Sugyo Aya, Tsuji Atsushi B, Sudo Hitomi, Takano Kanako, Kusakabe Moriaki, Higashi Tatsuya
Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institute for Quantum and Radiological Science and Technology (QST-NIRS), Chiba 263-8555, Japan.
Graduate School of Agricultural and Life Science, The University of Tokyo, Tokyo 113-8654, Japan.
Cancers (Basel). 2020 Dec 5;12(12):3652. doi: 10.3390/cancers12123652.
In treatment-refractory cancers, tumor tissues damaged by therapy initiate the repair response; therefore, tumor tissues must be exposed to an additional burden before successful repair. We hypothesized that an agent recognizing a molecule that responds to anticancer treatment-induced tissue injury could deliver an additional antitumor agent including a radionuclide to damaged cancer tissues during repair. We selected the extracellular matrix glycoprotein tenascin-C (TNC) as such a molecule, and three antibodies recognizing human and murine TNC were employed to evaluate X-irradiation-induced changes in TNC uptake by subcutaneous tumors. TNC expression was assessed by immunohistochemical staining of BxPC-3 tumors treated with or without X-irradiation (30 Gy) for 7 days. Antibodies against TNC (3-6, 12-2-7, TDEAR) and a control antibody were radiolabeled with In and injected into nude mice having BxPC-3 tumors 7 days after X-irradiation, and temporal uptake was monitored for an additional 4 days by biodistribution and single-photon emission computed tomography with computed tomography (SPECT/CT) studies. Intratumoral distribution was analyzed by autoradiography. The immunohistochemical signal for TNC expression was faint in nontreated tumors but increased and expanded with time until day 7 after X-irradiation. Biodistribution studies revealed increased tumor uptake of all three In-labeled antibodies and the control antibody. However, a statistically significant increase in uptake was evident only for In-labeled 3-6 (35% injected dose (ID)/g for 30 Gy vs. 15% ID/g for 0 Gy at day 1, < 0.01), whereas limited changes in In-labeled TDEAR2, 12-2-27, and control antibody were observed (several % ID/g for 0 and 30 Gy). Serial SPECT/CT imaging with In-labeled 3-6 or control antibody provided consistent results. Autoradiography revealed noticeably stronger signals in irradiated tumors injected with In-labeled 3-6 compared with each of the nonirradiated tumors and the control antibody. The signals were observed in TNC-expressing stroma. Markedly increased uptake of In-labeled 3-6 in irradiated tumors supports our concept that an agent, such as an antibody, that recognizes a molecule involved in tissue injury repair, such as TNC, could enhance drug delivery to tumor tissues that have undergone therapy. The combination of antibody 3-6 coupled to a tumoricidal drug and conventional therapy has the potential to achieve better outcomes for patients with refractory cancer.
在难治性癌症中，受治疗损伤的肿瘤组织会启动修复反应；因此，在成功修复之前，肿瘤组织必须承受额外的负担。我们假设，一种能够识别对抗癌治疗诱导的组织损伤产生反应的分子的试剂，可以在修复过程中将包括放射性核素在内的额外抗肿瘤试剂递送至受损的癌组织。我们选择细胞外基质糖蛋白腱生蛋白-C（TNC）作为这样一种分子，并使用三种识别人和小鼠TNC的抗体来评估X射线照射引起的皮下肿瘤对TNC摄取的变化。通过对接受或未接受X射线照射（30 Gy）7天的BxPC-3肿瘤进行免疫组织化学染色来评估TNC的表达。将抗TNC抗体（3-6、12-2-7、TDEAR）和一种对照抗体用铟进行放射性标记，并在X射线照射7天后注射到患有BxPC-3肿瘤的裸鼠体内，通过生物分布和单光子发射计算机断层扫描与计算机断层扫描（SPECT/CT）研究，在接下来的4天内监测其随时间的摄取情况。通过放射自显影分析肿瘤内分布。在未处理的肿瘤中，TNC表达的免疫组织化学信号微弱，但随着时间推移而增加并扩展，直至X射线照射后第7天。生物分布研究显示，所有三种铟标记的抗体和对照抗体在肿瘤中的摄取均增加。然而，仅铟标记的3-6抗体的摄取有统计学意义的显著增加（第1天，30 Gy时为35%注射剂量（ID）/g，0 Gy时为15% ID/g，P<0.01），而铟标记的TDEAR2、12-2-27抗体和对照抗体的变化有限（0 Gy和30 Gy时均为百分之几ID/g）。用铟标记的3-6抗体或对照抗体进行的系列SPECT/CT成像提供了一致的结果。放射自显影显示，与未照射的肿瘤和对照抗体相比，注射了铟标记的3-6抗体的照射肿瘤中的信号明显更强。这些信号出现在表达TNC的基质中。照射肿瘤中铟标记的3-6抗体摄取显著增加，支持了我们的概念，即一种能够识别参与组织损伤修复的分子（如TNC）的试剂（如抗体），可以增强向接受过治疗的肿瘤组织的药物递送。将与杀肿瘤药物偶联的3-6抗体与传统疗法相结合，有可能为难治性癌症患者带来更好的治疗效果。
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