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Synthesis of a metal-chelating polymer with NOTA pendants as a carrier for 64Cu, intended for radioimmunotherapy
European Polymer Journal ( IF 6 ) Pub Date : 2020-02-01 , DOI: 10.1016/j.eurpolymj.2020.109501
Hyungjun Cho , Peng Liu , Amanda J. Boyle , Raymond M. Reilly , Mitchell A. Winnik

Abstract As a positron emitter, 64Cu is useful for positron emission tomography. It can also generate Auger electrons that are useful for therapy. Many radioimmunoconjugates labelled with 64Cu involve covalent attachment of bifunctional chelators directly to the antibody (Ab) of interest. To increase its therapeutic potential, a metal-chelating polymer (MCP) with multiple chelators can be conjugated the Ab. In this way, one can incorporate multiple 64Cu ions per Ab. Here we describe the synthesis of a MCP designed for attachment to trastuzumab (tmab), an antibody (Ab) used to treat breast cancer patients with tumours that overexpress human epidermal growth factor receptor 2. We chose 1,4,7-triazacyclononane-N,N',N''-triacetic acid (NOTA) chelator to complex with 64Cu, and in our design, the polymer would carry multiple copies of the NOTA chelator as pendant groups. The Cu2+/NOTA complex has a net negative charge. We began by using RAFT polymerization to synthesize an end-functional poly(2-aminoethyl acrylamide) polymer, in which we could use the amino groups to attach the chelator and other substituents. In a previous study (Biomacromolecules. 13 (2012) 2831–2842), we found that MCP radioimmunoconjugates with a negative charge in the repeat unit led to high liver up-take in a mouse model. Thus, we chose to introduce ca. 50% methoxy-dodecaethylene glycol (mPEG12) pendant groups to confer “stealth”. As a control, we also synthesized a similar polymer with ca. 50% methoxyethyl pendants (EO1). NOTA chelators were attached to remaining pendant groups. We then end-capped the MCPs with succinic acid, radiolabeled the MCPs with 64Cu and injected the radiolabeled MCPs into healthy Balb/c mice via the tail vein. We observed that a large amount of the MCPs were retained in the kidneys. We discuss what properties of the MCPs may have contributed to its accumulation in the kidneys.

中文翻译:

合成金属螯合聚合物,带有 NOTA 悬垂物作为 64Cu 的载体,用于放射免疫治疗

摘要 作为一种正电子发射体,64Cu 可用于正电子发射断层扫描。它还可以产生对治疗有用的俄歇电子。许多用 64Cu 标记的放射免疫偶联物涉及双功能螯合剂与目标抗体 (Ab) 的直接共价连接。为了增加其治疗潜力,可以将具有多种螯合剂的金属螯合聚合物 (MCP) 与 Ab 结合。通过这种方式,每个 Ab 可以包含多个 64Cu 离子。在这里,我们描述了设计用于连接曲妥珠单抗 (tmab) 的 MCP 的合成,曲妥珠单抗 (tmab) 是一种抗体 (Ab),用于治疗患有过度​​表达人表皮生长因子受体 2 的肿瘤的乳腺癌患者。我们选择了 1,4,7-三氮杂环壬烷-N ,N',N''-三乙酸 (NOTA) 螯合剂与 64Cu 络合,在我们的设计中,聚合物将携带多个拷贝的 NOTA 螯合剂作为侧基。Cu2+/NOTA 复合物带有净负电荷。我们首先使用 RAFT 聚合来合成末端官能的聚(2-氨基乙基丙烯酰胺)聚合物,其中我们可以使用氨基连接螯合剂和其他取代基。在之前的一项研究 (Biomacromolecules. 13 (2012) 2831–2842) 中,我们发现重复单元中带有负电荷的 MCP 放射免疫偶联物导致小鼠模型中的高肝脏摄取。因此,我们选择引入ca。50% 甲氧基十二甘醇 (mPEG12) 侧基赋予“隐形”。作为对照,我们还合成了一种类似的聚合物。50% 甲氧基乙基悬垂物 (EO1)。NOTA 螯合剂连接到剩余的侧基上。然后我们用琥珀酸封端 MCP,用 64Cu 对 MCP 进行放射性标记,并通过尾静脉将放射性标记的 MCP 注射到健康的 Balb/c 小鼠体内。我们观察到大量的 MCP 保留在肾脏中。我们讨论了 MCP 的哪些特性可能有助于其在肾脏中的积累。
更新日期:2020-02-01
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