Preparation And Properties Of Thermosensitive Drug-loaded Micellar Nanofiber Membranes

Compared with traditional drug delivery,drug delivery system can significantly improve the solubility and stability of drugs.It can be administered directly to the target position of human tissue,effectively control the release rate of the drug,and improve the utilization efficiency of the drug.The combination of two or more drugs into a multiple drug delivery system can gain better synergistic effect of drugs.At present,electrospinning technology is not only the most widely studied,but also the most simple and convenient method to construct drug delivery system.Based on flexible spinning methods,multiple drug delivery systems can be prepared to meet different treatment needs.Therefore,in this paper,aimed at fungal wound repair,two kinds of nanofibers loaded with different drugs were designed and prepared by electrospinning technology.Each component is endowed with thermosensitivity to achieve accurate and controllable release of the two drugs to meet the different needs of drugs at different stages of wound repair.(1)N-isopropylacrylamide(NIPAAm)and dimethylacrylamide(DMAAm)were copolymerized by free radical polymerization,and then lactide was introduced by ring-opening polymerization to prepare amphiphilic block copolymers(P(NIPAAm-co-DMAAm)-PLA)with thermosensitive abiltiy.Curcumin-loaded micellar(Cur M)was prepared by combining amphiphilic block copolymers with curcumin(Cur)by dialysis.The prepared samples were characterized by NMR,IR,UV and TEM.The results showed that the amphiphilic block copolymer of lower critical solution temperature(LCST)at 41℃ had a critical micelle concentration(CMC)of 11.4 mg/L and could form a micelle with stable core-shell structure in water.The maximum drug loading of Cur M was 13.9 %,and the particle size in aqueous solution was 292.8 nm.Cur was stably loaded in the micelle in an amorphous state.The drug release experiment in vitro showed that the drug release rate of Cur M at 42℃(T>LCST)was higher than that at 37 ℃(T<LCST).Cur M could respond to temperature stimuli,thus regulating controlled release of drugs.(2)Poly(vinyl alcohol)(PVA)with good hydrophilicity,biocompatibility and biodegradability was used as a matrix and blended with thermosensitive Cur M for electrospinning to prepare composite nanofibers embedded with drug-loaded thermosensitive micelles(PVA/Cur M).The samples were characterized by SEM,TEM,XRD,IR,contact angle meter and laser confocal microscope.The results showed that when the mass ratio of PVA/Cur M was 4:1,the spinning voltage was15 k V,the receivingdistance was 15 cm and the liquid flow rate was 0.5 m L/h,the composite nanofibers with good morphology,smooth and uniform thickness could be prepared,and the average diameter of the fiber was 251 nm.It could be observed that the micelle can be successfully embedded in the nanofiber and distributed along the fiber axis,with Cur stably loaded in the micelle in an amorphous state.PVA/Cur M nanofibers treated with25 % glutaraldehyde for 6 h could significantly enhance the stability of the fiber membrane in water.In vitro drug release experiments showed that the drug-loaded micelles embedded in nanofibers could maintain the thermosensitivity,and enabled the nanofibers the temperature-controlled release function: inhibiting drug release at normal body temperature(37℃),whilepromoting drug release when the temperature was higher than LCST(41℃).(3)Polycaprolactone(PCL)with good biocompatibility and mechanical properties was added to polyisopropylacrylamide(PNIPAAm)with thermosensitivity to be used as the composite matrix.Ketoconazole(KCZ)was blended together with the matrix for electrospinning to prepare thermosensitive drug loaded composite nanofibers(PCL/PNIPAAm/KCZ).The samples were characterized by SEM,TEM,XRD,IR,contact angle meter and laser confocal microscope.The results showed that the electrospun fibers of PCL/PNIPAAm/KCZ had good fiber morphology when the spinning voltage was 15 k V,the receiving distance was 15 cm and the liquid flow rate was 0.5 m L/h.The fibers were smooth and uniform in thickness,and the average diameter was about 990～1230 nm.KCZ was loaded into nanofibers in an amorphous form and distributed in the fiber along with the fiber axis.When the temperature was higher than LCST(32℃),PCL/PNIPAAm/KCZ composite nanofiber membrane could change from hydrophilicity to hydrophobicity under the stimulus of temperature.The drug release experiment in vitro showed that the drug-loaded composite nanofibers could delay the release of KCZ at normal body temperature(37℃)while promote the release of KCZ when the temperature was lower than LCST(32℃).(4)A two-component double drug-loaded composite nanofiber membrane was prepared by combining PVA/Cur M and PCL/PNIPAAm/KCZ drug delivery components through double-needle electrospinning.The samples were characterized by SEM,TEM,XRD,IR,contact angle meter and laser confocal microscope.The results showed that there were two kinds of nanofibers with clear thickness,interpenetrating and good morphology in the composite nanofiber membrane.The thicker fiber was formed by PCL/PNIPAAm/KCZ component while the finer one was formed by PVA/Cur M component.Cur and KCZ could be successfully loaded into the nanofiber as amorphous form,and distributed in the fiber along with the fiber axis.The stability of PVA/Cur Mcomponent nanofibers in water were enhanced by glutaraldehyde cross-linking treatment of the composite nanofibers for 6 h.There was no obvious fusion and cross-linking between the fibers,which could maintain a good fiber morphology.The drug release experiment in vitro showed that the two-component double drug-loaded composite nanofibers could release KCZ,quickly at 25℃,slow release of KCZ for a long time when the temperature reached 37 ℃,and Cur could be released quickly when the temperature was increased to 42℃.In this paper,two-component double-drug-loaded composite nanofibers containing two kinds of drugs(Cur and KCZ)with different temperature response properties were prepared.Among them,KCZ can play a long-term bactericidal and bacteriostatic effect in the process of wound repair,while Cur can play a role in anti-inflammation and promoting skin repair.The two-component double drug-loaded composite nanofibers with thermosensitivity can be used as wound repair dressings in the treatment of wound fungal infection,which can not only treat the wound pertinently,but also regulate the release of the corresponding drug through adjusting the temperature at the different stages of wound repair,so as to promote the cure.