Targeting the Gastrin-Releasing Peptide Receptor (GRP-R) in Cancer Therapy: Development of Bombesin-Based Peptide–Drug Conjugates

Abstract

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.

N-Functionalization of β-aminophosphonates: cytotoxic effects of the new derivatives

“…This highly effective clinically used agent shows 50% inhibition in all cell lines reported here at 0.16-1.2 µM concentration (IC 50 value). These numbers are literature IC 50 values, [41][42][43][44][45] or were obtained by our measurements on A431 and Ebc-1 cell lines as 1.2 µM and 0.76 µM, respectively. However, this cytostatic drug does not show selectivity for cell types.…”

Oxime-Linked Peptide–Daunomycin Conjugates as Good Tools for Selection of Suitable Homing Devices in Targeted Tumor Therapy: An Overview

“…Nevertheless, the results of the in vivo acute and chronic toxicity measurements were representative of the other conjugates with different homing peptides too. Similarly, bombesin-based Dau conjugates were reported to be safe up to 20 mg Dau content/kg on the NSG mice in chronic toxicity studies [84]. In contrast, free Dau showed remarkable toxicity at a dose >2 mg/kg on the healthy mice and >1 mg/kg on the immunodeficient mice.…”

Design and Characterization of a Multistage Peptide-Based Vaccine Platform to Target Mycobacterium tuberculosis Infection

“…The rat liver lysosomal homogenate preparation and the protein content were obtained as previously described . The protein concentration was 71.76 μg/μL.…”

“…The rat liver lysosomal homogenate preparation and the protein content were obtained as previously described. 79 The protein concentration was 71.76 μg/μL. The lysosomal homogenate was diluted in a 0.2 M NaOAc buffer (pH 5) solution to have a final protein concentration of 0.22 μg/μL.…”