Synthesis and characterization of biodegradable polyurethanes with folate side chains conjugated to hard segments

Abstract

In this study, a novel folate-conjugated chain extender (LDDFA) was designed and synthesized to enhance site-specific intracellular delivery of drug carriers against folate receptor overexpressing tumors. A series of biodegradable polyurethanes containing high folate content were prepared using poly(ε-caprolactone) (PCL) and poly(ethylene glycol) (PEG) as soft segments, and 1,3-propanediol (PDO), L-lysine ethyl ester diisocyanate (LDI) and LDDFA as hard segments. The resultant polyurethanes were characterized with proton nuclear magnetic resonance spectroscopy (¹H NMR), Fourier-transform infrared (FTIR) spectroscopy and gel permeation chromatography (GPC). The folate contents were quantitatively analyzed with ultraviolet (UV) spectrophotometry. The folate-conjugated polymers could self-assemble into micelles with particularly loose hydrophobic cores and exhibiting low critical micelle concentration (CMC) in aqueous solution, in which folic acid (FA) molecules were located in the micelle shells and the PEG segments were in the outer corona, as confirmed by pyrene fluorescence probe techniques, transmission electron microscopy (TEM), dynamic lighting scattering (DLS), and dissipative particle dynamics (DPD) simulation. The folate-conjugated polyurethane micelles displayed enhanced drug loading capacity for doxorubicin (DOX), sustained drug release, preferential internalization by the human epidermoid carcinoma cell line (KB cells) and pronounced cytotoxicity compared to polyurethane micelles without FA, as verified by typical confocal microscopy images (CLSM) and methyl tetrazolium (MTT) assay, respectively. Our present work provides a new route for the preparation of folate-conjugated polyurethanes with high FA content, which could be a good candidate for active targeting conjugates for multifunctional carriers to achieve efficient drug delivery.