Preparation Of Carboxymethyl Cellulose Fatty Acid Ester Grafted With Folic Acid And Its Application In Controlled Drug Release

At present,chemotherapeutic drugs have great toxic and side effeets when used to treat cancer patients due to their non-specific delivery.For achieving the best therapeutic results,researchers are working to develop drug delivery systems to deliver drugs specifically to the cancerous tissues and release the drug molecules inside the tissues controllably.Amphiphilic polymers can self-assemble into aggregates with different shapes in aqueous solution,such as micelles,vesicles,etc.These aggregates have hydrophobic microzones which could be used to encapsulate hydrophobic substances.However,the poor biocompatibility and difficult degradation of synthetic polymers limit their applications in medicine,cosmetics and food fields.Cellulose is a natural polysaccharide with good biocompatibility and biodegradability,non-toxic and renewable,which could be produced through plant photosynthesis,extracted from trees,cotton,straw and other higher plants.It is the most abundant natural polysaccharide on earth.However,a large number of intramolecular and intermolecular hydrogen bonds in cellulose molecules result in insolubility of cellulose in water and common organic solvents.Carboxymethyl cellulose(CMC),a common cellulose derivative,is obtained by alkalization and etherification from cellulose with different degrees of substitution,in the form of sodium carboxymethyl cellulose,usually.CMC is soluble in water and is widely used in food and cosmetics industries.In order to use CMC in drug delivery,hydrophobic modification is needed to make CMC amphiphilic.In this paper,the amphiphilic carboxymethyl cellulose fatty acid ester was synthesized by grafting the aliphatic chain to the main chain of CMC through esterification.The micellation behavior of cellulose fatty acid ester in aqueous solution was studied systematically.Folate,a targeting moiety of various anti-cancer agents,was grafted onto the modified CMC through esterification.The micellation behavior of folate grafted carboxymethyl cellulose fatty acid ester in aqueous solution was studied systematically.The micelle formed by the polymer,folate grafted carboxymethyl cellulose fatty acid ester,was used to encapsulate doxorubicin.The release behavior of drug-loading micelle under different conditions was investigated.The specific research and conclusions are as follows:(1)Sodium carboxymethyl cellulose and octanoyl chloride,lauroyl chloride,palmitoyl chloride as raw materials,pyridine as acid-binding agent,dimethyl sulfoxide(DMSO)as the solvent,the amphiphilic polymer carboxymethyl cellulose fatty acid ester(CMC-Cn)was obtained through esterification reaction.The products were characterized by infrared spectra(IR),C nuclear magnetic resonance(C NMR),thermogravimetry(TG),etc.The results showed that the carboxymethyl cellulose fatty acid ester was synthesized successfully.The influences of reaction temperature,reaction time,dosage of pyridine and reactant concentration were inspected,systematacially.It was shown in the result that the grafting rate of CMC-C12 could reach 0.57 in the reaction conditions as followed:the CMC concentration is 0.05 g/mL,nPyridine/nRCOCl=1:1,the reaction temperature is 80? and reaction time was 1.5 h.(2)A series of CMC-Cn with different alkyl chain lengths and CMC-C12 with different graft degrees were synthesized and dissolved in aqueous solutions,subsequently,to form micelles by self-assembly.The micellization behavior of CMC-Cn was studied by surface tension,pyrene fluorescence spectrum,conductivity and rheology.The size and morphology of the micelles was characterized by dynamic light scattering(DLS)and transmission electron microscopy(TEM),respectively.The results show that,at a similar degree of substitution,the longer the alkyl chain length of CMC-Cn is,the lower the solution surface tension,critical micelle eoncentration and viscosity are,and the larger the micelles size is.When the graft degree was about 0.35,the critical micelle concentrations of CMC-C8,CMC-C12,and CMC-C16 were about 3 mg/mL,1.5 mg/mL,and 0.8 mg/mL,and the particle sizes were about 350 nm,450 nm,and 600 nm,respectively.At the same concentration,with the increase of the degree of substitution of CMC-C12,from 0.184 to 0.721,the solution surface tension,critical micelle concentration and viscosity are lower,and the micelles size is larger.The critical micelle concentration decreased between 3 and 0.2 mg/mL.The micellar particle size increased at 400 nm-800 nm.The results of TEM show that CMC-Cn is a kind of spherical self-assembly micelle in aqueous solution.(3)Folic acid,activated by NHS and DCC,was grafted onto CMC-Cn by esterification reaction.The structure of the products was analyzed by FT-IR and NMR.The results show that folic acid has been grafted onto CMC-Cn to form carboxymethyl cellulose fatty acid ester(FA-CMC-Cn).Micellization of FA-CMC-Cn was studied by surface tension,pyrene fluorescence spectrum and rheological characterization.The size and morphology of the micelles was characterized by DLS and TEM,respectively.The results showed that the viscosity of the solution was lower than that of CMC solution of the same concentration.With the increase of alkyl chain length,the critical micelle concentrations of FA-CMC-C8,FA-CMC-C12 and FA-CMC-C16 are decreased,about 4 mg/mL,3 mg/mL and 1 mg/mL,respectively.The particle sizes of the micelle are increased,about 550 nm,650 nm and 750 nm,respectively.The morphology was spherical.The FA-CMC-Cn/doxorubicin(DOX)loaded micelles were prepared.The drug loading capacity and encapsulation rate were tested.The size and morphology of the drug carrier micelle were observed by DLS and TEM.The results showed that the drug loading efficiency of the drug carrier micelle was the highest when the dose was 40%.With the increase of FA-CMC-Cn fat chain length,the drug loading and encapsulation rate of the drug carrier micelle increased.The average drug loading and encapsulation rate of FA-CMC-C16 were 22.6%and 72.9%,respectively.The drug carrier micelles were spherical and the particle size increased with the increase of fat chain.The sustained release of DOX under different pH conditions and B-cyclodextrin(B-CD)were studied.The results showed that the drug release rate in PBS buffer solution with the pH value of 5.6 was slightly higher than that in PBS buffer solution with a pH value of 7.4.In PBS buffer solution with a pH value of 5.6,with the addition of p-CD,the drug release rate is about 3 times of without ?-CD.Studies have shown that ?-CD can trigger the release of DOX by interacting with the alkyl chain of FA-CMC-Cn.