Influence Of Polycationic Core Structure On Properties Of PH-responsive Nanoparticles

Recently,to achieve the goals of improving the therapeutic efficacy while suppressing the adverse effects of anticancer drugs,great progresses of stimuli-responsive drug delivery system?SRDDS?have been made.Among these SRDDS,the pH-responsive nanocarriers are one of the most wide-ranging nanocarriers,which needs a very sharp change in physical properties within an appropriate narrow pH window,because the typical pH gradients exist in different tissues and cellular compartments.The pKa of poly?2-azepane ethyl methacrylate??PAEMA?was around 6.5 to 6.7,which is a idea pH window to design the pH-responsive nanocarriers,because the pKa values of PAEMA is in accordance with the tumor extracellular microenvioment?pH=6.5-6.8?.Therefore,in this paper,a novel pH-responsive nanoparticles?NPs?was designed based on biodegradable poly?ethylene glycol?-b-polycaprolactone?PEG-b-PCL?and pH-responsive polymer PAEMA to investigate the influences of polycation core structure on the properties of size,charge switch,drug release,cellular uptake of hydrophobic drug,and cytotoxicity towards tumor cells.Firstly,pH-responsive poly?ethylene glycol?₁₁₃-b-poly??-caprolactone?_x-b-poly?2-azepane ethyl methacrylate?_y(mPEG₁₁₃-b-PCL_x-b-PAEMA_y,PELAz)were synthesized via ring open polymerization?ROP?and reversible addition fragmentation chain transfer?RAFT?polymerization.Then the PELAz NPs-pH7.4,PELA4 NPs-pHx,CUR-loaded PELAz NPs-pH7.4 and CUR-loaded PELA4 NPs-pHx were prepared via nanoprecipitation method to investigate the influence of PAEMA lengths and the pH values of preparing NPs on the properties of size,charge switching,drug release,cellular uptake and cytotoxicity towards HepG-2 cells.At physiological condition?pH=7.4?,the PELAz NPs-pH7.4 and PELA4 NPs-pHx showed impacted spherical structure with particle size around 100 nm.With the decreasing of pH from 7.4 to 5.0,PELAz NPs-pH7.4 and PELA4NPs-pHx displayed obvious swelling property with significant positive zeta potentials,which were related to the PAEMA lengths and the pH condition of preparing NPs.The in vitro cellular uptake and cytotoxicity of CUR-loaded PELAz NPs-pH7.4 and CUR-loaded PELA4 NPs-pHx were investigated by HepG-2 cells.In addition,the results indicated that the PELA4 NPs-pH6.5,prepared at pH 6.5,could promote the cellular uptake and enhance the cytotoxicity of CUR obviously.Secondly,pH-responsive mPEG₁₁₃-b-(PCL₂₃-g-PAEMA₄₈)?PEBA4?was synthesized via ROP and atom transfer radical polymerization?ATRP?.The PEBA4NPs-pH6.5 and CUR-loaded PEBA4 NPs were also prepared via nanoprecipitation method at pH 6.5 to investigate the influence of branched chain structure on properties of size,charge switching,drug release,cellular uptake and cytotoxicity towards HepG-2 cells,compared with PELA4 NPs-pH6.5.At physiological condition?pH=7.4?,the PEBA4 NPs-pH6.5 also showed impacted spherical structure with particle size around100 nm.But with the decreasing of pH from 7.4 to 5.0,the swelled rate of PEBA4 NPs-pH6.5 was obviously faster than that of PELA4 NPs-pH6.5.Moreover,the results of in vitro cytotoxicity against HepG-2 cells indicated that the he PEBA4 NPs-pH6.5 could further enhance the cytotoxicity of CUR.