the most commonly used systemic agent against advanced hepatocellular carcinoma (HCC), which is the most common type of liver cancer. However, HCC patients have only limited benefit and suffer a serious side effect from SRF. Therefore, new approaches are urgently needed to improve the therapeutic effectiveness of SRF and reduce its side effect. In our current study, we developed a self-imaging and self-delivered nanodrug with SRF and indocyanine (ICG) to improve the therapeutic effect of sorafenib against HCC. With the pi-pi stacking effect between SRF and ICG, a one-step nanoprecipitation method was designed to obtain the SRF/ICG nanoparticles (SINP) via self-assembly. Pluronic F127 was used to shield the SINP to further improve the stability in an aqueous environment. The stability, photothermal effect, cell uptake, ROS production, cytotoxicity, tumor imaging, and tumor-targeting and tumor-killing efficacy of the SINP were evaluated in vitro and in vivo by using an HCC cell line Huh7 and its xenograft tumor model. We found that our designed SINP showed monodisperse stability and efficient photothermal effect both in vitro and in vivo. SINP could rapidly enter Huh7 cells and achieve potent cytotoxicity under near-infrared (NIR) laser irradiation partly by producing a great amount of reactive oxygen species (ROS). SINP had significantly improved stability and blood half-life, and could specifically target tumor via the enhanced permeability and retention (EPR) effect in vivo. In addition, SINP showed improved cytotoxicity in both subcutaneous and orthotopic HCC implantation models in vivo. Overall, this rationally designed sorafenib delivery system with a very high loading capacity (33%) has considerably improved antitumor efficiency in vitro and could completely eliminate subcutaneous tumors without any regrowth in vivo. In conclusion, our self-imaging and self-delivered nanodrug could improve the efficacy of SRF and might be a potential therapy for HCC patients.