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核心技术专利：CN118964589B侵权必究
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金属螯合聚合物（MCPs）通过链霉亲和素-生物素系统与曲妥珠单抗 Fab 片段结合对 111In 的影响及其在小鼠肿瘤和正常组织中的分布。

The effect of metal-chelating polymers (MCPs) for 111In complexed via the streptavidin-biotin system to trastuzumab Fab fragments on tumor and normal tissue distribution in mice.

机构信息

Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada.

出版信息

Pharm Res. 2013 Jan;30(1):104-16. doi: 10.1007/s11095-012-0853-y. Epub 2012 Aug 21.

DOI:10.1007/s11095-012-0853-y
PMID:22907419
Abstract

PURPOSE: To study the effects of backbone composition and charge of biotin-functionalized metal-chelating polymers (Bi-MCPs) for (111)In complexed to streptavidin (SAv)-trastuzumab Fab fragments on tumor and normal tissue localization. METHODS: Bi-MCPs were synthesized with a polyacrylamide [Bi-PAm(DTPA)(40)], polyaspartamide [Bi-PAsp(DTPA)(33)] or polyglutamide [Bi-PGlu(DTPA)(28)] backbone and harboured diethylenetriaminepentaacetic acid (DTPA) chelators for (111)In. Bi-PAm(DTPA)(40) had a net negative charge; Bi-PAsp(DTPA)(33) and Bi-PGlu(DTPA)(28) were zwitterionic with a net neutral charge. Binding to HER2+ SKOV-3 human ovarian carcinoma cells was determined. Tissue uptake was studied in Balb/c mice by MicroSPECT/CT imaging and biodistribution studies. Tumor and normal tissue uptake of (111)In-labeled Bi-PAsp(DTPA)(33) or Bi-PGlu(DTPA)(28) complexed to SAv-Fab was evaluated 48 h post-injection in athymic mice with subcutaneous SKOV-3 xenografts. RESULTS: SAv-Fab complexed to MCPs bound specifically to SKOV-3 cells; but specific binding was decreased 2-fold. Liver uptake was 5-13 fold higher for Bi-PAm(DTPA)(40) than Bi-PAsp(DTPA)(33) and Bi-PGlu(DTPA)(28) but was reduced by decreasing negative charges by saturation with indium. (111)In-Bi-PAsp(DTPA)(33) complexed to SAv-Fab accumulated in SKOV-3 tumors; low tumor uptake was found for (111)In-Bi-PGlu(DTPA)(28)-SAv-Fab. CONCLUSIONS: Zwitterionic MCPs composed of polyaspartamide with a net neutral charge are most desirable for constructing radioimmunoconjugates.

摘要

目的：研究生物素功能化金属螯合聚合物（Bi-MCPs）的骨架组成和电荷对（111）In 标记的链霉亲和素-曲妥珠单抗 Fab 片段与肿瘤和正常组织定位的影响。

方法：合成了具有聚丙酰胺[Bi-PAm(DTPA)(40)]、聚天冬酰胺[Bi-PAsp(DTPA)(33)]或聚谷氨酸[Bi-PGlu(DTPA)(28)]骨架的 Bi-MCPs，并含有二乙三胺五乙酸（DTPA）螯合剂用于（111）In。Bi-PAm(DTPA)(40)带负净电荷；Bi-PAsp(DTPA)(33)和 Bi-PGlu(DTPA)(28)带净中性电荷。测定了与 HER2+ SKOV-3 人卵巢癌细胞的结合情况。通过 MicroSPECT/CT 成像和生物分布研究，在 Balb/c 小鼠中研究了组织摄取情况。在皮下 SKOV-3 异种移植的无胸腺小鼠中，48 小时后评估了（111）In 标记的 SAv-Fab 与 Bi-PAsp(DTPA)(33)或 Bi-PGlu(DTPA)(28)复合的 MCP 摄取情况。

结果：SAv-Fab 与 MCP 复合物特异性结合到 SKOV-3 细胞；但特异性结合降低了 2 倍。与 Bi-PAsp(DTPA)(33)和 Bi-PGlu(DTPA)(28)相比，Bi-PAm(DTPA)(40)的肝脏摄取率高 5-13 倍，但通过用铟饱和降低负电荷，肝脏摄取率降低。（111）In-Bi-PAsp(DTPA)(33)与 SAv-Fab 复合物在 SKOV-3 肿瘤中积累；（111）In-Bi-PGlu(DTPA)(28)-SAv-Fab 的肿瘤摄取率较低。

结论：带净中性电荷的聚天冬酰胺组成的两性离子 MCP 最适合构建放射性免疫偶联物。

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本文引用的文献

[1]
Biotinylated polyacrylamide-based metal-chelating polymers and their influence on antigen recognition following conjugation to a trastuzumab Fab fragment.

Biomacromolecules. 2012-8-7

[2]
Effect of pendant group structure on the hydrolytic stability of polyaspartamide polymers under physiological conditions.

Biomacromolecules. 2012-4-3

[3]
A comparison of 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT.

EJNMMI Res. 2011-8-17

[4]
Block copolymer micelles target Auger electron radiotherapy to the nucleus of HER2-positive breast cancer cells.

Biomacromolecules. 2012-1-17

[5]
Curious results with palladium- and platinum-carrying polymers in mass cytometry bioassays and an unexpected application as a dead cell stain.

Biomacromolecules. 2011-9-28

[6]
The effect of surface charge on in vivo biodistribution of PEG-oligocholic acid based micellar nanoparticles.

Biomaterials. 2011-2-4

[7]
A kit to prepare (111)In-DTPA-trastuzumab (Herceptin) Fab fragments injection under GMP conditions for imaging or radioimmunoguided surgery of HER2-positive breast cancer.

Nucl Med Biol. 2010-9-1

[8]
Anionic amino acid dendrimer-trastuzumab conjugates for specific internalization in HER2-positive cancer cells.

Mol Pharm. 2010-8-2

[9]
Biodegradable polyamino acid-based polycations as safe and effective gene carrier minimizing cumulative toxicity.

Biomaterials. 2010-2-13

[10]
Trastuzumab-resistant breast cancer cells remain sensitive to the auger electron-emitting radiotherapeutic agent 111In-NLS-trastuzumab and are radiosensitized by methotrexate.

J Nucl Med. 2008-9

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