New Transferrin Receptor-Targeted Peptide-Doxorubicin Conjugates: Synthesis and In Vitro Antitumor Activity

Poor selectivity to tumor cells is a major drawback in the clinical application of the antitumor drug doxorubicin (DOX). Peptide-drug conjugates (PDCs) constructed by modifying antitumor drugs with peptide ligands that have high affinity to certain overexpressed receptors in tumor cells are increasingly assessed for their possibility of tumor-selective drug delivery. However, peptide ligands composed of natural L-configuration Amino acids have the defects of easy enzymatic degradation and insufficient biological stability. In this study, two new PDCs (^LT7-SS-DOX and ^DT7-SS-DOX) were designed and synthesized by conjugating a Transferrin Receptor (TfR) peptide ligand ^LT7 (HAIYPRH) and its retro-inverso analog ^DT7 (hrpyiah), respectively, with DOX via a disulfide bond linker. Both conjugates exhibited targeted antiproliferative effects on TfR overexpressed tumor cells and little toxicity to TfR low-expressed normal cells compared with free DOX. Moreover, the ^DT7-SS-DOX conjugate possessed higher serum stability, more sustained reduction-triggered drug release characteristics, and stronger in vitro antiproliferative activity as compared to ^LT7-SS-DOX. In conclusion, the coupling of antitumor drugs with the ^DT7 peptide ligand can be used as a promising strategy for the further development of stable and efficient PDCs with the potential to facilitate TfR-targeted drug delivery.

DT7; doxorubicin; peptide–drug conjugates; targeted antitumor activity; transferrin receptor.