In vivo imaging characterization and anticancer efficacy of a novel HER2 affibody and pemetrexed conjugate in lung cancer model
In vivo imaging characterization and anticancer efficacy of a novel HER2 affibody and pemetrexed conjugate in lung cancer model
复制标题
新型 HER2 亲和体和培美曲塞缀合物在肺癌模型中的体内成像表征和抗癌功效
DOI：
10.1016/j.nucmedbio.2018.11.004
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发表时间：
2019-01-01
影响因子：
3.1
通讯作者：
Wang, Jianfang
中科院分区：
文献类型：
--
作者：
Jiao, Honglei;Zhao, Xinming;Wang, Jianfang
简介：本研究合成了一种由HER2特异性亲和体Z(HER2:v2)和化疗药物培美曲塞组成的新制剂，以开发一种新的靶向药物。通过99m锝放射性标记，在细胞水平和异种移植模型中评估其生物学特性和抗癌功效。方法：合成Z(HER2:v2)-培美曲塞缀合物后，以其C端4个氨基酸(Gly-Gly-Gly-Cys)作为螯合部分对缀合物进行放射性标记。 [Tc-99m]Tc-Z(HER2)(:v)(2)-培美曲塞的放射化学产率通过即时薄层色谱法 (ITLC) 进行鉴定。在体外和体内研究了放射性标记缀合物的稳定性。在 A549 细胞（HER2 阳性）中进行了探针的体外结合亲和力和细胞内化研究。通过 A549 细胞和 H23 细胞（HER2 阴性）的体外摄取测定，以及 A549 和 H23 荷瘤小鼠的体内生物分布和 SPELLED 成像来评估肿瘤摄取。在细胞和异种移植模型中评估Z(HER2:v2)-培美曲塞缀合物的抗肿瘤功效。结果：成功合成Z(HER2:v2)-培美曲塞并与锝-99 m缀合，放化收率为97.0+/-0.3%。 [ Tc-99m]Tc-Z(HER2:v2)-培美曲塞在生理盐水和人血清中稳定性良好。该放射性标记试剂在体外表现出优异的HER2结合特异性和亲和力，并逐渐内化到细胞中。生物分布研究显示，A549 异种移植物中有明显的肿瘤摄取（每克注射剂量百分比，注射后 4 小时为 2.6 +/- 1.0%ID/g），而 HER2 阴性 H23 肿瘤的摄取要低得多（注射后 4 小时为 0.2 +/- 0.1%ID/g，P < 0.01）。 SPEC 成像在 A549 异种移植物中显示出强度，该强度可以被过量的 Z(HER2:v2) 培美曲塞阻断。 Z(HER2:v2)-培美曲塞治疗显着损害肿瘤生长（P < 0.05），且体重减轻少于培美曲塞。结论：[Tc-99m]Tc-Z(HER2:v2)-培美曲塞显示出理想的特性和 HER2 特异性。 Z(HER2:v2)培美曲塞缀合物可以抑制HER2阳性肺腺癌的肿瘤生长，并有可能成为肺癌靶向药物。知识的进步和对患者护理的影响：本文描述的化合物具有良好的抗癌功效，具有良好的抗癌功效，并为进一步的肿瘤治疗提供了新的靶向策略的潜力。 (C) 2018 Elsevier Inc. 保留所有权利。
Introduction: In this study, a new agent consisting of HER2-specific affibody Z(HER2:v2) and chemotherapy drug pemetrexed was synthesized to develop a new targeted drug. Its biological characteristics and anticancer efficacy were assessed in cells level and xenografts models by radiolabeling with technetium-99m.Methods: After the Z(HER2:v2)-pemetrexed conjugate was synthesized, radiolabeling of the conjugate was performed using its C-terminal 4 amino acids (Gly-Gly-Gly-Cys) as the chelating moiety. The radiochemical yield of the [Tc-99m]Tc-Z(HER2)(:v)(2) -pemetrexed was identified by instant thin-layer chromatography (ITLC). Stability of the radiolabeled conjugate was investigated both in vitro and in vivo. In vitro binding affinity and cell internalization study of the probe were performed in A549 cells (HER2-positive). Tumor uptake was evaluated by in vitro uptake assay in A549 cells and H23 cells (HER2-negative), and by in vivo biodistribution and SPELT imaging in A549 and H23 tumor-bearing mice. The antitumor efficacy of the Z(HER2:v2) -pemetrexed conjugate was evaluated in cells and xenograft models.Results: The Z(HER2:v2) -pemetrexed was successfully synthesized and conjugated with technetium-99 m, and acquired the radiochemical yield of 97.0 +/- 0.3%. The stability of [ Tc-99m]Tc-Z(HER2:v2)-pemetrexed was good in both physiological saline and human serum. The radiolabeled agent displayed excellent HER2-binding specificity and affinity in vitro, and was gradually internalized into the cells. Biodistribution study revealed obvious tumor uptake in A549 xenografts (percentage injected dose per gram, 2.6 +/- 1.0%ID/g at 4 h postinjection), while the uptake in HER2-negative H23 tumors was much lower (0.2 +/- 0.1%ID/g at 4 h postinjection, P < 0.01). SPEC' imaging exhibited an intensity in the A549 xenograft which could be blocked by excess Z(HER2:v2) pemetrexed. Treatment with Z(HER2:v2) -pemetrexed significantly impaired the tumor growth (P < 0.05), with less weight loss than pemetrexed.Conclusion: [Tc-99m]Tc-Z(HER2:v2) -pemetrexed showed desirable property and HER2-specificity. The Z(HER2:v2)pemetrexed conjugate could inhibit tumor growth of HER2-positive lung adenocarcinoma and may have the potential to become a targeted drug for lung cancer.Advances in knowledge and implications for patient care: The compound described herein performs HER2-targeting with favorable anticancer efficacy and offers the potential of novel targeting strategies for further tumor therapy. (C) 2018 Elsevier Inc. All rights reserved.