DiWB-1: A Luteinizing Hormone Releasing Hormone (LHRH)-Targeted Peptide-Drug Conjugate (PDC) With Enhanced Tumor Selectivity and PI3K Inhibition Efficacy

Phosphoinositide 3-kinase (PI3K) inhibitors have demonstrated efficacy in cancer therapy; yet, their clinical use is often restricted by off-target toxicity. Peptide-drug conjugates (PDCs) have emerged as a strategy to improve tumor selectivity by targeting receptors overexpressed in malignant cells. Luteinizing hormone-releasing hormone receptors (LHRHR), upregulated in several cancers, present an attractive target for such approaches. In this study, we obtained an LHRHR-targeting peptide IV-6, characterized by high receptor affinity and robust metabolic stability. IV-6 was then conjugated to the PI3K inhibitor buparlisib, forming the target PDC, DiWB-1. In Vitro, DiWB-1 exhibited superior antineoplastic effects against LHRHR-positive MDA-MB-231 cells, with an IC₅₀ of 1.8 μM, compared with 2.4 μM for buparlisib, and demonstrated reduced toxicity in normal cells. In Vivo, DiWB-1 showed considerable tumor-suppressive effects while minimizing systemic toxicity, avoiding the hepatic and renal damage, as well as hyperglycemia, observed with buparlisib treatment. Pharmacokinetic studies further indicated that DiWB-1 had favorable metabolic stability, with a half-life of 5.6 h, slightly exceeding that of triptorelin (4.2 h). These findings suggest that DiWB-1 holds promise as a selective, potent, and long-acting anticancer PDC, warranting further investigation.