Molecular Radiopharmacy, INRASTES, NCSR "Demokritos", 15341 Athens, Greece.
Molecular Pharmacology, School of Medicine, University of Crete, Heraklion, 70013 Crete, Greece.
Int J Mol Sci. 2020 Oct 26;21(21):7926. doi: 10.3390/ijms21217926.
The overexpression of neurotensin subtype 1 receptors (NTS1Rs) in human tumors may be elegantly exploited for directing neurotensin (NT)-based radionuclide carriers specifically to cancer sites for theranostic purposes. We have recently shown that [Tc]Tc-DT1 ([Tc]Tc-[N-Gly]NT(7-13)) and [Tc]Tc-DT5 ([Tc]Tc-[N-Ala,Dab]NT(7-13)) show notably improved uptake in human colon adenocarcinoma WiDr xenografts in mice treated with neprilysin (NEP) inhibitors and/or angiotensin-converting enzyme (ACE) inhibitors compared with untreated controls. Aiming toward translation of this promising approach in NTS1R-positive pancreatic ductal adenocarcinoma (PDAC) patients, we now report on the impact of registered NEP/ACE inhibitors on the performance of [Tc]Tc-DT1 and [Tc]Tc-DT5 in pancreatic cancer models.
The cellular uptake of [Tc]Tc-DT1 and [Tc]Tc-DT5 was tested in a panel of pancreatic cell lines, and their stability was assessed in mice treated or not treated with Entresto, lisinopril, or their combinations. Biodistribution was conducted in severe combined immunodeficiency (SCID) mice bearing pancreatic AsPC-1 xenografts.
The Entresto + lisinopril combination maximized the metabolic stability of the fast-internalizing [Tc]Tc-DT1 in mice, resulting in notably enhanced tumor uptake (7.05 ± 0.80% injected activity (IA)/g vs. 1.25 ± 0.80% IA/g in non-treated controls at 4 h post-injection; < 0.0001).
This study has shown the feasibility of optimizing the uptake of [Tc]Tc-DT1 in pancreatic cancer models with the aid of clinically established NEP/ACE inhibitors, in favor of clinical translation prospects.
神经降压素亚型 1 受体 (NTS1R) 在人类肿瘤中的过表达，可能被巧妙地利用，将神经降压素 (NT) 为基础的放射性核素载体专门导向癌症部位，用于治疗和诊断目的。我们最近表明，[Tc]Tc-DT1([Tc]Tc-[N-Gly]NT(7-13)) 和 [Tc]Tc-DT5([Tc]Tc-[N-Ala,Dab]NT(7-13)) 在接受神经肽酶 (NEP) 抑制剂和/或血管紧张素转换酶 (ACE) 抑制剂治疗的小鼠人结肠腺癌 WiDr 异种移植瘤中的摄取明显增加，与未治疗的对照组相比。为了将这一有前途的方法转化为 NTS1R 阳性胰腺导管腺癌 (PDAC) 患者，我们现在报告在 PDAC 模型中，已注册的 NEP/ACE 抑制剂对 [Tc]Tc-DT1 和 [Tc]Tc-DT5 性能的影响。
在一系列胰腺细胞系中测试了 [Tc]Tc-DT1 和 [Tc]Tc-DT5 的细胞摄取，并在接受 Entresto、赖诺普利或它们的组合治疗或未治疗的小鼠中评估其稳定性。在携带胰腺 AsPC-1 异种移植瘤的严重联合免疫缺陷 (SCID) 小鼠中进行了生物分布研究。
Entresto + 赖诺普利联合用药最大限度地提高了快速内化的 [Tc]Tc-DT1 在小鼠体内的代谢稳定性，导致肿瘤摄取显著增加 (4 h 后，7.05 ± 0.80%注射活性 (IA)/g，而非治疗对照组为 1.25 ± 0.80% IA/g；<0.0001)。
这项研究表明，借助临床已确立的 NEP/ACE 抑制剂，优化 [Tc]Tc-DT1 在胰腺癌细胞模型中的摄取是可行的，有利于临床转化前景。
