Precision targeting of fat metabolism in triple negative breast cancer with a biotinylated copolymer

Abstract

Mitochondrial CPT1-mediated fatty acid β-oxidation (FAO) critically contributes to the accelerated metastatic expansion of triple negative breast cancer (TNBC). Hence, inhibition of FAO through active CPT1 targeting could be a promising therapeutic approach in anti-TNBC therapies. Herein, we strategically synthesized a pyrene chain end labelled copolymer bearing biotin pendants, CP4, that actively targets CPT1 and efficiently blocks FAO in metastatic TNBC. Following the comprehensive characterization and synthesis of CP4, in silico negative docking score and Ramachandran plot analyses confirmed its on-target binding potential to CPT1. As a result, CP4 disrupts mitochondrial membrane potential, generates excessive ROS, and restricts excessive ATP production by impairing mitochondrial respiration, glycolytic function, and FAO. Subsequently, CP4 suppressed FA uptake and regulated FAO-associated gene expressions, exhibiting successive metastatic growth inhibition and apoptosis induction. Also, in an animal model, CP4 demonstrated active binding to CPT1, as evidenced by the significant depletion of CPT1A expression in tumor and liver tissue, akin to the specific CPT1-targeted drug. This active targeting of CPT1 has further consolidated the healing of altered lipid and oxidative stress, resulting in remarkable tumor regression, highlighting CP4 as a promising anticancer therapy focused on mitochondrial FAO, advancing future breast cancer treatments.