Laboratory of Biomedical Engineering for Cancer, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan.
Biomedical Engineering Cancer Research Center, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan.
Cancer Sci. 2023 Jan;114(1):227-235. doi: 10.1111/cas.15562. Epub 2022 Oct 18.
Chemotherapy using a lymphatic drug delivery system (LDDS) targeting lymph nodes (LNs) in the early stage of metastasis has a superior antitumor effect to systemic chemotherapy. An LDDS produces a higher drug retention rate and tissue selectivity in LNs. To expand the therapeutic coverage of LDDS from local treatment of metastatic LNs to prevention of distant metastases, the combination of treatment with therapies that enhance systemic tumor immune effects is an important therapeutic strategy. Recently, total body irradiation (TBI) has been shown to activate immune responses and alter the tumor microenvironment. Here we show that combination therapy with TBI and LDDS improves the antitumor effect of metastatic LNs and lung metastasis. Tumor cells were inoculated into the subiliac LN (SiLN) to induce metastasis into the proper axillary LN (PALN) and lung in a mouse model. TBI was carried out on day 4 after inoculation using a gamma irradiator. Lymphatic drug delivery into the accessory axillary LN was used to treat PALN. In vivo bioluminescence imaging, high-frequency ultrasound, and histology showed that combination therapy using TBI (total dose 1.0 Gy once) and the LDDS suppressed tumor growth in LNs and lung metastases and was more effective than using LDDS or TBI alone. Quantitative RT-PCR of spleens after combination therapy revealed increased expression of CD4, CD8, and IL-12b, indicating an activated immune response. The results show that combination therapy with TBI and LDDS is a method to improve the efficacy of LN metastases and distant metastases therapy and is a promising novel approach to treat cancer patients.
利用针对转移早期淋巴结（LN）的淋巴药物递送系统（LDDS）进行化疗，其抗肿瘤效果优于全身化疗。LDDS 可使 LN 中药物保持更高的保留率和组织选择性。为了将 LDDS 的治疗范围从转移性 LN 的局部治疗扩展到预防远处转移，联合使用增强全身肿瘤免疫效应的治疗方法是一种重要的治疗策略。最近，全身照射（TBI）已被证明可激活免疫反应并改变肿瘤微环境。在这里，我们表明 TBI 和 LDDS 联合治疗可改善转移性 LN 和肺转移的抗肿瘤效果。在小鼠模型中，通过将肿瘤细胞接种到髂下淋巴结（SiLN）中来诱导转移到适当的腋窝淋巴结（PALN）和肺部。在接种后第 4 天使用伽马辐照仪进行 TBI。将淋巴药物递送至辅助腋窝淋巴结，以治疗 PALN。体内生物发光成像、高频超声和组织学显示，与单独使用 LDDS 或 TBI 相比，使用 TBI（总剂量 1.0Gy 一次）和 LDDS 的联合治疗可抑制淋巴结和肺转移中的肿瘤生长，效果更好。联合治疗后脾脏的定量 RT-PCR 显示 CD4、CD8 和 IL-12b 的表达增加，表明免疫反应被激活。结果表明，TBI 和 LDDS 的联合治疗是一种提高 LN 转移和远处转移治疗效果的方法，是治疗癌症患者的一种很有前途的新方法。
