A Novel Multi-target Drug with Nanoparticle Precision for Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) is a clinically aggressive subtype characterized by hypoxia-driven metabolic reprogramming, contributing to therapeutic resistance and poor prognosis. Two key metabolic enzymes, lactate dehydrogenase A (LDHA) and carbonic anhydrase IX (CAIX), are consistently overexpressed in TNBC and represent actionable targets for disrupting tumor adaptation under hypoxia.This study presents the computational design and in silico validation of Inhibitron-LC, a novel dual inhibitor that targets both LDHA and CAIX and aims to overcome the limitations of existing single-target agents such as FX11 and acetazolamide.Structure-based molecular docking demonstrated the high binding affinity of Inhibitron-LC for both targets. ADMET profiling indicated favorable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. A comparative evaluation against vorinostat, a clinically approved epigenetic modulator, revealed the potential for enhanced metabolic disruption and synergistic efficacy.To improve delivery and tumor targeting, PEGylated pH-responsive liposomal nanoparticles were designed for encapsulating Inhibitron-LC. Physiologically based pharmacokinetic (PBPK) modeling predicted improved tumor accumulation, reduced systemic toxicity, and an increased circulation half-life.These findings provide a compelling computational framework for a multitarget therapeutic strategy in TNBC, combining metabolic pathway inhibition with nanoparticle delivery. Future directions include in vitro cytotoxicity assays and translational preclinical studies.