Fabrication And Performance Of Cellulose-based Stimulus-responsive Drug-loaded Injectable Hydrogel

Injectable hydrogel drug delivery systems have attracted extensive attention due to their ability to deliver the desired drug to the target site minimally invasive,without releasing any drug dose to other parts of the body.Among them,stimuli-responsive injectable hydrogels can respond to external stimuli,so such hydrogels have excellent application prospects in the field of drug release.In the early days,most of these injectable hydrogels came from synthetic polymers,which potential toxicity limited their applications in the biomedical field.In recent years,most researchers started to use biomass-based natural polymers instead of synthetic polymers to synthesize injectable hydrogels.Cellulose is the most abundant biomass-based natural polymer in the world.It has the advantages of being renewable,cheap,environmentally friendly,biodegradable,and accessible to chemical modification.However,the current cellulose-base injectable hydrogel drug delivery system had some problems,such as uncontrollable process,low hydrophobic drug loading rate,and short sustained-release cycle.Based on the above issues,the cellulose-based thermo-sensitive injectable hydrogel was prepared by grafting NIPAAm on the cellulose chain in this paper,which used the ARGET-ATRP technology and organic photocatalytic ATRP technology.Based on this,fluorescent monomers were introduced to make the hydrogel possess fluorescence properties.Furthermore,polydopamine nanoparticles(PDA-NPs)were introduced to realize the controlled release of anticancer drugs under near-infrared light,and the photothermal effect of PDA-NPs was also used to assist the killing of cancer cells.The main contents are as follows:1)A cellulose-grafted-poly(N-isopropylacrylamide)(cellulose-g-PNIPAAm)copolymer with thermo-responsivity was synthesized using ARGET-ATRP technique.The MCC was used as raw material in this process,and NIPAAm was used as a monomer.The prepared cellulose-g-PNIPAAm was a transparent solution in water or PBS at low temperature and concentration,and could self-assemble into micelles at 37℃.TEM showed that the micelles formed in water and PBS buffer had a spherical shape.However,the cellulose-g-PNIPAAm copolymer at a concentration over 4.2% by weight in water formed an injectable thermoresponsive hydrogel composed of micelles when the temperature increased to 37℃.The cellulose-based injectable thermosensitive hydrogel was used to load the anticancer drug doxorubicin(DOX).In vitro release studies demonstrated that this hydrogel could continuously release DOX for up to 20 days,and there was no sudden drug release.Furthermore,the cytotoxicity test showed that the hydrogel had high biocompatibility.Based on the above results,this cellulose-based injectable hydrogel has strong potential for application in intelligent drug delivery systems.2)Injectable hydrogels were prepared by introducing fluorophore into the cellulosebased thermo-responsive injectable hydrogel.Cellulose-based injectable hydrogel with thermo-responsivity and fluorescence characteristics was prepared by grafting NIPAAm and carbazole derivatives(Cz)on the MCC chain.And we investigated the effect of carbazole group amount on the properties of the block copolymer.During the preparation process,two block copolymers were obtained by controlling the content of carbazole,which was recorded as cellulose block copolymer 1(cellulose-g-(PNIPAAm&PCz)1)and cellulose block copolymer 2(cellulose-g-(PNIPAAm&PCz)2).It showed that cellulose-g-(PNIPAAm&PCz)1had similar properties to the cellulose-g-PNIPAAm.However,the micelles obtained from cellulose-g-(PNIPAAm&PCz)1 were more compact than those obtained from cellulose-gPNIPAAm.The hydrogels composed of cellulose-g-(PNIPAAm&PCz)1 had thermoenhanced fluorescence,which is contrary to the decrease of the fluorescence of the monomer when the temperature increased.Cellulose-g-(PNIPAAm&PCz)2 cannot be uniformly dispersed at low temperatures and cannot form hydrogel at 37℃ due to its abundant hydrophobic carbazole groups.On the other hand,the cellulose-g-(PNIPAAm&PCz)2 was