Our aim was to evaluate the effectiveness and normal tissue toxicity of radioimmunotherapy (RIT) of s.c. PANC-1 human pancreatic cancer (PnCa) xenografts in NRG mice using anti-EGFR panitumumab linked to metal-chelating polymers (MCPs) that present 13 DOTA chelators to complex the β-emitter, ¹⁷⁷Lu. The clonogenic survival (CS) of PANC-1 cells treated in vitro with panitumumab-MCP-¹⁷⁷Lu (0.3–1.2 MBq) and DNA double-strand breaks (DSBs) in the nucleus of these cells were measured by confocal immunofluorescence microscopy for γ-H2AX. Subcellular distribution of radioactivity for panitumumab-MCP-¹⁷⁷Lu was measured, and absorbed doses to the cell nucleus were calculated. Normal tissue toxicity was assessed in non tumor-bearing NRG mice by monitoring body weight, complete blood cell counts (CBC), serum alanine aminotransferase (ALT), and creatinine (Cr) after i.v. injection of 6 MBq (10 μg) of panitumumab-MCP-¹⁷⁷Lu. RIT was performed in NRG mice with s.c. PANC-1 tumors injected i.v. with 6 MBq (10 μg) of panitumumab-MCP-¹⁷⁷Lu. Control mice received nonspecific human IgG-MCP-¹⁷⁷Lu (6 MBq; 10 μg), unlabeled panitumumab (10 μg), or normal saline. The tumor growth index (TGI) was compared. Tumor and normal organ doses were estimated based on biodistribution studies. Panitumumab-MCP-¹⁷⁷Lu reduced the CS of PANC-1 cells in vitro by 7.7-fold at the highest amount tested (1.2 MBq). Unlabeled panitumumab had no effect on the CS of PANC-1 cells. γ-H2AX foci were increased by 3.8-fold by panitumumab-MCP-¹⁷⁷Lu. Panitumumab-MCP-¹⁷⁷Lu deposited 3.84 Gy in the nucleus of PANC-1 cells. Administration of panitumumab-MCP-¹⁷⁷Lu (6 MBq; 10 μg) to NRG mice caused no change in body weight, CBC, or ALT and only a slight increase in Cr compared to NRG mice treated with normal saline. Panitumumab-MCP-¹⁷⁷Lu strongly inhibited tumor growth in NRG mice (TGI = 2.3 ± 0.2) compared to normal saline-treated mice (TGI = 5.8 ± 0.5; P < 0.01). Unlabeled panitumumab had no effect on tumor growth (TGI = 6.0 ± 1.6; P > 0.05). The absorbed dose of PANC-1 tumors was 12.3 Gy. The highest normal organ doses were absorbed by the pancreas, liver, spleen, and kidneys. We conclude that EGFR-targeted RIT with panitumumab-MCP-¹⁷⁷Lu was able to overcome resistance to panitumumab in KRAS mutant PANC-1 tumors in NRG mice and may be a promising approach to treatment of PnCa in humans.

中文翻译：

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金属螯合聚合物与¹⁷⁷ Lu复合修饰的帕尼单抗对NRG小鼠PANC-1人胰腺癌异种移植物的放射免疫治疗。

我们的目的是使用与13种DOTA螯合剂结合的金属螯合聚合物（MCP）的抗EGFR panitumumab评估sc PANC-1人胰腺癌（PnCa）异种移植物在NRG小鼠中的放射免疫疗法（RIT）的有效性和正常组织毒性复配¹⁷⁷ Lu的β-发射极 通过共聚焦免疫荧光显微镜检测用panitumumab-MCP- ¹⁷⁷ Lu（0.3–1.2 MBq）体外处理的PANC-1细胞的克隆形成存活（CS）和这些细胞核中的DNA双链断裂（DSB）。 -H2AX。帕尼单抗-MCP- ¹⁷⁷放射活性的亚细胞分布测量Lu，并计算对细胞核的吸收剂量。通过监测体重，全血细胞计数（CBC），血清丙氨酸氨基转移酶（ALT）和肌酐（Cr）的静脉注射6 MBq（10μg）panitumumab- MCP- ¹⁷⁷路。在NRG小鼠中进行了RIT治疗，该小鼠的sc PANC-1肿瘤经静脉注射了6 MBq（10μg）的panitumumab-MCP- ¹⁷⁷ Lu。对照小鼠接受非特异性人IgG-MCP- ¹⁷⁷ Lu（6 MBq； 10μg），未标记的帕尼单抗（10μg）或生理盐水。比较了肿瘤生长指数（TGI）。根据生物分布研究估算了肿瘤和正常器官的剂量。帕尼单抗-MCP- ¹⁷⁷Lu在测试的最高量（1.2 MBq）下将PANC-1细胞的CS降低了7.7倍。未标记的帕尼单抗对PANC-1细胞的CS没有影响。帕尼单抗-MCP- ¹⁷⁷ Lu使γ-H2AX病灶增加了3.8倍。Panitumumab-MCP- ¹⁷⁷ Lu在PANC-1细胞核中沉积了3.84 Gy。与用生理盐水处理的NRG小鼠相比，向NRG小鼠施用panitumumab-MCP- ¹⁷⁷ Lu（6 MBq; 10μg）不会引起体重，CBC或ALT的变化，而Cr只会稍微增加。与生理盐水处理的小鼠（TGI = 5.8±0.5；P <0.01）相比，帕尼单抗-MCP- ¹⁷⁷ Lu在NRG小鼠（TGI = 2.3±0.2）中强烈抑制肿瘤生长。未标记的帕尼单抗对肿瘤生长没有影响（TGI = 6.0±1.6；P > 0.05）。PANC-1肿瘤的吸收剂量为12.3 Gy。正常器官最高剂量被胰腺，肝脏，脾脏和肾脏吸收。我们得出的结论是，以panitumumab-MCP- ¹⁷⁷ Lu靶向EGFR的RIT能够克服NRG小鼠KRAS突变PANC-1肿瘤对panitumumab的耐药性，可能是治疗人类PnCa的有前途的方法。