Targeting the Gastrin-Releasing Peptide Receptor (GRP-R) in Cancer Therapy: Development of Bombesin-Based Peptide-Drug Conjugates.
Jacopo GomenaBalázs VáriRita Oláh-SzabóBeáta Biri-KovácsSzilvia Erika BőszeAdina BorbélyÁdám SoósIvan RanđelovićJózsef TóváriGábor MezőPublished in: International journal of molecular sciences (2023)
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.
Keyphrases
- cancer therapy
- prostate cancer
- drug delivery
- small cell lung cancer
- endoplasmic reticulum stress
- cell surface
- gene expression
- radical prostatectomy
- endothelial cells
- high resolution
- stem cells
- emergency department
- radiation therapy
- molecular docking
- papillary thyroid
- amino acid
- dna binding
- lymph node metastasis
- cell therapy