Kanellopoulos Panagiotis, Nock Berthold A, Krenning Eric P, Maina Theodosia
Molecular Radiopharmacy, INRaSTES, NCSR "Demokritos", 15341 Athens, Greece.
Cyclotron Rotterdam BV, Erasmus MC, 3015 CE Rotterdam, The Netherlands.
Pharmaceutics. 2025 Feb 28;17(3):310. doi: 10.3390/pharmaceutics17030310.
: Radiotheranostics of neurotensin subtype 1 receptor (NTSR)-expressing tumors, like pancreatic, gastrointestinal, or prostate cancer, has attracted considerable attention in recent years. Still, the fast degradation of neurotensin (NT)-based radioligands, by angiotensin-converting enzyme (ACE), neprilysin (NEP), and other proteases, has considerably compromised their efficacy. The recently introduced [Tc]Tc-DT11 (DT11, N-Lys(MPBA-PEG4)-Arg-Arg-Pro-Tyr-Ile-Leu-OH; N, 6-(carboxy)-1,4,8,11-tetraazaundecane) has displayed promising uptake in NTSR-positive tumors in mice and enhanced resistance to both ACE and NEP by virtue of the lateral MPBA-PEG4 (MPBA, 4-(4-methylphenyl)butyric acid; PEG4, 14-amino-3,6,9,12-tetraoxatetradecan-1-oic acid) chain attached to the ε-NH of Lys. We were next interested in investigating whether these qualities could be retained in DT14D, likewise modified at Lys but carrying the universal chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) via a (βAla) spacer at the α-NH of Lys. This chelator switch enables the labeling of DT14D with a wide range of trivalent radiometals suitable for true theranostic applications, not restricted to the diagnostic imaging of NTSR-positive lesions only by single-photon emission computed tomography (SPECT). : DT14D was labeled with Ga-67 (a surrogate for the positron emission tomography radionuclide Ga-68), In-111 (for SPECT), and Lu-177 (applied in radiotherapy). The resulting radioligands were tested in NTSR-expressing pancreatic cancer AsPC-1 cells and mice models. : [Ga]Ga/[In]In/[Lu]Lu-DT14D displayed high affinity for human NTSR and internalization in AsPC-1 cells. They remained >70% intact 5 min after entering the mice's circulation, displaying NTSR-specific uptake in AsPC-1 xenografts. : Suitably side-chain modified NT analogs show enhanced metabolic stability and hence better prospects for radiotheranostic application in NTSR-positive cancer.
近年来，对表达神经降压素1型受体（NTSR）的肿瘤（如胰腺癌、胃肠道癌或前列腺癌）进行放射性核素显像诊断已引起了相当大的关注。然而，基于神经降压素（NT）的放射性配体被血管紧张素转换酶（ACE）、中性内肽酶（NEP）和其他蛋白酶快速降解，这在很大程度上损害了它们的疗效。最近引入的[锝]Tc-DT11（DT11，N-赖氨酸（MPBA-聚乙二醇4）-精氨酸-精氨酸-脯氨酸-酪氨酸-异亮氨酸-亮氨酸-OH；N，6-（羧基）-1,4,8,11-四氮杂十一烷）在小鼠NTSR阳性肿瘤中显示出有前景的摄取，并且由于连接到赖氨酸ε-NH上的侧链MPBA-聚乙二醇4（MPBA，4-（4-甲基苯基）丁酸；聚乙二醇4，14-氨基-3,6,9,12-四氧杂十四烷-1-酸）链而增强了对ACE和NEP的抗性。接下来，我们感兴趣的是研究在DT14D中是否能保留这些特性，DT14D同样在赖氨酸处进行了修饰，但通过赖氨酸α-NH处的（β-丙氨酸）间隔基携带通用螯合剂DOTA（1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸）。这种螯合剂的转换使得DT14D能够用多种适合真正的诊疗应用的三价放射性金属进行标记，而不仅限于通过单光子发射计算机断层扫描（SPECT）对NTSR阳性病变进行诊断成像。：DT14D用镓-67（正电子发射断层扫描放射性核素镓-68的替代物）、铟-111（用于SPECT）和镥-177（用于放射治疗）进行标记。所得的放射性配体在表达NTSR的胰腺癌AsPC-1细胞和小鼠模型中进行了测试。：[镓]Ga/[铟]In/[镥]Lu-DT14D对人NTSR显示出高亲和力，并在AsPC-1细胞中内化。它们在进入小鼠循环5分钟后仍保持>70%完整，在AsPC-1异种移植瘤中显示出NTSR特异性摄取。：适当侧链修饰的NT类似物显示出增强的代谢稳定性，因此在NTSR阳性癌症的放射性核素显像诊断应用中有更好的前景。
