A novel luteinizing hormone-releasing hormone (LHRH) receptor-targeting peptide LHRH-III': Design and application for targeted breast cancer therapy

Abstract

Breast cancer is one of the most common malignant tumors among women, with approximately 50–60 % of cases overexpressing the luteinizing hormone-releasing hormone receptor (LHRH-R), making it an important therapeutic target. To overcome the limitations of conventional chemotherapy, this study designed and synthesized a novel LHRH-R-targeting peptide, LHRH-III′, based on the structure of natural LHRH-III with rational structural modifications. Fluorescence labeling experiments demonstrated that this peptide binds to 4T1 cells with an affinity comparable to or superior to that of the classical LHRH-R targeting peptide [D-Lys⁶]-LHRH-I, while its cellular internalization efficiency was increased by more than 6-fold. Subsequently, LHRH-III′ was conjugated to camptothecin (CPT) or doxorubicin (Dox) via a disulfide bond linker to construct peptide-drug conjugates (PDCs). Among these conjugates, LHRH-III′–SS–CPT exhibited more efficient glutathione (GSH)-responsive drug release than LHRH-III′–SS–Dox. In antitumor evaluations, LHRH-III′–SS–CPT demonstrated significant antitumor activity both in vitro and in vivo. Biodistribution studies revealed that hepatic accumulation of LHRH-III′ was only one-sixth of that observed with the control peptide [D-Lys⁶]-LHRH-I, substantially reducing the risk of potential hepatotoxicity caused by off-target accumulation. In summary, the novel targeting peptide LHRH-III′ developed in this study exhibits excellent targeting capability for breast cancer. The lead PDC based on LHRH-III′ (LHRH-III′–SS–CPT) demonstrate promising antitumor efficacy and low toxicity, highlighting their potential application value as a targeted therapeutic strategy for breast cancer.