Fabrication Of Dual Responsive Prodrug Nanoparticles Via RAFT Dispersion Polymerization Induced Self-assembly

Cancer chemotherapy has become an important means of cancer treatment today,because of its rapid development in drug delivery methods,multi-drug combination chemotherapy and postoperative adjuvant chemotherapy.However,traditional chemotherapeutic drugs face many clinical problems,including poor solubility,low cell uptake efficiency,and inability to target,which can cause toxic side effects on healthy tissues.As a drug carrier,stimuli-responsive polymer nanoparticles can respond to external environments such as pH?temperature?and light to trigger the "on-demand"release of drugs.They are highly efficient,target tumor cells,and reduce drug side effects,therefore,it has been widely concerned by scientists in the design of drug carriers.And,Polymerization Induced Self-Assembly(PISA)developed in recent years is an efficient method for preparing polymer nanoparticles.PISA combines polymerization and self-assembly in one step,which effectively simplifies the preparation process of polymer nanoparticles,and can prepare polymer nanoparticles(solid content up to 50%)at extremely high concentrations.Although there is currently much work on the preparation of responsive nanoparticles,the use of polymerization-induced self-assembly(PISA)to prepare nanoparticles with tumor acidity and reduction-responsive surface charge changes has not been reported.In addition,under normal circumstances,the slow release of the drug can effectively maintain the blood drug concentration for a period of time,reduce the frequency of administration,and control the cost of drug administration of the patient.However,in cancer treatment,the rapid release of drugs in tumor cells can inhibit the drug resistance of cancer cells,so it has a better therapeutic effect than slow release.The release kinetics of the drug has a great influence on the therapeutic effect,so studying the influence of composition of the prodrug nanoparticle on the release behavior is of great significance for the preparation of smart drug carriers.Based on the above background,we used camptothecin monomer(CPTM)to prepare prodrug nanoparticles of tumor acidity and reduction-responsive charge changes by polymerization-induced self-assembly(PISA);and study the effect of the components of prodrug nanoparticles on drug release behavior.The specific research results are as follows:1.Prodrug nanoparticles with reductive response release and pH-responsive charge reversal were prepared by polymerization induced self-assembly.A camptothecin analogue(CPTM)was developed as the monomer for PISA to fabricate prodrug nanoparticles at 10%solid concentration in one-pot.First,a binary mixture of macro-RAFT agents comprising poly(N-(2-hydroxypropyl)methacrylamide)(PHPMA)and poly(2-(diethylamino)ethyl methacrylate)(PDEAEMA)(molar ratio 9/1)was used,RAFT dispersion polymerization of camptothecin monomer(CPTM)in ethanol to prepare prodrug nanoparticles.The resultant prodrug nanoparticles are stabilized with PHPMA and PDEAEMA.The PDEAEMA chains are hydrophobic and collapsed at the physiological pH values.In contrast,under tumor acidity conditions,the tertiary amine group of the PDEAEMA chain rapidly protonated,resulting in a rapid hydrophile-hydrophobic transition and a charge transition,and the effect of this rapid charge transition on the endocytosis of tumor cells was studied.The results show that this rapid charge change enhances the endocytosis of the prodrug nanoparticles by the tumor cells,so it has a good anti-cancer effect.2.Using poly(ethylene glycol)as macro chain transfer agent(PEO114-CPADB),copolymerize 2-diisopropylaminoethyl methacrylate(DIPEMA)and camptothecin monomer(CPTM)at a solid content of 5%(50 mg/g)via polymerization-induced self-assembly(PISA).A series of DIPEMA/CPTM PEO-b-P(DIPEMA-co-CPTM)prodrug nanoparticles were prepared with 2-diisopropylaminoethyl methacrylate(DIPEMA)and camptothecin monomer(CPTM).Then DLS was used to characterize its pH response behavior,and finally the effect of DIPEMA and CPTM on the cumulative release rate of camptothecin(CPT)prodrug nanoparticles was studied by fluorescence photometer.The protonation of DIPEMA under acidic conditions changes the solubility of the hydrophobic segment,thereby changing the morphology of the nanoparticles.This will affect the release behavior of the prodrug nanoparticles,so the purpose of regulating the drug release rate can be achieved.