Near Infrared Photoimmunotherapy Targeting EGFR Positive Triple Negative Breast Cancer: Optimizing the Conjugate-Light Regimen.
Near Infrared Photoimmunotherapy Targeting EGFR Positive Triple Negative Breast Cancer: Optimizing the Conjugate-Light Regimen.
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DOI：
10.1371/journal.pone.0136829
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kobayashi H
中科院分区：
文献类型：
--
作者：
Nagaya T;Sato K;Harada T;Nakamura Y;Choyke PL;Kobayashi H
三阴性乳腺癌（TNBC）被认为是最具侵袭性的乳腺癌亚型之一。近红外光免疫疗法 (NIR-PIT) 是一种癌症治疗方法，采用抗体-光敏剂缀合物 (APC)，然后暴露近红外光以激活对目标癌细胞的选择性细胞毒性，并可能应用于 TNBC。为了最大限度地减少 APC 剂量，同时最大限度地提高治疗效果，需要优化 APC 和 NIR 光的剂量。在本研究中，我们研究了西妥昔单抗 (cet)-IR700 NIR-PIT 对两种乳腺癌模型 MDAMB231（TNBC，EGFR 中度）和 MDAMB468（TNBC，EGFR 高）细胞系的体外和体内疗效，并展示了一种优化 APC 和 NIR 光剂量的方法。在验证体外细胞特异性细胞毒性后，使用源自 TNBC 肿瘤的细胞系在小鼠模型中研究了 NIR-PIT 治疗效果。将荷瘤小鼠分为4组进行以下治疗：（1）不治疗（对照）； (2) 300 μg cet-IR700 静脉注射（仅限 APC 静脉注射）； (3) 仅 NIR 光照射，第 1 天以 50 J/cm2 照射 NIR 光，第 2 天以 100 J/cm2 照射 NIR 光（仅 NIR 光）； (4) 静脉注射 300 μg cet-IR700，注射后第 1 天以 50 J/cm2 照射 NIR 光，注射后第 2 天以 100 J/cm2 照射 NIR 光（单次 NIR-PIT）。为了比较固定剂量 APC 的不同治疗方案，我们添加了以下治疗 (5) 静脉注射 100 μg cet-IR700、第 1 天以 50 J/cm2 照射 NIR 光以及静脉注射 50 μg cet-IR700。 NIR-PIT 后立即进行，然后在第 2 天以 100 J/cm2 照射 NIR 光，每周进行两次（“两次分割”NIR-PIT）和 (6) 静脉注射 100 μg cet-IR700，在第 1 天以 50 J/cm2 照射 NIR 光，在第 2 天以 100 J/cm2 照射 NIR 光，每周进行 3 次（“三分割”）近红外-坑）。在体外，MDAMB468 细胞的特异性结合和 NIR-PIT 效应均大于 MDAMB231 细胞。体内 MDAMB468 肿瘤中 cet-IR700 的肿瘤积累显着高于 MDAMB231 肿瘤（p < 0.05）。 NIR-PIT 治疗组中 MDAMB231 荷瘤小鼠的肿瘤生长和存活率显着降低 (p < 0.05)。在携带 MDAMB468 的小鼠中，与对照组相比，所有治疗方案中 NIR-PIT 治疗组的肿瘤生长和存活率均显着改善（单次 NIR-PIT；p < 0.05，“两次分裂”NIR-PIT；p < 0.01，“三次分裂”NIR-PIT；p < 0.001）。无论 EGFR 的表达如何，NIR-PIT 对 TNBC 都是有效的，然而，在体外，EGFR 表达较高的肿瘤显示出更大的细胞杀伤力。在所有治疗方案中，NIR-PIT 都能抑制肿瘤生长，从而显着延长生存期，通过分割 APC 剂量和使用重复光照射进一步改善生存期。
Triple-negative breast cancer (TNBC) is considered one of the most aggressive subtypes of breast cancer. Near infrared photoimmunotherapy (NIR-PIT) is a cancer treatment that employs an antibody-photosensitizer conjugate (APC) followed by exposure of NIR light for activating selective cytotoxicity on targeted cancer cells and may have application to TNBC. In order to minimize the dose of APC while maximizing the therapeutic effects, dosing of the APC and NIR light need to be optimized. In this study, we investigate in vitro and in vivo efficacy of cetuximab (cet)-IR700 NIR-PIT on two breast cancer models MDAMB231 (TNBC, EGFR moderate) and MDAMB468 (TNBC, EGFR high) cell lines, and demonstrate a method to optimize the dosing APC and NIR light. After validating in vitro cell-specific cytotoxicity, NIR-PIT therapeutic effects were investigated in mouse models using cell lines derived from TNBC tumors. Tumor-bearing mice were separated into 4 groups for the following treatments: (1) no treatment (control); (2) 300 μg of cet-IR700 i.v., (APC i.v. only); (3) NIR light exposure only, NIR light was administered at 50 J/cm2 on day 1 and 100 J/cm2 on day 2 (NIR light only); (4) 300 μg of cet-IR700 i.v., NIR light was administered at 50 J/cm2 on day 1 after injection and 100 J/cm2 of light on day 2 after injection (one shot NIR-PIT). To compare different treatment regimens with a fixed dose of APC, we added the following treatments (5) 100 μg of cet-IR700 i.v., NIR light administered at 50 J/cm2 on day 1 and 50 μg of cet-IR700 i.v. immediately after NIR-PIT, then NIR light was administered at 100 J/cm2 on day 2, which were performed two times every week (“two split” NIR-PIT) and (6) 100 μg of cet-IR700 i.v., NIR light was administered at 50 J/cm2 on day 1 and 100 J/cm2 on day 2, which were performed three times per week (“three split” NIR-PIT). Both specific binding and NIR-PIT effects were greater with MDAMB468 than MDAMB231 cells in vitro. Tumor accumulation of cet-IR700 in MDAMB468 tumors was significantly higher (p < 0.05) than in MDAMB231 tumors in vivo. Tumor growth and survival of MDAMB231 tumor bearing mice was significantly lower in the NIR-PIT treatment group (p < 0.05). In MDAMB468 bearing mice, tumor growth and survival was significantly improved in the NIR-PIT treatment groups in all treatment regimens (one shot NIR-PIT; p < 0.05, “two split” NIR-PIT; p < 0.01, “three split” NIR-PIT; p < 0.001) compared with control groups. NIR-PIT for TNBC was effective regardless of expression of EGFR, however, greater cell killing was shown with higher EGFR expression tumor in vitro. In all treatment regimens, NIR-PIT suppressed tumor growth, resulting in significantly prolonged survival that further improved by splitting the APC dose and using repeated light exposures.