Askoxylakis Vasileios, Zitzmann Sabine, Mier Walter, Graham Keith, Krämer Susanne, von Wegner Frederic, Fink Rainer H A, Schwab Manfred, Eisenhut Michael, Haberkorn Uwe
Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, University of Heidelberg, Germany.
Clin Cancer Res. 2005 Sep 15;11(18):6705-12. doi: 10.1158/1078-0432.CCR-05-0432.
Selective delivery of drugs into the target tissue is expected to result in high drug concentrations in the tissue of interest and therefore enhanced drug efficacy. To develop a peptide-based radiopharmaceutical, we investigated the properties of a peptide with affinity for human breast cancer, which has been selected through phage display.
The bioactivity of the p160 peptide (VPWMEPAYQRFL) was evaluated in vitro and in vivo. The specific binding to human breast cancer MDA-MB-435 cells was confirmed in competition experiments. Internalization of the peptide was investigated with confocal microscopy. Furthermore, the biodistribution of (131)I-labeled p160 was studied in tumor-bearing mice. In vivo stability was evaluated at different periods after tracer administration using high-performance liquid chromatography analysis.
The binding of (125)I-labeled p160 was inhibited up to 95% by the unlabeled peptide with an IC(50) value of 0.6 micromol/L. In addition, 40% of the total bound activity was found to be internalized into the human breast cancer cells. Although a rapid degradation was seen, biodistribution studies in nude mice showed a higher uptake in tumor than in most of the organs. Perfusion of the animals caused a reduction of the radioligand accumulation in the healthy tissues, whereas the tumor uptake remained constant. A comparison of [(131)I]p160 with a (131)I-labeled Arg-Gly-Asp peptide revealed a higher tumor-to-organ ratio for [(131)I]p160.
p160 has properties that make it an attractive carrier for tumor imaging and the intracellular delivery of isotopes or chemotherapeutic drugs.
将药物选择性地递送至靶组织有望在目标组织中产生高药物浓度，从而提高药物疗效。为了开发一种基于肽的放射性药物，我们研究了一种通过噬菌体展示筛选出的对人乳腺癌具有亲和力的肽的特性。
在体外和体内评估了p160肽（VPWMEPAYQRFL）的生物活性。在竞争实验中证实了其与人乳腺癌MDA-MB-435细胞的特异性结合。用共聚焦显微镜研究了该肽的内化情况。此外，还研究了131I标记的p160在荷瘤小鼠体内的生物分布。使用高效液相色谱分析在给予示踪剂后的不同时间段评估体内稳定性。
未标记的肽对125I标记的p160的结合抑制率高达95%，IC50值为0.6 μmol/L。此外，发现总结合活性的40%被内化到人乳腺癌细胞中。尽管观察到快速降解，但裸鼠体内生物分布研究显示肿瘤摄取高于大多数器官。对动物进行灌注导致放射性配体在健康组织中的积累减少，而肿瘤摄取保持不变。[(131)I]p160与131I标记的精氨酸-甘氨酸-天冬氨酸肽的比较显示，[(131)I]p160的肿瘤与器官比值更高。
p160具有使其成为肿瘤成像以及同位素或化疗药物细胞内递送的有吸引力载体的特性。
