Preparation Of S-PLLA/HA-SH Composite Hydrogel And Its Application As Dual Drug Carrier

The research and application of polymer microspheres have developed rapidly in recent years.Due to their special size and morphology,polymer microspheres have special properties that other materials do not have.Microspheres are used in the controlreleased medicine and as medium in the separation of proteins.Biomedical hydrogel is a kind of gel with water as the dispersion medium,which can quickly absorb water but insoluble in water.It can maintain a certain shape of three-dimensional network structure with good biocompatibility so as to support cell proliferation and migration,and release bioactive factors and pharmaceuticals.Therefore,the Complex Hydrogel Microsphere prepared by combining polymer microspheres with biomedical hydrogels can improve the properties of hydrogels such as mechanics and swelling.As a drug carrier,it has a broad application prospect.Compared with linear polylactic acid(L-PLLA),star polylactic acid(S-PLLA)has lower melt viscosity,crystallinity,diffusion coefficient and stronger fluidity.In this study,L-lactide and pentaerythritol were used as raw materials to synthesize S-PLLA of four arms under the condition of catalyst,high temperature and vacuum.The average molecular weight of S-PLLA was 21328.The results showed that during the the preparation of S-PLLA microspheres by TIPS(Thermally Induced Phase Separation),the best pelletization was achieved when the concentration of S-PLLA was 2%,the rotation speed was 800 r/min,and the ratio of water to oil was 1:4.Hyaluronic Acid(HA),a natural polysaccharide material widely found in nature,is widely distributed in organisms.In this paper,HA was used as the raw material to activate the carboxyl group on the side chain of HA.Then L-cysteine was condensed with the activated carboxyl group to form amide bond,and finally sulfhydrylated hyaluronic acid(HA-SH)was prepared.The content of free sulfhydryl group was 316.67±5.31 mol/g.A rapid prototyping hydrogel was successfully prepared by using Sodium β-glycerophosphate(β-GP)to link the sulfhydryl groups on the side chain of HA-SH to form disulfide bonds.The mechanical properties of HA-SH hydrogels with concentrations of 2 %,4 % and 6 % were observed,and the hydrogels with concentrations of 4 % had the best effect.The hydrogel prepared by the combination of S-PLLA microspheres and HA-SH showed significantly enhanced mechanical properties with decreased swelling ratio,and no significant difference in cell compatibility compared with HA-SH.Cancer is a malignant tumor originated from epithelial tissue,which has become a threat to human physical and mental health.Curcumin(Cur)is a kind of plant polyphenol extracted from curcumin,which is a widely concerned anticancer pharmaceutical.Doxorubicin(Dox)is an anti-tumor antibiotic that inhibits the production of DNA or RNA and has an effect on a variety of tumors.The good dispersibility of Cur in organic reagent can be used in preparing Cur/S-PLLA/HA-SH hydrogels while loading pharmaceuticals to S-PLLA microspheres and combining with HA-SH.Dox was dispersed in aqueous solution and loaded onto HA-SH to prepare Dox/HA-SH hydrogel.Then the two pharmaceuticals were combined to prepare(Cur)S-PLLA/(Dox)HA-SH double-loading hydrogel.The addition of pharmaceuticals shortened the gel forming time and the concentration of pharmaceuticals did not have a great impact on the mechanical properties of the gel.The results of cell experiments showed that Dox could be released rapidly in a short time,while Cur was released slowly.So the inhibition effect of double-loading hydrogel on cancer cells was the most obvious.