University of Basel Hospital, Clinic of Radiology and Nuclear Medicine, Division of Radiopharmaceutical Chemistry, Petersgraben 4, 4031 Basel, Switzerland.
Pharmaceuticals (Basel). 2014 May 27;7(6):662-75. doi: 10.3390/ph7060662.
Radiolabeled peptides which target tumor-specific membrane structures of cancer cells represent a promising class of targeted radiopharmaceuticals for the diagnosis and therapy of cancer. A potential drawback of a number of reported radiopeptides is the rapid washout of a substantial fraction of the initially delivered radioactivity from cancer cells and tumors. This renders the initial targeting effort in part futile and results in a lower imaging quality and efficacy of the radiotracer than achievable. We are investigating the combination of internalizing radiopeptides with molecular entities specific for an intracellular target. By enabling intracellular interactions of the radioconjugate, we aim at reducing/decelerating the externalization of radioactivity from cancer cells. Using the "click-to-chelate" approach, the 99mTc-tricarbonyl core as a reporter probe for single-photon emission computed tomography (SPECT) was combined with the binding sequence of bombesin for extracellular targeting of the gastrin-releasing peptide receptor (GRP-r) and peptidic inhibitors of the cytosolic heat shock 90 protein (Hsp90) for intracellular targeting. Receptor-specific uptake of the multifunctional radioconjugate could be confirmed, however, the cellular washout of radioactivity was not improved. We assume that either endosomal trapping or lysosomal degradation of the radioconjugate is accountable for these observations.
放射性标记肽靶向癌细胞的肿瘤特异性膜结构，代表了一类有前途的用于癌症诊断和治疗的靶向放射性药物。一些已报道的放射性肽的一个潜在缺点是大量初始放射性活性从癌细胞和肿瘤中迅速洗脱。这使得初始靶向努力部分无效，并导致放射性示踪剂的成像质量和疗效低于预期。我们正在研究将内吞放射性肽与针对细胞内靶标的分子实体相结合。通过使放射性缀合物发生细胞内相互作用，我们旨在减少/减缓放射性从癌细胞中外泄。使用“点击螯合”方法，将 99mTc-三羰基核心作为单光子发射计算机断层扫描 (SPECT) 的报告探针，与蛙皮素的结合序列结合，用于胃泌素释放肽受体 (GRP-r) 的细胞外靶向，以及细胞溶质热休克蛋白 90 蛋白 (Hsp90) 的肽抑制剂用于细胞内靶向。可以证实多功能放射性缀合物的受体特异性摄取，但是放射性活性的细胞洗脱没有得到改善。我们假设放射性缀合物的内体捕获或溶酶体降解是造成这些观察结果的原因。
