<br>基于 CXCR4 的治疗诊断分子 CPCR4 探针的合成、筛选和评估,Molecular Pharmaceutics

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基于 CXCR4 的治疗诊断分子 CPCR4 探针的合成、筛选和评估
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2024-04-12 , DOI: 10.1021/acs.molpharmaceut.3c01221
Tingting Yang _{1,

2} , Dai Shi _{1,

2} , Qingyu Lin _{1,

2} , Hua Shen ₃ , Hui Tan _{1,

2} , Yuxia Liu ₃ , Hongcheng Shi _{1,

2} , Dengfeng Cheng _{1,

2}

Affiliation

趋化因子和趋化因子受体在恶性肿瘤的发生发展中发挥着关键作用，是不可或缺的。作为表达最广泛的趋化因子受体之一，趋化因子（CXC基序）受体4（CXCR4）一直是热门的研究热点。在大多数肿瘤中，CXCR4 表达显着上调。此外，针对CXCR4的综合核素诊断和治疗显示出巨大的潜力。 [ ⁶⁸ Ga]Ga-pentixafor 是一种靶向 CXCR4 的放射性配体，在体内和体外均表现出对 CXCR4 的强亲和力。然而，[ ¹⁷⁷ Lu]Lu-pentixather（[ ⁶⁸ Ga]Ga-pentixafor 的治疗伴侣）需要显着改进以减轻其明显的肝脏生物分布。本研究的目的是合成具有卓越 CXCR4 靶向功能的治疗诊断分子示踪剂。本研究使用高表达CXCR4的Daudi细胞系和弱表达CXCR4的MM.1S细胞系。基于pentixafor的药效团环( -d -Tyr-n-me- d -Orn- l -Arg-L-2-NAL-Gly-)(CPCR4)，合成了六种示踪剂：[ ¹²⁴ I]I-1 ([ ¹²⁴ I]I-CPCR4)、[ ^99m Tc]Tc-2 ([ ^99m Tc]Tc-HYNIC-CPCR4)、[ ¹²⁴ I]I-3 ([ ¹²⁴ I]I-pentixafor)、[ ¹⁸ F] AlF-4 ([ ¹⁸ F]AlF-NETA-CPCR4)、[ ^99m Tc]Tc-5 ([ ^99m Tc]Tc-MAG ₃ -CPCR4) 和 [ ¹²⁴ I]I-6 ([ ¹²⁴ I]I-pentixafor -Ga)及其放射化学纯度均高于95%。正电子发射断层扫描（PET）/单光子发射计算机断层扫描（SPECT）成像后，[ ¹²⁴ I]I-6 组表现出最佳的靶标与非靶标比率。同时，比较[ ⁶⁸ Ga]Ga-pentixafor组与[ ¹²⁴ I]I-6组，我们发现[ ¹²⁴ I]I-6组具有更好的靶标与非靶标比率以及较低的非靶标摄取器官。因此，选择化合物6用于治疗性放射性核素( ¹³¹ I)标记，并用[ ¹³¹ I]I-6治疗荷瘤动物模型。与对照组相比，治疗组肿瘤部位体积明显缩小，且未发现明显副作用。 [ ¹²⁴ I]I-6和[ ¹³¹ I]I-6对CXCR4表现出优异的亲和力，在CXCR4高表达肿瘤的综合诊断和治疗方面显示出巨大的潜力。

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Synthesis, Screening, and Evaluation of Theranostic Molecular CPCR4-Based Probe Targeting CXCR4

Chemokines and chemokine receptors are indispensable to play a key role in the development of malignant tumors. As one of the most widely expressed chemokine receptors, chemokine (C-X-C motif) receptor 4 (CXCR4) has been a popular research focus. In most tumors, CXCR4 expression is significantly upregulated. Moreover, integrated nuclide diagnosis and therapy targeting CXCR4 show great potential. [⁶⁸Ga]Ga-pentixafor, a radioligand targeting CXCR4, exhibits a strong affinity for CXCR4 both in vivo and in vitro. However, [¹⁷⁷Lu]Lu-pentixather, the therapeutic companion of [⁶⁸Ga]Ga-pentixafor, requires significant refinement to mitigate its pronounced hepatic biodistribution. The objective of this study was to synthesize theranostic molecular tracers with superior CXCR4 targeting functions. The Daudi cell line, which highly expressed CXCR4, and the MM.1S cell line, which weakly expressed CXCR4, were used in this study. Based on the pharmacophore cyclo (-d-Tyr-n-me-d-Orn-l-Arg-L-2-NAL-Gly-) (CPCR4) of pentixafor, six tracers were synthesized: [¹²⁴I]I-1 ([¹²⁴I]I-CPCR4), [^99mTc]Tc-2 ([^99mTc]Tc-HYNIC-CPCR4), [¹²⁴I]I-3 ([¹²⁴I]I-pentixafor), [¹⁸F]AlF-4 ([¹⁸F]AlF-NETA-CPCR4), [^99mTc]Tc-5 ([^99mTc]Tc-MAG₃-CPCR4) and [¹²⁴I]I-6 ([¹²⁴I]I-pentixafor-Ga) and their radiochemical purities were all higher than 95%. After positron emission tomography (PET)/single-photon emission computed tomography (SPECT) imaging, the [¹²⁴I]I-6 group exhibited the best target-nontarget ratio. At the same time, comparing the [⁶⁸Ga]Ga-pentixafor group with the [¹²⁴I]I-6 group, we found that the [¹²⁴I]I-6 group had a better target-nontarget ratio and lower uptake in nontarget organs. Therefore, compound 6 was selected for therapeutic radionuclide (¹³¹I) labeling, and the tumor-bearing animal models were treated with [¹³¹I]I-6. The volume of the tumor site was significantly reduced in the treatment group compared with the control group, and no significant side effects were found. [¹²⁴I]I-6 and [¹³¹I]I-6 showed excellent affinity for targeting CXCR4, and they showed great potential for the integrated diagnosis and treatment of tumors with high CXCR4 expression.

更新日期：2024-04-12

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