碳酸酐酶 IX 靶向 Mn(II) 基磁共振分子成像探针，用于缺氧肿瘤,Bioconjugate Chemistry

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碳酸酐酶 IX 靶向 Mn(II) 基磁共振分子成像探针，用于缺氧肿瘤
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2023-06-07 , DOI: 10.1021/acs.bioconjchem.3c00232
Weidong Cao _{1,

2} , Jianqiong Yang _{1,

3} , Chunrong Zhu ₁ , Zuhua Zeng _{1,

2} , Chenwu Yang ₁ , Tianwu Chen ₁ , Jiang Zhu _{1,

2}

Affiliation

肿瘤微环境中的生理性缺氧条件和随之而来的碳酸酐酶IX（CA IX）的过度表达是许多类型的实体恶性肿瘤共有的两个特征。早期检测缺氧评估对于改善缺氧肿瘤的预后和治疗效果至关重要。在此，使用乙酰唑酰胺（AZA）作为CA IX靶向部分，我们设计并合成了一种基于Mn（II）的MR成像探针（命名为AZA-TA-Mn），该探针结合了AZA和Mn-TyEDTA的两种Mn（II）螯合物在刚性三嗪（TA）支架上。AZA-TA-Mn的每 Mn 弛豫率比单体 Mn-TyEDTA 高 2 倍，这使得它能够对缺氧肿瘤进行低剂量成像。在食管鳞状细胞癌（ESCC）异种移植小鼠模型中，低剂量与非特异性 Gd-DTPA (0.1 mmol/kg) 相比，AZA-TA-Mn (0.05 mmol/kg) 可以选择性地在肿瘤中产生持久且更强的对比增强。一项共注射游离 AZA 和 Mn(II) 探针的竞争性研究证实了AZA-TA-Mn的体内肿瘤选择性，导致肿瘤与肌肉的对比噪声比降低了 2.5 倍以上（注射后 60 分钟的 ΔCNR）。Mn 组织水平的定量分析进一步支持了 MR 成像结果，因为共注射游离 AZA 导致肿瘤组织中 Mn 积累显着减少。最后，组织切片的免疫荧光染色证实了AZA-TA-Mn的肿瘤积累之间的正相关性。和 CA IX 过度表达。因此，使用 CA IX 作为缺氧生物标志物，我们的结果说明了开发缺氧肿瘤新型成像探针的实用策略。

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Carbonic Anhydrase IX Targeting Mn(II)-Based Magnetic Resonance Molecular Imaging Probe for Hypoxia Tumors

Physiological hypoxic conditions in the tumor microenvironment and consequential overexpression of carbonic anhydrase IX (CA IX) are two characteristics shared by numerous types of solid malignant tumors. Early detection with hypoxia assessment is crucial to improve the prognosis and therapy outcomes of hypoxia tumors. Herein, using acetazolamide (AZA) as a CA IX-targeting moiety, we design and synthesize an Mn(II)-based MR imaging probe (named AZA-TA-Mn) incorporating AZA and two Mn(II) chelates of Mn-TyEDTA on a rigid triazine (TA) scaffold. The per Mn relaxivity of AZA-TA-Mn is 2-fold higher than its monomeric Mn-TyEDTA, which allows it for low-dose imaging of hypoxic tumors. In a xenograft mice model of esophageal squamous cell carcinoma (ESCC), a low dosage of AZA-TA-Mn (0.05 mmol/kg) can selectively produce prolonged and stronger contrast enhancement in the tumor compared to the non-specific Gd-DTPA (0.1 mmol/kg). A competition study of co-injection of free AZA and Mn(II) probes confirms the in vivo tumor selectivity of AZA-TA-Mn, resulting in a more than 2.5-fold decreased tumor-to-muscle contrast-to-noise ratio (ΔCNR) at 60 min post-injection. MR imaging results were further supported by the quantitative analysis of Mn tissue levels, as the co-injection of free AZA resulted in significantly reduced Mn accumulation in tumor tissues. Finally, immunofluorescence staining of tissue sections confirms the positive correlation between the tumor accumulation of AZA-TA-Mn and CA IX overexpression. Hence, using CA IX as the hypoxia biomarker, our results illustrate a practical strategy for the development of novel imaging probes for hypoxic tumors.

更新日期：2023-06-07

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