向临床转化迈进了一步：在接受恩格列净治疗的小鼠中，[锝]Tc-DB4和[铟]In-SG4的肿瘤靶向性增强

One Step Closer to Clinical Translation: Enhanced Tumor Targeting of [Tc]Tc-DB4 and [In]In-SG4 in Mice Treated with Entresto.

作者信息

Kanellopoulos Panagiotis, Kaloudi Aikaterini, Rouchota Maritina, Loudos George, de Jong Marion, Krenning Eric P, Nock Berthold A, Maina Theodosia

机构信息

Molecular Radiopharmacy, INRASTES, NCSR "Demokritos", 15341 Athens, Greece.

Molecular Pharmacology, School of Medicine, University of Crete, 70013 Heraklion, Greece.

出版信息

Pharmaceutics. 2020 Nov 26;12(12):1145. doi: 10.3390/pharmaceutics12121145.

BACKGROUND

Peptide radioligands may serve as radionuclide carriers to tumor sites overexpressing their cognate receptor for diagnostic or therapeutic purposes. Treatment of mice with the neprilysin (NEP)-inhibitor phosphoramidon was previously shown to improve the metabolic stability and tumor uptake of biodegradable radiopeptides. Aiming to clinical translation of this methodology, we herein investigated the impact of the approved pill Entresto, releasing the potent NEP-inhibitor LBQ657 in vivo, on the stability and tumor uptake of two radiopeptides.

METHODS

The metabolic stability of [Tc]Tc-DB4 (DB4, N-Pro-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Nle-NH) and [In]In-SG4 (SG4, DOTA-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH) was tested in LBQ657/Entresto-treated mice vs. untreated controls. The uptake in gastrin-releasing peptide receptor (GRPR)-, or cholecystokinin subtype 2 receptor (CCKR)-positive tumors respectively, was compared between LBQ657/Entresto-treated mice and untreated controls.

RESULTS

LBQ657/Entresto treatment induced marked stabilization of [Tc] Tc-DB4 and [In]In-SG4 in peripheral mice blood, resulting in equally enhanced tumor uptake at 4 h post-injection. Accordingly, the [Tc]Tc-DB4 uptake of 7.13 ± 1.76%IA/g in PC-3 tumors increased to 16.17 ± 0.71/17.50 ± 3.70%IA/g (LBQ657/Entresto) and the [In]In-SG4 uptake of 3.07 ± 0.87%IA/g in A431-CCKR(+) tumors to 8.11 ± 1.45/9.61 ± 1.70%IA/g. Findings were visualized by SPECT/CT.

CONCLUSIONS

This study has shown the efficacy of Entresto to notably improve the profile of [Tc]Tc-DB4 and [In]In-SG4 in mice, paving the way for clinical translation of this approach.

背景

肽放射性配体可作为放射性核素载体，用于将其携带至过表达同源受体的肿瘤部位，以达到诊断或治疗目的。先前的研究表明，用中性内肽酶（NEP）抑制剂磷酰胺素处理小鼠，可提高可生物降解放射性肽的代谢稳定性和肿瘤摄取。为了将该方法转化至临床应用，我们在此研究了已获批的药物恩格列净（Entresto）（其可在体内释放强效NEP抑制剂LBQ657）对两种放射性肽的稳定性和肿瘤摄取的影响。

方法

在接受LBQ657/恩格列净治疗的小鼠与未治疗的对照小鼠中，测试了[锝（Tc）]Tc-DB4（DB4，N-脯氨酰-谷氨酰胺-精氨酸-酪氨酸-甘氨酸-天冬酰胺-谷氨酰胺-色氨酸-丙氨酸-缬氨酸-甘氨酸-组氨酸-亮氨酸-正亮氨酸-酰胺）和[铟（In）]In-SG4（SG4，四氮杂环十二烷四乙酸-谷氨酸-丙氨酸-酪氨酸-甘氨酸-色氨酸-正亮氨酸-天冬氨酸-苯丙氨酸-酰胺）的代谢稳定性。比较了接受LBQ657/恩格列净治疗的小鼠与未治疗的对照小鼠在胃泌素释放肽受体（GRPR）或胆囊收缩素2型受体（CCKR）阳性肿瘤中的摄取情况。

结果

LBQ657/恩格列净治疗可显著稳定外周血中的[Tc]Tc-DB4和[In]In-SG4，导致注射后4小时肿瘤摄取同样增强。因此，PC-3肿瘤中[Tc]Tc-DB4的摄取量从7.13±1.76%IA/g增加至16.17±0.71/17.50±3.70%IA/g（LBQ657/恩格列净），A431-CCKR（+）肿瘤中[In]In-SG4的摄取量从3.07±0.87%IA/g增加至8.11±1.45/9.61±1.70%IA/g。通过单光子发射计算机断层扫描/计算机断层扫描（SPECT/CT）观察到了这些结果。