Harada Satoshi, Sato Takahiro, Yoshioka Kunihiro
Department of Radiology, School of Medicine, Iwate Medical University, 1-1 1-Chome Idai-Dori, Yahaba, Shiwa, 028-3694, Japan.
National Institutes for Quantum Science and Technology, Takasaki Ion Accelerators for Advanced Radiation Application, Foundational Quantum Technology Research Directorate, Takasaki Institute for Advanced Quantum Science, 1233 Watanuki, Takasaki, Japan.
Jpn J Radiol. 2025 Apr 17. doi: 10.1007/s11604-025-01782-w.
A theranostic nanomedicine for CD3 bispecific antibodies targeting glycoprotein-100 (GP-100) was tested in vivo using two radiation sessions. CT-imageable nanoparticles composed of hyaluronate-alginate and designed to release their contents upon radiation exposure were evaluated in a mouse model of B16-melanoma model in the left hind leg with pulmonary metastases.
In session 1, IFN-γ was encapsulated during the Fe polymerization of hyaluronate-alginate nanoparticles. Nine hours after the intravenous injection of 1 × 10 IFN-γ nanoparticles, enough to observe dose escalation of either 10 or 20 Gy was administered using 140 keV-X-ray to the primary and metastatic tumors. In session 2, tebentafusp was encapsulated using the same method as in session 1. Seventy-two hours after the intravenous injection of 1 × 10 tebentafusp-loaded nanoparticles, radiation was administered under conditions identical to those in session 1.
In session 1, IFN-γ-loaded nanoparticles selectively accumulated in the primary tumor and pulmonary metastasis by passing through the coarse endothelium of tumor vasculature, which could be visualized using CT. IFN-γ nanoparticles continuously released IFN-γ, facilitating the formation of the HLA-A02:01-GP100-complex. In session 2, the tebentafusp-loaded nanoparticles continuously released tebentafusp, leading to the formation of an immunological synapse consisting of HLA-A02:01-GP100, tebentafusp, and CD3 on T cells. CD3 T cells release perforin and granzymes, resulting in the cytolysis of the primary tumor and pulmonary metastasis. This effect was synergistic with that of radiation, resulting in Enhancement Factor (EF) more than 1.
Theranostic nanomedicine demonstrated potential as a dual therapeutic and diagnostic strategy for targeting tumors and metastases, with synergistic effects observed when combined with radiation.
使用两个放射疗程在体内测试一种用于靶向糖蛋白-100（GP-100）的CD3双特异性抗体的治疗诊断纳米药物。在左后肢有肺转移的B16黑色素瘤模型小鼠中，评估了由透明质酸-藻酸盐组成且设计为在辐射暴露时释放其内容物的可进行CT成像的纳米颗粒。
在第一个疗程中，在透明质酸-藻酸盐纳米颗粒的铁聚合过程中包封干扰素-γ（IFN-γ）。静脉注射1×10个IFN-γ纳米颗粒9小时后，使用140keV-X射线对原发性肿瘤和转移性肿瘤给予足以观察到10或20Gy剂量递增的辐射。在第二个疗程中，使用与第一个疗程相同的方法包封替贝福单抗。静脉注射1×10个负载替贝福单抗的纳米颗粒72小时后，在与第一个疗程相同的条件下给予辐射。
在第一个疗程中，负载IFN-γ的纳米颗粒通过肿瘤脉管系统的粗大内皮选择性地积聚在原发性肿瘤和肺转移灶中，这可以通过CT可视化。IFN-γ纳米颗粒持续释放IFN-γ，促进HLA-A02:01-GP100复合物的形成。在第二个疗程中，负载替贝福单抗的纳米颗粒持续释放替贝福单抗，导致在T细胞上形成由HLA-A02:01-GP100、替贝福单抗和CD3组成的免疫突触。CD3 T细胞释放穿孔素和颗粒酶，导致原发性肿瘤和肺转移灶的细胞溶解。这种效应与辐射效应具有协同作用，导致增强因子（EF）大于1。
治疗诊断纳米药物显示出作为靶向肿瘤和转移灶的双重治疗和诊断策略的潜力，与辐射联合使用时观察到协同效应。
