Choline Transporter-Targeted Nanoparticles for Dual Inhibition of Lipid Metabolism and DNA Methylation in Cancer Therapy

 Choline is an essential nutrient involved in cellular membrane biosynthesis and one-carbon metabolism, serving as a precursor for phosphatidylcholine and betaine. Because of their high proliferative activity, cancer cells show increased choline demand and often overexpress choline transporters to sustain enhanced metabolic flux. In this study, we developed a polymeric nanomedicine platform designed to specifically inhibit choline uptake in cancer cells through transporter targeting.
 For this purpose, choline-functionalized poly(ε-caprolactone) (CholPCL-P) was synthesized and self-assembled into choline-decorated nanoparticles (CholPCL-NPs). These nanoparticles competitively interacted with choline transporters on the cancer cell membrane, reducing intracellular choline availability. As a result, the biosynthesis of phosphatidylcholine, a major membrane phospholipid, and betaine, a key methyl donor in one-carbon metabolism, was significantly suppressed. This metabolic disruption impaired lipid metabolism and DNA methylation processes, leading to inhibited cell proliferation, loss of epigenetic homeostasis, and ultimately cancer cell death.
 To further improve therapeutic effectiveness, doxorubicin-loaded nanoparticles (DOX@CholPCL-NPs) were developed and tested. The combined effects of blocking the choline transporter and delivering the chemotherapeutic drug led to increased anticancer activity compared to standard treatments. These findings show that CholPCL-NPs serve not only as a drug delivery system but also as an active therapeutic nanomedicine that can simultaneously modulate lipid and DNA methylation pathways. This polymer-based approach offers a promising strategy for targeted cancer therapy through metabolic intervention.