寡聚苯乙炔修饰RM26的177Lu标记和细胞内化研究

促胃泌素多肽受体（gastrin-releasing peptide receptor, GRPR）在多种肿瘤细胞中过度表达，可以被GRPR拮抗剂靶向。高的细胞内化率有助于提高放射性治疗药物的治疗效果，减少给药剂量。激动剂的内化率优于拮抗剂，但是严重的副作用限制了激动剂的应用。将具有跨膜能力的寡聚苯乙炔（OPE）和GRPR拮抗剂RM26偶联，可以提高拮抗剂的内化能力。本研究合成了两种多功能化合物NOTA-OPE-1-RM26和NOTA-OPE-2-RM26，分别进行¹⁷⁷Lu标记，得到了高放化纯度的标记物。标记化合物¹⁷⁷Lu-NOTA-OPEs-RM26在生理盐水、高糖培养液、新生牛血清中稳定存在。体外稳定性实验表明，引入OPE-1少量增加了化合物的内化率，而引入OPE 2显著增加了化合物的内化率。此外，引入OPE并没有改变RM26的特异性结合能力。实验结果表明，引入跨膜基团提高拮抗剂药物细胞内化率可行。

177Lu Radiolabeling of RM26 Modified with Oligo-Phenylene-Ethynylene and its Cellular Internalization

Gastrin releasing peptide receptor (GRPR) is overexpressed in various tumors, and these GRPR-positive tumors have successfully and widely been targeted with GRPR antagonists. To achieve a good therapeutic effectiveness and less radioactive dosage administration, high cellular internalization is required. The cellular internalization of agonists is better than that of antagonists, but the severe side effects of agonists restrict their applications. In this study, we hypothesized that introducing membrane penetrating oligo-phenylene-ethynylene (OPE) to GRPR antagonist RM26 could increase the cellular internalization of antagonists. Therefore, two multi-functional compounds NOTA-OPE-1-RM26 and NOTA-OPE-2-RM26 were synthesized and labelled with 177Lu with high efficiency. The ¹⁷⁷Lu labelled compounds ¹⁷⁷Lu-NOTA-OPEs-RM26 were stable in saline, dulbecco’s modified eagle medium (DMEM) and newborn bovine serum. The in vitro experimental results indicated that the introduction of OPE-1 slightly increased the cellular internalization of the radiolabelled compounds while OPE-2 significantly increased the cellular internalization. In addition, the introduction of OPEs did not change the specific binding ability of RM26. The investigations indicated that introducing the OPE to increase the internalization was feasible.