dissolved in an organic solvent,and micelles were obtained by dialysis.Furthermore,the cytotoxicity test showed that the hydrogel had high biocompatibility.Based on the above results,the injectable hydrogels and micelles obtained from the cellulose grafted block copolymer have potential applications in the field of drug delivery and fluorescent probes.3)Cellulose-g-PNIPAAm&PDA composite injectable hydrogels with near-infrared photothermal response were prepared by introducing PDA-NPs into the cellulose-based thermo-responsive injectable hydrogel.SEM and TEM tests showed that the PDA-NPs had a regular spherical structure and uniform particle size distribution.The experimental results indicated that the addition of PDA-NPs did not affect the thermal stability and sol-gel transition of the injectable hydrogel.In addition,rheological tests showed that the injectable hydrogel’s yield strain and mechanical strength improved by adding PDA-NPs.Moreover,the composite hydrogel displayed a good photothermal effect due to the addition of PDA-NPs.The photothermal irradiation indicated that the composite hydrogels contained 1mg/m L PDANPs exposed to a NIR for 80s;The surface temperature could be increased to more than 50℃.The DOX was also loaded into the injectable composite hydrogel.In vitro release studies demonstrated that the drug release rate of the composite hydrogel was promoted by NIR laser exposure,which is expected to develop a nondestructive drug release treatment.4)Cellulose nanocrystals enhanced cellulose-based injectable hydrogels.Cellulose-gPNIPAAm&PDA composite injectable hydrogel had low strength.The strength of injectable hydrogels was improved by preparing PNIPAAm/CNCs&PDA composite hydrogels and adding CNCs into cellulose-g-PNIPAAm&PDA composite injectable hydrogels to meet different needs.The PNIPAAm/CNCs&PDA composite hydrogels with near-infrared response were prepared by using NIPAAm as the monomer,PDA-NPs as the functional coupling agent,and CNCs as enhancement agent.SEM showed that PDA-NPs were dispersed in composite hydrogels evenly.However,due to introducing too many chemical reagents in the preparation process,the composite hydrogels needed dialysis treatment before use,so they could not use as injectable hydrogels like cellulose-g-PNIPAAm&PDA.Therefore,cellulosebased injectable hydrogels with strong mechanical properties were prepared by directly introducing CNCs into cellulose-g-PNIPAAm&PDA composite injectable hydrogel.Rheological tests showed that the elastic modulus of cellulose-g-PNIPAAm&PDA injectable hydrogels increased from 1KPa to 10 KPa when added 2% CNCs.Moreover,this value was higher than the elastic modulus of PNIPAAm/CNCs&PDA composite hydrogels with the same 2% CNCs addition amount.Therefore,high-strength cellulose-base injectable hydrogels could be prepared by adding a small amount of CNCs to cellulose-g-PNIPAAm&PDA composite hydrogel.5)Cellulose-based thermo-responsive injectable hydrogel were prepared by organic catalytic ATRP technique.Finally,to further reduce the cytotoxicity of cellulose-based injectable hydrogels and enhance their biocompatibility.Cellulose-based thermo-responsive injectable hydrogels were prepared by organic catalytic ATRP technique.In this study,MCC was used as raw material,NIPAAm was used as monomer and 10-phenylphenothiazine(PTH)was used as a photocatalyst to carry out organic catalytic ATRP reaction under 365 nm UV light.FTIR and 13 C NMR indicated that the structure of cellulose-g-PNIPAAm* prepared by organic catalytic ATRP was consistent with that of cellulose-g-PNIPAAm and had the same sol-gel transition properties.In addition,TEM indicated that cellulose-g-PNIPAAm* could also self-assemble into micelles.SEM observed that the injectable hydrogels composed of cellulose-g-PNIPAAm* presented a good three-dimensional network structure.In addition,in vitro release studies showed that the hydrogel could release DOX for up to 10 days,and there was no sudden drug release.In addition,the cytotoxicity indicated that the hydrogel was biocompatible.It has been proved that organic catalyst ATRP could apply to the preparation of cellulose-based injectable hydrogels.