Reduction-responsive poly (ethylene glycol)-dexamethasone biarm conjugate and its self-assembled nanomicelles: Preparation, physicochemical characterization, and thiol-triggered drug release

In this study, a reduction-responsive poly (ethylene glycol)-dexamethasone biarm conjugate was synthesized as intracellular targeted drug delivery carriers. The hydroxyl end group of methoxy poly (ethylene glycol) (mPEG) was modified to introduce a biarm structure with bioreducible disulfide bond and amine end groups. Dexamethasone (Dex) as a nuclear targeting moiety was conjugated to the amine end groups of mPEG biarm derivatives, mPEG-(NH₂)₂ or mPEG-(ss-NH₂)₂, with or without bioreducible disulfide bonds. The bioreducible and nonreducible mPEG-Dex biarm conjugates, R-mPEG-Dex and N-mPEG-Dex, were synthesized and characterized by various analytical methods, proton nuclear magnetic resonance (¹H-NMR), Fourier transform infraredspectroscopy (FT-IR), dynamic light scattering (DLS), and fluorescence measurements. Amphiphilic mPEG-Dex conjugates self-assembled in aqueous solutions to form nanoparticles (NPs) with a size range of 130 to 150 nm, and their critical micelle concentrations (CMCs) were determined to be 12.4 and 15.3 mg/L, respectively, for bioreducible and nonreducible ones. The R-mPEG-Dex NPs maintained good colloidal stability in the presence of bovine serum albumin (BSA) for more than 1 week but demonstrated a significant change in colloidal stability in the presence of dithiothreitol (DTT). In DTT-containing phosphate-buffered saline (PBS), the bioreducible NPs showed not only reduction-responsive destabilization with PEG shedding but also thiol-dependent drug release profile. Our observations indicated that the R-mPEG-Dex NPs have a promising prospective as an efficient nanocarrier for intracellular targeted delivery of various anticancer drugs.