Preparation And Research Of Acid-sensitive Polyurethane Drug Delivery System With Hydrazone Bond/Electrostatic Binding Doxorubicin

Antitumor drugs are mostly hydrophobic small molecules,which results in metabolizing rapidly in vivo,and they lack selectivity,so their bioavailability decrease greatly.According to the differences between tumor tissues and normal tissues,a variety of polymer nano drug delivery systems have been prepared to improve their performances and achieve the effects of target location,high concentration enrichment,controlled/sustained release drug.In this paper,amphiphilic polyurethane with carboxyl pendent groups(PU-COOH)was synthesized by prepolymerization method.Carboxyl goups in polymer were modified by hydrazine,and then reacted with doxorubicin.Finally,polyurethane-doxorubicin prodrug(PU-hyd-DOX)with acid-sensitivity was obtained.The structures of the obtained products were characterized by Fourier transform infrared spectroscopy(FT-IR),Nuclear magnetic resonance spectroscopy(~1H NMR),gel-permeation chromatograph(GPC)and UV-visible spectroscopy(UV-vis).The results indicated that the drug loading content of PU-hyd-DOX reached 17.6 wt%.In vitro drug release experiments showed that PU-hyd-DOX had good pH-sensitive drug release property.CCK-8 assay demonstrated that PU-COOH had no toxicity to MCF-7 cells and PU-hyd-DOX had excellent effects on the inhibition proliferation of MCF-7 cells.DOX-loaded polyurethane nanoparticles(PU·DOX)were facilely prepared in weakly alkaline aqueous solution by electrostatic interactions between PU-COOH and cationic drug doxorubicin(DOX·HCl).The structures of the obtained products were characterized by FT-IR,~1H NMR,GPC,UV-vis and dynamic light scattering(DLS).The PU·DOX nanoparticles had negative surface charge,and had a high drug loading content of 17.6 wt%.In vitro drug release properties of PU·DOX nanoparticles exhibited good pH-sensitive drug release property.In vitro cellular uptake assay and CCK-8 assay demonstrated that PU·DOX nanoparticles had a higher level of cellular internalization and higher inhibitory effects on the proliferation of human breast cancer(MCF-7)cells than pure DOX.The enhancement of inhibition effects was resulted from increasing apoptosis-inducing effects on MCF-7 cells,which was related to the enhancement of Bax expression and the reduction of Bcl-2 expression confirmed by TUNEL assay,real-time PCR assay and western blot assay.