Pro-organic radical contrast agents (“pro-ORCAs”) for real-time MRI of pro-drug activation in biological systems,Polymer Chemistry

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Pro-organic radical contrast agents (“pro-ORCAs”) for real-time MRI of pro-drug activation in biological systems
Polymer Chemistry ( IF 4.1 ) Pub Date : 2020-06-26 , DOI: 10.1039/d0py00558d
Hung V-T Nguyen _{1,

2,

3,

4,

5} , Alexandre Detappe _{2,

3,

4,

5,

6} , Peter Harvey ₇ , Nolan Gallagher ₁ , Clelia Mathieu _{3,

4} , Michael P Agius _{3,

4} , Oksana Zavidij _{3,

4} , Wencong Wang ₁ , Yivan Jiang ₁ , Andrzej Rajca ₈ , Alan Jasanoff _{7,

9,

10} , Irene M Ghobrial _{3,

4} , P Peter Ghoroghchian _{2,

3,

4} , Jeremiah A Johnson _{1,

2}

Affiliation

Nitroxide-based organic-radical contrast agents (ORCAs) are promising as safe next-generation magnetic resonance imaging (MRI) tools. Nevertheless, stimuli-responsive ORCAs that enable MRI monitoring of prodrug activation have not been reported; such systems could open new avenues for prodrug validation and image-guided drug delivery. Here, we introduce a novel “pro-ORCA” concept that addresses this challenge. By covalent conjugation of nitroxides and drug molecules (doxorubicin, DOX) to the same brush-arm star polymer (BASP) through chemically identical cleavable linkers, we demonstrate that pro-ORCA and prodrug activation, i.e., ORCA and DOX release, leads to significant changes in MRI contrast that correlate with cytotoxicity. This approach is shown to be general for a range of commonly used linker cleavage mechanisms (e.g., photolysis and hydrolysis) and release rates. Pro-ORCAs could find applications as research tools or clinically viable “reporter theranostics” for in vitro and in vivo MRI-correlated prodrug activation.

中文翻译：

用于生物系统中前体药物激活的实时 MRI 的前有机自由基造影剂（“pro-ORCA”）

基于氮氧化物的有机自由基造影剂（ORCA）有望成为安全的下一代磁共振成像（MRI）工具。然而，尚未报道能够通过 MRI 监测前药激活的刺激响应 ORCA；此类系统可以为前药验证和图像引导药物输送开辟新途径。在这里，我们引入了一个新颖的“pro-ORCA”概念来应对这一挑战。通过化学上相同的可裂解接头将硝基氧和药物分子（阿霉素，DOX）共价缀合到相同的刷臂星形聚合物（BASP）上，我们证明原ORCA和前药激活，即ORCA和DOX释放，导致显着的与细胞毒性相关的 MRI 对比度变化。该方法被证明对于一系列常用的接头裂解机制（例如，光解和水解）和释放速率是通用的。Pro-ORCA 可以作为研究工具或临床上可行的“报告治疗诊断学”应用，用于体外和体内MRI 相关的前药激活。

更新日期：2020-07-28

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