Institute of Chemistry, Faculty of Science, Eötvös Loránd University, 1117 Budapest, Hungary.
ELKH-ELTE Research Group of Peptide Chemistry, 1117 Budapest, Hungary.
Int J Mol Sci. 2023 Feb 8;24(4):3400. doi: 10.3390/ijms24043400.
Targeted tumour therapy has proved to be an efficient alternative to overcome the limitations of conventional chemotherapy. Among several receptors upregulated in cancer cells, the gastrin-releasing peptide receptor (GRP-R) has recently emerged as a promising target for cancer imaging, diagnosing and treatment due to its overexpression on cancerous tissues such as breast, prostate, pancreatic and small-cell lung cancer. Herein, we report on the in vitro and in vivo selective delivery of the cytotoxic drug daunorubicin to prostate and breast cancer, by targeting GRP-R. Exploiting many bombesin analogues as homing peptides, including a newly developed peptide, we produced eleven daunorubicin-containing peptide-drug conjugates (PDCs), acting as drug delivery systems to safely reach the tumour environment. Two of our bioconjugates revealed remarkable anti-proliferative activity, an efficient uptake by all three tested human breast and prostate cancer cell lines, high stability in plasma and a prompt release of the drug-containing metabolite by lysosomal enzymes. Moreover, they revealed a safe profile and a consistent reduction of the tumour volume in vivo. In conclusion, we highlight the importance of GRP-R binding PDCs in targeted cancer therapy, with the possibility of further tailoring and optimisation.
靶向肿瘤治疗已被证明是克服传统化疗局限性的有效方法。在癌细胞中上调的几种受体中，胃泌素释放肽受体（GRP-R）由于在乳腺癌、前列腺癌、胰腺癌和小细胞肺癌等癌组织中的过度表达，最近成为癌症成像、诊断和治疗的有前途的靶点。在此，我们报告了通过靶向 GRP-R 体外和体内选择性地将细胞毒性药物柔红霉素递送至前列腺癌和乳腺癌。利用许多蛙皮素类似物作为归巢肽，包括一种新开发的肽，我们制备了 11 种含有柔红霉素的肽-药物偶联物（PDC），作为药物递送系统以安全到达肿瘤环境。我们的两种生物缀合物显示出显著的抗增殖活性，能够被所有三种测试的人乳腺癌和前列腺癌细胞系有效摄取，在血浆中高度稳定，并通过溶酶体酶迅速释放含药物的代谢物。此外，它们在体内显示出安全的特性和一致的肿瘤体积减小。总之，我们强调了 GRP-R 结合 PDC 在靶向癌症治疗中的重要性，并有进一步的定制和优化的可能性。
