Construction of esterase-responsive hyperbranched polyprodrug micelles and their antitumor activity in vitro

Abstract

This research constructs an esterase-responsive hyperbranched polyprodrug nano pharmaceutical and investigates their antitumor activity. Polyprodrug micelle was prepared by one-pot method based on glutathione (GSH), doxorubicin (DOX), and polyethylene glycol (PEG) under the catalyst of N,N-dicyclohexylcarbodiimide (DCC), 4-dimethylaminopyridine (DMAP), and 1-hydroxybenzotriazole (HOBt). The polyprodrug was characterized by nuclear magnetic resonance (NMR), Fourier transform infrared spectrometer (FT-IR), ultraviolet-visible spectrophotometer (UV-Vis), dynamic light scattering (DLS), and transmission electron microscope (TEM), respectively. The antitumor activity of polyprodrug micelle was evaluated by Hela cell and the distributions of micelles in cells were observed by fluorescent microscope. The NMR and FT-IR confirmed that the DOX-GSH-PEG polyprodrug was successfully synthesized. The drug loading rate is 10.21% and particle size is 106.4 ± 1 nm with a narrowed polydispersity (PDI = 0.145). The DLS showed that the micelles were stable during 7 days at 25°C. The drug release results showed that the micelles could be esterase-responsive disrupted, and the drug release rate could reach 43% during 72 h. Cell uptake and cell viability demonstrated that the micelles could distribute to cell nuclei during 8 h and induce cell apoptosis during 48 h. Overall, these hyperbranched polyprodrug micelles prepared by one-pot method could be esterase-responsive disrupted and release the antitumor drugs in a high esterase environment for cancer therapy in vitro. These results confirm that DOX-GSH-PEG is an effective nanomedicine in vitro and the endogenous-based strategy with one-pot synthesis to construct esterase-responsive polyprodrug would probably be a preferred choice in the future.

Keywords

• doxorubicin
• polyprodrug micelles
• esterase-responsiveness
• drug controlled-release
• antitumor