Theranostic Nanodots with Aggregation-Induced Emission Characteristic for Targeted and Image-Guided Photodynamic Therapy of Hepatocellular Carcinoma
Theranostic Nanodots with Aggregation-Induced Emission Characteristic for Targeted and Image-Guided Photodynamic Therapy of Hepatocellular Carcinoma
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具有聚集诱导发射特性的治疗诊断纳米点用于肝细胞癌的靶向和图像引导光动力治疗
DOI：
10.7150/thno.29101
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Li, Min
中科院分区：
文献类型：
--
作者：
Gao, Yang;Zheng, Qi Chang;Li, Min
光敏剂（PS）是光动力疗法（PDT）的核心要素。使用常见的纳米粒子 (NP) 进行 PDT 通常会因不良的聚集引起的猝灭 (ACQ) 效应而变得不太有效，导致荧光猝灭和活性氧 (ROS) 生成减少，从而降低成像质量和 PDT 功效。为了克服ACQ效应并提高PDT的整体疗效，本文基于红色发射聚集诱导发射（AIE）PS设计并合成了用于图像引导PDT的整合素α（nu）β（3）靶向有机纳米点。方法：通过纳米沉淀方法制备TPETS纳米点，并通过点击反应与硫醇化cRGD（cRGD-SH）进一步缀合，得到靶向TPETS纳米点（T-TPETS 纳米点）。对纳米点的封装效率、共轭率、粒径、吸收和发射光谱以及 ROS 产生进行了表征。在体外和体内评估了 T-TPETS 纳米点的靶向荧光成像和抗肿瘤功效。探讨了T-TPETS纳米点介导的PDT诱导细胞凋亡的机制。采用细胞毒性试验、溶血试验、血液生化试验和组织学染色等方法对纳米点的生物相容性和毒性进行了检测。结果：所得纳米点在聚集状态下显示出明亮的红色荧光和高效的O-1(2)生成。体外和体内实验均表明，纳米点表现出优异的肿瘤靶向成像性能，有助于在肝细胞癌模型中进行图像引导的 PDT 肿瘤消融。详细分析表明，纳米点介导的 PDT 能够诱导时间和浓度依赖性细胞死亡。在高 PDT 强度下使用 PDT 会导致直接细胞坏死，而在低 PDT 强度下则通过线粒体介导的途径实现细胞凋亡。结论：我们的结果表明，精心设计的 AIE 纳米点在图像引导 PDT 应用中具有广阔的前景。
Photosensitizer (PS) serves as the central element of photodynamic therapy (PDT). The use of common nanoparticles (NPs) for PDT has typically been rendered less effective by the undesirable aggregation-caused quenching (ACQ) effect, resulting in quenched fluorescence and reduced reactive oxygen species (ROS) generation that diminish the imaging quality and PDT efficacy. To overcome the ACQ effect and to enhance the overall efficacy of PDT, herein, integrin alpha(nu)beta(3)-targeted organic nanodots for image-guided PDT were designed and synthesized based on a red emissive aggregation-induced emission (AIE) PS.Methods: The TPETS nanodots were prepared by nano-precipitation method and further conjugated with thiolated cRGD (cRGD-SH) through a click reaction to yield the targeted TPETS nanodots (T-TPETS nanodots). Nanodots were characterized for encapsulation efficiency, conjugation rate, particle size, absorption and emission spectra and ROS production. The targeted fluorescence imaging and antitumor efficacy of T-TPETS nanodot were evaluated both in vitro and in vivo. The mechanism of cell apoptosis induced by T-TPETS nanodot mediated-PDT was explored. The biocompatibility and toxicity of the nanodots was examined using cytotoxicity test, hemolysis assay, blood biochemistry test and histological staining.Results: The obtained nanodots show bright red fluorescence and highly effective O-1(2) generation in aggregate state. Both in vitro and in vivo experiments demonstrate that the nanodots exhibit excellent tumor-targeted imaging performance, which facilitates image-guided PDT for tumor ablation in a hepatocellular carcinoma model. Detailed analysis reveals that the nanodot-mediated PDT is able to induce time- and concentration-dependent cell death. The use of PDT at a high PDT intensity leads to direct cell necrosis, while cell apoptosis via the mitochondria-mediated pathway is achieved under low PDT intensity.Conclusion: Our results suggest that well-designed AIE nanodots are promising for image-guided PDT applications.