PH Responsiveness Of Acetal-based Nano Drug Delivery System Modified By Polycationic

Recently,with the continuous development of nanotechnology and nanomaterials,the stimuli-responsive biomaterials have been widely developed and applied to controlled drug delivery.Tumor cells have a lower pH environment than normal cells due to rapid metabolism.By designing pH-responsive materials,precise and controlled drug release can be achieved,which in turn reduces toxic and side effects.In this article,based on monomers（2-hydroxymethyl-2-methyl-propanediol cinnamal acetal）methacrylate（CQMA）,N-（2-hydroxyethyl）hexamethylenediamine ethyl methacrylate（AEMA）and Dimethylaminoethyl methacrylate（DMAEMA）,a series of pH-sensitive amphiphilic polymers were prepared to investigate the effect of polycations on the pH responsiveness of acetal-based nano drug delivery system.Firstly,four kinds of amphiphilic polymers with different AEMA contents（methoxy poly（ethylene gycol）-b-poly（（2-hydroxymethyl-2-methyl-propanediol cinnamal acetal）methacrylate-co-N-（2-hydroxyethyl）hexamethylenediamine ethyl methacrylate））(mPEG₁₁₃-b-P（CQMA_x-co-AEMA_y）)（PECAE-z,z=0～3）,were prepared using CQMA and AEMA as comonomers by reversible addition-fracture chain transfer（RAFT）copolymerization.The methoxy poly（ethylene glycol）modified by s-1-dodecyl-s’-（α,α’’-dimethyl-α’’-acetic acid）trithiocarbonate as the macromolecular RAFT reagent were used.Nano-precipitation technology and dialysis method were used to prepare（PECAE-z-pHx）nanoparticles and DOX-loaded（PECAE-z-pHx（DOX））nanoparticles at different pH environment.DLS and TEM results showed that as the cation content increases and the pH of the preparation environment decreases,the size of the nanoparticles increases.Nanoparticles prepared at pH 7.4 displayed low critical micelle concentration and had better drug loading capacity.pH sensitivity experiments showed that the higher the PAEMA content in the hydrophobic segment,the faster the hydrolysis of cinnamaldehyde in CQMA.The hydrolysis behavior of the two nanoparticles was similar under different preparation conditions and the hydrolysis rate was faster at pH 6.5,but the disintegration pathways of the two nanoparticles were different.Besides,we found that within a certain range,the cytotoxicity of the blank material bonded to cinnamaldehyde increased as the concentration of cinnamaldehyde increased.As the cation concentration increases,the cytotoxicity first increases and then decreases.Cinnamaldehyde can inhibit the resistance of DOX and significantly improve the tumor suppression effect.Cytocytosis showed that the nanoparticles prepared under the conditions of pH 6.5 were conducive to cell internalization.DOX-loaded PECAE-2-pHx nanoparticles showed better cell endocytosis and lower cytotoxicity.RNA interference therapy could effectively inhibit the expression of target genes to achieve the purpose of treatment,but its escape efficiency was very low.To improve the escape efficiency of RNA,we systhesized a series of triblock polymers（methoxy poly（ethylene gycol）-b-poly（（2-hydroxymethyl-2-methyl-propanediol cinnamal acetal）methacrylate-co-Dimethylaminoethyl methacrylate）-b-Dimethylaminoethyl methacrylate）(mPEG₄₅-b-P（CQMA_x-co-DMAEMA_y）-b-DMAEMA_z)（DDCE-0～3）with different feed ratios of CQMA and DMAEMA by RAFT copolymerization.At pH7.4,DDCE nanoparticles with uniform particle size and good stability were prepared by nanoprecipitation.The pH sensitivity experiment showed that the introduction of PDMAEMA in the hydrophobic segment significantly promoted the hydrolysis of CQMA,and the higher the content of the PDMAEMA,the faster the hydrolysis of CQMA.When the cation content was the same,the increase of PCQMA content caused the hydrophobic inner core to be too tight,which then inhibit its hydrolysis.Particle size changes were consistent with hydrolysis results.Gel electrophoresis experiments proved that the materials could effectively encapsulate the gene when the cationic segment of the block reached a certain content and the carrier/siRNA mass ratio reached10:1.Cytotoxicity experiments revealed that the nanocomplexes loaded with siRNA exhibited good biocompatibility.