Nucleus-targeting near-infrared nanoparticles based on TAT peptide-conjugated IR780 for photo-chemotherapy of breast cancer
Nucleus-targeting near-infrared nanoparticles based on TAT peptide-conjugated IR780 for photo-chemotherapy of breast cancer
复制标题
基于 TAT 肽缀合 IR780 的核靶向近红外纳米粒子用于乳腺癌光化疗
DOI：
10.1016/j.cej.2019.122458
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发表时间：
2020-01-15
影响因子：
15.1
通讯作者：
Wang, Yinsong
中科院分区：
文献类型：
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作者：
Wan, Guoyun;Cheng, Yuanyuan;Wang, Yinsong
乳腺癌是女性中最常见的恶性肿瘤。光疗法主要包括光热疗法（PTT）和光动力疗法（PDT），在乳腺癌治疗中具有空间选择性高、无创、耐药可忽略等优点。此外，最近的研究表明，核靶向PTT可以通过“燃烧”细胞核更直接、更有效地杀死癌细胞。在这项研究中，我们开发了一种核靶向纳米颗粒系统，用于联合PTT/PDT和化疗治疗乳腺癌。IR780是一种近红外（NIR）荧光染料，具有较强的PTT和PDT抗癌作用，首先通过氯原子与巯基的取代反应与TAT肽偶联，得到了具有明显水溶性和光学稳定性的共轭物TAT-IR780。接下来，化疗药物多柔比星（DOX）和TAT-IR780在水介质中自组装形成约100 nm的小尺寸TID纳米颗粒。无论在体内还是体外，与游离IR780相比，TID纳米颗粒都能显著提高PTT/PDT效率。通过TAT肽的介导，TID纳米颗粒显著改善了乳腺癌细胞中IR780的细胞内化，并将其主要递送到核周区域。在785 nm激光照射下，TID纳米颗粒迅速破坏乳腺癌细胞的遗传物质，并有效诱导乳腺癌细胞凋亡。在乳腺癌小鼠瘤内注射局部激光照射的TID纳米颗粒，实现了荧光和光热成像引导下的核靶向PTT/PDT与化疗的联合治疗，对乳腺肿瘤消融和复发具有显著的协同作用。总之，本研究为双重成像引导的乳腺癌光化学治疗提供了一个核靶向纳米平台。
Breast cancer is the most common malignant tumor in women. Phototherapy, mainly including photothermal therapy (PTT) and photodynamic therapy (PDT), shows many advantages such as high spatial selectivity, noninvasive nature, and negligible drug resistance for breast cancer treatment. Additionally, recent investigations have shown that nucleus-targeted PTT can kill cancer cells more directly and more efficiently by "burning" cell nuclei closely. In this study, we developed a nucleus-targeting nanoparticle system for combining PTT/PDT and chemotherapy to treat breast cancer. IR780, a near-infrared (NIR) fluorescence dye that has potent anticancer efficacy of PTT and PDT, was firstly conjugated with TAT peptide through substitution reaction between chlorine atom and sulfhydryl group, thus obtained a conjugate TAT-IR780 with notably enhanced water solubility and optical stability. Next, chemotherapeutic drug doxorubicin (DOX) and TAT-IR780 self-assembled in aqueous medium to form TID nanoparticles with a small size of approximately 100 nm. Both in vitro and in vivo, TID nanoparticles showed greatly enhanced PTT/PDT efficiencies as compared with free IR780. Through the mediation of TAT peptide, TID nanoparticles significantly improved the cellular internalization of IR780 in breast cancer cells and delivered it mostly to the perinuclear region. Upon laser irradiation at 785 nm, TID nanoparticles rapidly destroyed the genetic substances and potently induced the apoptosis of breast cancer cells. In the mice bearing breast cancer, intratumoral injection of TID nanoparticles with local laser irradiation realized fluorescence and photothermal imaging-guided combination treatment of nucleus-targeted PTT/PDT and chemotherapy, and achieved significant synergistic effects on breast tumor ablation and recurrence. In summary, this study provides a nucleus-targeting nanoplatform for dual imaging-guided photo-chemotherapy for breast cancer treatment.