Department of Radiology and Nuclear Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam 3015 GD, the Netherlands.
Erasmus MC Cancer Institute, Rotterdam 3015 GD, the Netherlands.
Bioconjug Chem. 2024 Nov 20;35(11):1823-1834. doi: 10.1021/acs.bioconjchem.4c00413. Epub 2024 Oct 12.
The main challenges of conventional chemotherapy lie in its lack of selectivity and specificity, leading to significant side effects. Using a small-molecule drug conjugate (SMDC) ensures specific delivery of a cytotoxic drug to the tumor site by coupling it to a targeting vector. This promising strategy can be applied to neuroendocrine tumors (NETs) by choosing a targeting vector that binds specifically to somatostatin receptor subtype 2 (SSTR2). Additionally, incorporation of a bifunctional chelate into the molecule enables complexation of both diagnostic and therapeutic radionuclides. Thus, it facilitates monitoring of the distribution of the SMDC in the body and allows for the implementation of combination therapy. In our study, we designed eSOMA-DM1, a SMDC combining the SSTR2-targeted octreotate peptide and the cytotoxic agent DM1 via a chelate-bridged linker (N-Py-DOTAGA). This approach warrants conjugation of the targeting vector and the drug at opposite sites to avoid undesired steric hindrance effects. Synthesis of the DM1 moiety () involved a three-step synthetic route, followed by the conjugation to the cyclic peptide, N-Py-DOTAGA-d-Phe-cyclo[Cys-Tyr-d-Trp-Lys-Thr-Cys]-Thr-OH, through a copper-free click reaction, resulting in eSOMA-DM1. Subsequent labeling with [In]InCl gave a high radiochemical yield and purity. In vitro assessments of eSOMA-DM1 binding, uptake, and internalization were conducted in SSTR2-transfected U2OS cells. Ex vivo biodistribution and fluorescence imaging were performed in H69-tumor bearing mice. eSOMA-DM1 exhibited an IC value for SSTR2 similar to the gold standard DOTA-TATE. The uptake of [In]In-eSOMA-DM1 in U2OS.SSTR2 cells was 1.2-fold lower than that of [In]In-DOTA-TATE. Tumor uptake in H69-xenografted mice was higher for [In]In-eSOMA-DM1 at all-time points compared to [In]In-DOTA-TATE. Prolonged blood circulation led to increased accumulation of [In]In-eSOMA-DM1 in highly vascularized tissues, such as the lungs, skin, and heart. Excretion through the kidneys, liver, and spleen was also observed. eSOMA-DM1 is a SMDC developed for NET showing promising characteristics in vitro. However, the in vivo results obtained with [In]In-eSOMA-DM1 suggest the need for adjustments to optimize its distribution.
传统化疗的主要挑战在于其缺乏选择性和特异性，导致严重的副作用。通过将细胞毒性药物与靶向载体偶联，可以使用小分子药物偶联物 (SMDC) 将细胞毒性药物特异性递送至肿瘤部位。通过选择与生长抑素受体亚型 2 (SSTR2) 特异性结合的靶向载体，这种有前途的策略可以应用于神经内分泌肿瘤 (NET)。此外，将双功能螯合剂掺入分子中可以使诊断和治疗放射性核素络合。因此，它便于监测 SMDC 在体内的分布，并允许实施联合治疗。在我们的研究中，我们设计了 eSOMA-DM1，这是一种通过螯合桥连接头 (N-Py-DOTAGA) 将 SSTR2 靶向的奥曲肽肽和细胞毒性剂 DM1 偶联的 SMDC。这种方法需要将靶向载体和药物连接到相反的位置，以避免不必要的空间位阻效应。DM1 部分 () 的合成涉及三步合成路线，然后通过无铜点击反应与环肽 N-Py-DOTAGA-d-Phe-cyclo[Cys-Tyr-d-Trp-Lys-Thr-Cys]-Thr-OH 偶联，得到 eSOMA-DM1。随后用 [In]InCl 进行标记，得到高放射化学产率和纯度。在 SSTR2 转染的 U2OS 细胞中进行了 eSOMA-DM1 结合、摄取和内化的体外评估。在 H69 荷瘤小鼠中进行了外分布和荧光成像。eSOMA-DM1 对 SSTR2 的 IC 值与金标准 DOTA-TATE 相似。U2OS.SSTR2 细胞中 [In]In-eSOMA-DM1 的摄取比 [In]In-DOTA-TATE 低 1.2 倍。与 [In]In-DOTA-TATE 相比，H69 异种移植小鼠的肿瘤摄取在所有时间点均较高。通过肾脏、肝脏和脾脏的排泄也观察到。由于血液中延长的循环导致 [In]In-eSOMA-DM1 在富含血管的组织（如肺、皮肤和心脏）中积聚增加。eSOMA-DM1 是一种为 NET 开发的 SMDC，在体外具有有前途的特性。然而，用 [In]In-eSOMA-DM1 获得的体内结果表明，需要进行调整以优化其分布。
