Sato Kazuhide, Nagaya Tadanobu, Choyke Peter L, Kobayashi Hisataka
Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-1088.
Theranostics. 2015 Mar 19;5(7):698-709. doi: 10.7150/thno.11559. eCollection 2015.
Pleural metastases are common in patients with advanced thoracic cancers and are a cause of considerable morbidity and mortality yet is difficult to treat. Near Infrared Photoimmunotherapy (NIR-PIT) is a cancer treatment that combines the specificity of intravenously injected antibodies for targeting tumors with the toxicity induced by photosensitizers after exposure to NIR-light. Herein, we evaluate the efficacy of NIR-PIT in a mouse model of pleural disseminated non-small cell lung carcinoma (NSCLC). In vitro and in vivo experiments were conducted with a HER2, luciferase and GFP expressing NSCLC cell line (Calu3-luc-GFP). An antibody-photosensitizer conjugate (APC) consisting of trastuzumab and a phthalocyanine dye, IRDye-700DX, was synthesized. In vitro NIR-PIT cytotoxicity was assessed with dead staining, luciferase activity, and GFP fluorescence intensity. In vivo NIR-PIT was performed in mice with tumors implanted intrathoracic cavity or in the flank, and assessed by tumor volume and/or bioluminescence and fluorescence thoracoscopy. In vitro NIR-PIT-induced cytotoxicity was light dose dependent. In vivo NIR-PIT led significant reductions in both tumor volume (p = 0.002 vs. APC) and luciferase activity (p = 0.0004 vs. APC) in a flank model, and prolonged survival (p < 0.0001). Bioluminescence indicated that NIR-PIT lead to significant reduction in pleural dissemination (1 day after PIT; p = 0.0180). Fluorescence thoracoscopy confirmed the NIR-PIT effect on disseminated pleural disease. In conclusion, NIR-PIT has the ability to effectively treat pleural metastases caused by NSCLC in mice. Thus, NIR-PIT is a promising therapy for pleural disseminated tumors.
胸膜转移在晚期胸段癌症患者中很常见，是导致相当高发病率和死亡率的原因，且难以治疗。近红外光免疫疗法（NIR-PIT）是一种癌症治疗方法，它将静脉注射抗体靶向肿瘤的特异性与近红外光照射后光敏剂诱导的毒性相结合。在此，我们评估了NIR-PIT在胸膜播散性非小细胞肺癌（NSCLC）小鼠模型中的疗效。使用表达HER2、荧光素酶和绿色荧光蛋白的NSCLC细胞系（Calu3-luc-GFP）进行了体外和体内实验。合成了一种由曲妥珠单抗和酞菁染料IRDye-700DX组成的抗体-光敏剂偶联物（APC）。通过死细胞染色、荧光素酶活性和绿色荧光蛋白荧光强度评估体外NIR-PIT的细胞毒性。在胸腔内或侧腹植入肿瘤的小鼠中进行体内NIR-PIT，并通过肿瘤体积和/或生物发光以及荧光胸腔镜进行评估。体外NIR-PIT诱导的细胞毒性呈光剂量依赖性。在侧腹模型中，体内NIR-PIT导致肿瘤体积（与APC相比，p = 0.002）和荧光素酶活性（与APC相比，p = 0.0004）均显著降低，并延长了生存期（p < 0.0001）。生物发光表明NIR-PIT导致胸膜播散显著减少（PIT后1天；p = 0.0180）。荧光胸腔镜证实了NIR-PIT对播散性胸膜疾病的作用。总之，NIR-PIT有能力有效治疗小鼠中由NSCLC引起的胸膜转移。因此，NIR-PIT是一种有前景的胸膜播散性肿瘤治疗方法。
