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用中孔螯合剂 AAZTA 增强铋(III)配合物用于靶向 α 治疗 (TAT) 应用。

Boosting Bismuth(III) Complexation for Targeted α-Therapy (TAT) Applications with the Mesocyclic Chelating Agent AAZTA.

机构信息

Department of Physical Chemistry, University of Debrecen, Egyetem tér 1, 4010, Debrecen, Hungary.

Scanomed Ltd., Nagyerdei Krt. 98, 4032, Debrecen, Hungary.

出版信息

Angew Chem Int Ed Engl. 2022 Oct 24;61(43):e202207120. doi: 10.1002/anie.202207120. Epub 2022 Sep 29.

DOI:10.1002/anie.202207120
PMID:36073561
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9828418/
Abstract

Targeted α therapy (TAT) is a promising tool in the therapy of cancer. The radionuclide Bi shows favourable physical properties for this application, but the fast and stable chelation of this metal ion remains challenging. Herein, we demonstrate that the mesocyclic chelator AAZTA quickly coordinates Bi at room temperature, leading to a robust complex. A comprehensive study of the structural, thermodynamic and kinetic properties of [Bi(AAZTA)] is reported, along with bifunctional [Bi(AAZTA-C4-COO )] and the targeted agent [Bi(AAZTA-C4-TATE)] , which incorporates the SSR agonist Tyr -octreotate. An unexpected increase in the stability and kinetic inertness of the metal chelate was observed for the bifunctional derivative and was maintained for the peptide conjugate. A cyclotron-produced Bi mixture was used as a model of Bi in labelling, stability, and biodistribution experiments, allowing the efficiency of [ Bi(AAZTA-C4-TATE)] to be estimated. High accumulation in AR42J tumours and reduced kidney uptake were observed with respect to the macrocyclic chelate [ Bi(DOTA-TATE)] .

摘要

靶向 α 治疗（TAT）是癌症治疗中一种很有前途的工具。放射性核素 Bi 因其具有良好的物理性质而适用于这种应用，但这种金属离子的快速和稳定螯合仍然具有挑战性。在此，我们证明了中大环配体 AAZTA 可在室温下快速配位 Bi，形成稳定的配合物。本文详细研究了 [Bi(AAZTA)] 的结构、热力学和动力学性质，以及双功能 [Bi(AAZTA-C4-COO )] 和靶向试剂 [Bi(AAZTA-C4-TATE)]，后者结合了 SSR 激动剂 Tyr-octreotate。对于双功能衍生物，观察到金属螯合物的稳定性和动力学惰性显著提高，并在肽结合物中得到保持。使用回旋加速器生产的 Bi 混合物作为 Bi 的模型进行标记、稳定性和生物分布实验，从而可以估算 [ Bi(AAZTA-C4-TATE)] 的效率。与大环配体 [Bi(DOTA-TATE)] 相比，观察到 AR42J 肿瘤的高积聚和肾脏摄取减少。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4112/9828418/f45a10c95ecb/ANIE-61-0-g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4112/9828418/d964094d13c3/ANIE-61-0-g004.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4112/9828418/f45a10c95ecb/ANIE-61-0-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4112/9828418/a906e60b9856/ANIE-61-0-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4112/9828418/44fd4c41da53/ANIE-61-0-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4112/9828418/89aad815444c/ANIE-61-0-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4112/9828418/372110790406/ANIE-61-0-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4112/9828418/f45a10c95ecb/ANIE-61-0-g007.jpg

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本文引用的文献

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2
Bismuth-213 for Targeted Radionuclide Therapy: From Atom to Bedside.用于靶向放射性核素治疗的铋 - 213：从原子到床边
Pharmaceutics. 2021 Apr 21;13(5):599. doi: 10.3390/pharmaceutics13050599.
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