Synthesis And Drug Controlled Release Of PH-responsive Antitumor Nano-drug Delivery Systems

In recent years,stimuli-responsive nano-drug delivery systems have attracted increasing interest in the world.The specific drug targets of them have made substantial progress,and it is no drug leakage before delivering drugs to specific pathologic sites and can release drugs rapidly at the site of action.This can result in varying improvements for in vivo or in vitro drug release curve and increase the chance of binding to the target site.Among them,the pH-responsive nano-drug delivery systems have attracted more attention.They mainly include two kinds,one contain acid-labile bonds or protonated groups;The other take advantage of characteristics of substances to respond to acid,such as ZnO quantum dots(QDs)that can decompose under acidic conditions,so it can be based on the acidic environment of cancer cells to achieve controlled release of drugs and targeted drug,which improve the therapy effect of cancer.The main contents of the thesis are as follows:1.Synthesis of a novel pH-responsive micelle.We used p-nitrophenyl chloroformate to connect with polyethylene glycol(PEG).Then PEG macromolecular initiator containing hydroxyl was obtained by setting off a series of reactions,block copolymer(PEG-NH-N=CH-PCL)containing hydrazone bond was synthesized by ring-opening polymerization of?-caprolactone(?-CL)with different ratio,and loaded doxorubicin(DOX).The structure of the block copolymer was characterized by ~1H NMR.The size and morphology of the polymer micelles were observed by DLS,SEM and TEM.The particle size was about 98 nm.The polymer micelles were pH-dependent and showed sustained drug release,and the release of DOX in acidic environment was much better than that of neutral,thus it has a promising prospect for anticancer drug carriers.2.Synthesis of micelle-ZnO QDs.The Zn O QDs with green,yellow and orange fluorescence were synthesized in methanol,ethanol and hexanol respectively.The block copolymer(PEG-NH-N=CH-PCL)could encapsulate the ZnO QDs in the core of micelles in the process of self-assembly,which were characterized by TEM,UV/Vis and fluorescence spectroscopy.Take green QDs as an example,TEM images proved that the particles were spherical in shape with a size at about 100 nm.DOX could not only be loaded in the core of micelles,but also coordinated to the Zn O QDs.In vitro drug release indicated that the cumulative release rate of micelle-Zn O QDs was significantly higher than that of micelles at pH 5.0 and had a high drug loading rate.This kind of carrier obtained both the water-soluble ZnO QDs and good drug-loading performance,making the accumulation of drugs in the tumor site increase significantly and the fluorescence of ZnO QDs also provided a platform for other biomedical applications such as fluorescence imaging.3.Synthesis of water-soluble ZnO QDs modified by HPMA copolymer.First,we prepared zinc methacrylate as zinc precursor;second,macro-RAFT agent(PHPMA-RAFT)was synthesized by RAFT polymerization;third,PHPMA was chain extended with zinc methacrylate;finally,potassium hydroxide was added to form HPMA copolymer to coat ZnO QDs,ZnO QDs and their polymer layers had good biocompatibility.The water solubility and stability of the synthetic ZnO QDs,and the drug loading performance of DOX-loaded QDs were determined by UV/Vis.TEM and AFM images revealed that the size and morphology of particles,which still maintained a good crystal form.In vitro release studies indicated that at pH 5.0,about92.5%of DOX was released.The QDs were a potential pH-responsive nano-drug delivery system.In the future,they can be applied to marker tracing,cell imaging and other fields.