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Updated: Jun 5, 2025
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Precision targeting of fat metabolism in triple negative breast cancer with a biotinylated copolymer
Bhuban Ruidas1, Neha Choudhury2, Sutapa Som Chaudhury1
1Centre for Healthcare Science and Technology, Indian Institute of Engineering Science Technology, Shibpur, Howrah-711103, West Bengal, India. chitrangadam@chest.iiests.ac.in.
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.
Insights
A novel copolymer, CP4, effectively targets and inhibits mitochondrial fatty acid beta-oxidation (FAO) in triple-negative breast cancer (TNBC). This targeted FAO inhibition shows promise for treating metastatic TNBC by reducing tumor growth and inducing apoptosis.
Area of Science:
- Biochemistry
- Oncology
- Materials Science
Background:
- Mitochondrial fatty acid beta-oxidation (FAO) fuels metastatic triple-negative breast cancer (TNBC) progression.
- Targeting FAO via CPT1 inhibition presents a potential therapeutic strategy against TNBC.
Purpose of the Study:
- To synthesize and evaluate a novel copolymer, CP4, for targeted inhibition of CPT1 and FAO in metastatic TNBC.
- To assess CP4's efficacy in disrupting mitochondrial function, reducing tumor growth, and inducing apoptosis in TNBC models.
Main Methods:
- Synthesis and characterization of a pyrene chain end-labeled copolymer (CP4) with biotin pendants.
- In silico docking, in vitro assays assessing mitochondrial function (membrane potential, ROS, ATP), and gene expression analysis.
- In vivo studies using an animal model to evaluate CP4's CPT1 binding, tumor regression, and therapeutic effects.
Main Results:
- CP4 demonstrated strong in silico binding potential to CPT1.
- CP4 disrupted mitochondrial membrane potential, increased ROS, and reduced ATP production by inhibiting respiration, glycolysis, and FAO.
- CP4 suppressed fatty acid uptake, regulated FAO-related genes, inhibited metastasis, induced apoptosis, and achieved significant tumor regression in vivo.
Conclusions:
- CP4 is a promising therapeutic agent that actively targets CPT1 to inhibit mitochondrial FAO in metastatic TNBC.
- CP4's ability to restore lipid and oxidative stress balance contributes to tumor regression, offering a novel approach for breast cancer treatment.
