Studies On Stimuli-sensitive Nanoparticles Based On Polycaprolactone/Poly(Ethylene Glycol) Block Copolymers

The work of this paper aiming at improving the drug release properties of nanoparticles based on polycaprolactone(PCL)/poly(ethylene glycol)(PEG) block copolymers for anticancer drug delivery by enhancing the sensitivities of PCL/PEG block copolymers to environment was studied as follows.Redox-sensitie amphiphilic tirblock copolymer(PEGMA-PCL-SS-PCL-PEGMA(SPCE)) with a disulfide bond in PCL segment was synthesized. SPCE was characterized by nuclear magnetic resonance apparatus(1H NMR) and gel permeation chromatography(GPC). The critical micelle concentration(CMC), morphology, sizes, drug loading property and drug release property of SPCE nanoparticles were examined by fluorescence spectrum, transmission electron microscopy(TEM), laser particle size analyzer(LPSA) and UV-vis spectra. Results show that the molecular weight and structure of SPCE block copolymer are well controlled. SPCE can self-assemble into nanoparticles(NPs) in aqueous solution with an average size of about 70 nm. The CMC value tested by steady-state fluorescent-probe methodology is 7.6 mg/L. The results of in vitro drug release experiments demonstrate that the drug release rate of drug-loaded NPs in 10 mM glutathione(GSH) solution could be apparently improved as compared to conditions without any GSH.Redox/pH dual-sensitie amphiphilic triblock copolymer(mPEG-Hy-PCL-SS-PCL-Hy-mPEG(SCHE)) with disulfides and hydrazone bonds was also prepared. SCHE was characterized by fourier infrared spectrometer(FT-IR), 1H NMR and GPC. The self-assemble property and drug loading property of SCHE were studied by steady-state fluorescent-probe methodology, TEM, LPSA and UV-vis spectra. The influence of stimuli-sensitivities to size changes and drug release rate were studied. In vitro cellular uptake, the influence of stimuli to intracellular drug release property and cytotoxicity were investigated using Hela cells and 4T1 cells. CMC of SCHE tested by steady-state fluorescent-probe methodology is 10 mg/L. SCHE can self-assemble into stable spherical NPs in aqueous solution with an average size of 100 nm. In weak acid and/or GSH environment, the size tends to be larger and the size distribution tends to be broader. Compared to single stimulus of acid condition or redox condition, the dual-stimuli improve the release rate more greatly. Cell uptake results show that the fluorescence intensity in cell nuclei of GSH pretreated cells is apparently enhanced, which demonstrates that in the micro-environment of tumor cells with higher GSH concentration, the drug release rate can be accelatrated thus the mount of drug entering nuclei increases. Cytotoxicity assay shows good biocompatibility of blank SCHE NPs and high toxicity of DOX-loaded NPs towards Hela cells and 4T1 cells.