Fully Water-Soluble Polyphosphorhydrazone-Based Radical Dendrimers Functionalized with Tyr-PROXYL Radicals as Metal-Free MRI T1 Contrast Agents,ACS Applied Bio Materials

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Fully Water-Soluble Polyphosphorhydrazone-Based Radical Dendrimers Functionalized with Tyr-PROXYL Radicals as Metal-Free MRI T1 Contrast Agents
ACS Applied Bio Materials ( IF 4.6 ) Pub Date : 2020-01-09 , DOI: 10.1021/acsabm.9b00855
Luiz F Pinto _{1,

2} , Vega Lloveras _{1,

2} , Songbai Zhang ₁ , Flonja Liko ₁ , Jaume Veciana _{1,

2} , José L Muñoz-Gómez ₁ , José Vidal-Gancedo _{1,

2}

Affiliation

The finding of alternative imaging probes to Gadolinium (Gd) and other metal based contrast agents (CA) is crucial to overcome their established toxicity. Herein we describe the synthesis and characterization of an entirely organic metal-free magnetic resonance imaging (MRI) contrast agent based on polyphosphorhydrazone (PPH) dendrimers, fully functionalized with up to 48 organic nitroxide radical units. We propose an innovative synthetic procedure based on the use of an amino acid linker (Tyr) coupled to each dendrimer′s branch that permits the anchoring of the radicals and at the same time makes possible the control over their water solubility. We demonstrate that the negatively charged resulting PPH Gn-Tyr-PROXYL (n = 0–3) radical dendrimers are excellent candidates to be used as MRI contrast agents, suited for biomedical applications as they show high water solubility, no aggregation problems, and low cytotoxicity, as well as good stability in highly reducing environments. It is achieved a remarkable r₁ relaxivity, ca. four times higher (13 mM^–1 s^–1) than the gold-standard Gd-DTPA used in clinics. Furthermore, the r₁ and r₂ relaxivity per unit of radical showed an increase with the increase in generation of dendrimers.

中文翻译：

用 Tyr-PROXYL 自由基作为无金属 MRI T1 造影剂功能化的全水溶性聚磷腙基自由基树枝状大分子

寻找钆 (Gd) 和其他金属基造影剂 (CA) 的替代成像探针对于克服其已确立的毒性至关重要。在这里，我们描述了一种基于多磷腙 (PPH) 树枝状大分子的完全有机无金属磁共振成像 (MRI) 造影剂的合成和表征，它具有多达 48 个有机氮氧自由基单元的完全功能化。我们提出了一种创新的合成程序，该程序基于使用与每个树枝状大分子的分支偶联的氨基酸接头 (Tyr)，它允许锚定自由基，同时可以控制它们的水溶性。我们证明了带负电荷的 PPH Gn-Tyr-PROXYL ( n= 0–3) 自由基树枝状大分子是用作 MRI 造影剂的优秀候选者，适用于生物医学应用，因为它们显示出高水溶性、无聚集问题、低细胞毒性以及在高度还原环境中的良好稳定性。它实现了显着的r ₁弛豫率，约。比临床中使用的金标准 Gd-DTPA高四倍 (13 mM ^–1 s ^{–1 )。}此外，每单位自由基的r ₁和r ₂弛豫率随着树枝状大分子生成的增加而增加。

更新日期：2020-01-10

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