Preparation And Drug Delivery Performance Of Intelligent Responsive Nanocarriers Based On Chitosan Derivatives

The low tumor targeting efficiency of nano-drug delivery system affects its clinical application.The design of responsive drug carriers targeting the tumor microenvironment(such as low pH or high glutathione,etc.)can improve the efficacy and reduce drug side effects.Nanocarriers with better selectivity can be obtained by chemical modification according to the properties of specific drugs.This study is based on the preparation of natural cationic polysaccharide chitosan nanoparticle drug delivery system,not only has the basic characteristics of drug delivery materials,but also introduced the biological activity advantages of mucosal adhesion,enhancing the targeting of specific tissues,and reducing inflammatory response.A series of chitosan derivatives have physicochemical and biochemical properties required were obtained by deacetylation or chemical modification,which were applied to encapsulate or graft drugs to improve the bioavailability of drugs and give the effects of controlled release and sustained release of drugs.Two nano-drug delivery systems for doxorubicin(DOX)were prepared and their in vitro antitumor properties were investigated.The main research contents and results are as follows:(1)In this study,a kind of CMCS nanogel with dual response of pH and glutathione(GSH)was prepared based on carboxymethyl chitosan(CMCS).Firstly,GMCS were modified with glycidyl methacrylate(GMA),then cross-linked with N,N-bis(acrylyl)cysteamine(BAC)containing disulfide bonds next grafted with folic acid(FA).Finally,folic acid modified targeted nanogel was obtained by adding DOX.The performance of DOX delivery and release was studied.The products were characterized by transmission electron microscopy(TEM),Fourier transform infrared spectrophotometer(FT-IR),X-ray photoelectron spectroscopy(XPS)and elemental analysis.GCMCS-FA with particle size of 160.2±50.6 nm were prepared by optimization.The drug encapsulation efficiency(EE)and loading capacity(LC)of DOX were 15.6±0.12%and 94.77±0.83%,respectively.The particle size of GCMCS-FA-DOX nanoparticles loaded with DOX was 220.4±38.4 nm.The experimental results show that GCMCS-FA-DOX has great pH and GSH response performance.Cell experiment results showed that GCMCS-FA-DOX had a better inhibition effect on tumor cell proliferation than free DOX.GCMCS-FA-DOX could significantly improve the efficiency of drug uptake by cells,and the cytotoxicity of GCMCS-FA-DOX to HCT-116 tumor cells was higher than HepG-2 tumor cells.(2)The preparation of drug-loading nanoparticles(COS-DOX)with pH sensitive used the spontaneous reaction between the amino of chitosan oligosaccharides(COS)and DOX and the aromatic aldehyde of dibenzaldehyde polyethylene glycol(DF-PEG-DF).Then,pH sensitive benzene imine bond was form.COS-DOX point release in tumor weak acid condition.COS-DOX can improve the curative effect and reduce the side effects of drug research.In addition,the optimization of the particle size,loading rate and Zeta potential of nanoparticles was done by changing the proportion of aldehyde,amine and sodium tripolyphosphate(TPP).The materials were characterized by transmission electron microscopy(TEM),Fourier infrared spectrophotometry(FT-IR)and thermogravimetric analysis(TGA).Results show that by changing the proportion of each component of COS-DOX nanoparticles,can control the particle size of nanoparticles,which may affect the drug coating efficiency and transmission effect.We get the nanoparticles which have minimum size of 168.6±4.3 nm named COS-DOX2 and the nanoparticles named COS-DOX1 have highest potential was 35.1±1.9 mV and which size was 219.2±1.5 nm.The drug encapsulation efficiency(EE)and loading capacity(LC)of COS-DOX1 were 5.55±0.13%and 88.81±2.00%,respectively.The release properties and pH responsiveness of nanoparticles in vitro were also studied.COS-DOX was co-cultured with human colon cancer cells(HCT-116).The results showed that COS-based drug-carrying nanoparticles increased the drug uptake of tumor cells and significantly enhanced the cytotoxicity of drug to HCT-116 cells within a certain concentration.