Surface decoration of PLGA nanoparticles enables efficient transport of floxuridine oligomers into mammalian cells

Abstract

2′-deoxy-5-fluorouridine (Floxuridine, FdU) oligomers are repeated FdU residues linked to each other through phosphate groups exhibiting anticancer properties. One of the major hurdles exhibited by natural oligomers is their reduced stability and limited ability to impart cellular uptake. To overcome these drawbacks, electrostatic and covalent strategies have been used to combine oligomers with nanoparticles (NPs) to enhance stability and cellular internalization. Polymeric NPs, prepared from oil-in-water (O/W) PLGA nano-emulsions (NEs) using low-energy emulsification methods, have shown potential in many biomedical applications owing to their ability to transport drugs across cellular membranes. Carbodiimide-mediated amine coupling reaction and thiol-based Michael-type addition were used to attach FdU oligomers formed by five FdU residues (FdU₅) to PLGA NPs. Colloidally stable dispersions of FdU₅-decorated PLGA NPs were obtained and characterized in terms of size, surface charge, and morphology in physiological medium. Additionally, synthetic strategies were envisaged to functionalize the surface of FdU₅-decorated polymeric NPs with folic acid (FA). Cell culture experiments showed that FdU₅-decorated PLGA NPs were able to internalize efficiently inducing cytotoxic effect and inhibiting cell proliferation in tumor cells. These outcomes suggest the feasibility of grafting oligomeric FdU produgs in a covalent fashion into nanoscale platforms as a potential approach for cancer therapy.