Preparation And Application Of Electrospun PH And Thermo-sensitive Nanofibers

In recent years,sensitive polymers have drawn extensive attention in academia.These types of polymers have shown great values and potential in the fields including the preparation of ideal biomaterials,drug delivery system and bio-sensors ctc.Their physicochemical properties(like structure,size etc.)will responsive to the stimulus in the environment.These stimulis include temperature,pH,electric field,magnetic field,light,etc.Among these,the most common-studied ones should be pH and thermo-sensitive polymers.Electrospun nanofibers do not only have high porosity and high surface area-to-volume ratios,but also exhibit good biocompatibility,which have obtained huge achievement in several fields,especially as drug delivery system.They usually have high drug loadings and bring about ideal drug dissolution and release rates.Moreover,by selecting suitable materials,drug-loaded method and spinning technology,the gradual and controlled drug release system for various purposes could be designed and prepared.Based on these advantages,nanofibrous cancer therapy system and wound dressings also have great potential.For cancer therapy,nanofibers can achieve the gradual release of anti-cancer drugs to improve the availability,decrease the toxicity and intake frequency of the drugs.For wound dressings,the gradual and controlled release of the healing drugs could be achieved.Besides,nanofibrous wound dressings also show good hemostasis,semi-permeability,scar-free,controllability etc.These further improve the application values of electrospun nanofibers.However,few work succesfully fabricate sensitive polymers into stimuli-responsive nanofibers by using electrospinning to combine the advantages of them in recent years.And the applications of the existing products are still very simple and basic.The reasons are:(1)the preparations of the sensitive polymers are usually expensive and complicated.Moreover,most of they have poor spinnability.That wound be high-cost to apply them into nanofibers.(2)It is still not clear how to apply the resultant products.So it is impossible to combine their advantages into some fields to achieve their potential values.(3)For the existing sensitive nanofibers for certain purposes,their study lack more specific property study to support their values.Due to these limitations in this field,this work aims to fabricate pH and thermo-sensitive polymers with poor spinnability into sensitive nanofibers by improving the spinning technology.Then some active agents and model drugs will be loaded into the fibers to bring about some specific function with certain application purposes.After the characterizations for the final products,the applications of these pH and thermo-sensitive nanofibers as drug release system,cancer therapy and wound dressings will be studied emphatically to achieve the combination of the advantages from sensitive polymers and electrospinning technology.This work comprises three sections with 7 chapters.The first section contains Chapter 2 and 3,has mainly studied one common-used pH-sensitive polymer,Eudragit.After being electrospun into nanofibers,their potential as pH-responsive drug release system and colon cancer therapy was explored.This work combined the advantages of the pH sensitive polymers and electrospinning.The resultant pH sensitive nanofibers reserve the pH sensitivity and also have the advantages of nanofibrous drug delivery system.In Chapter 2,one typical polymer of Eudragit family,Eudragit L100-55 was chosen for electrospinning.By using electrospinning,the solutions were electrospun into nanofibers.The fibers had good morphology under the settled spinning parameters.Based on this technology,certain amount of model drug,KET was loaded into the fibers during spinning to construct the KET-loaded Eudragit L100-55 nanofibers as drug delivery system.They were immersed into HCl medium(pH 1.2)for 2 hours to simulate the gastric fluids in human body.Then they were moved to PBS medium(pH 7.4)to simulate the intestinal fluids to test the drug release behaviors of the fibers in vitro.Results showed that only tiny of the drugs released in HCl,but the release was faster in PBS.These indicated Eudragit L100-55 nanofibers have good pH-sensitivity and could be applied as colon-targeted oral administration.In Chapter 3,we further applied Eudragit L100-55 nanofibers as a kind of colon cancer therapy.By using coaxial-electrospinning,the core-shell nanofibers as oral administration for colon cancer therapy were produced.One photosensitizer,Rose Bengal and one anti-cancer compound,Carmofur were loaded into the mucoadhesive polymer,HPMC as the core layer of the formulation.Eudragit L100-55 was used as shell to protect the drugs from massive release in gastric fluids and release the drugs in the medium with high pH to complete the targeted delivery of the anti-cancer drugs.After the optimization of the spinning,the core-shell fibers were produced successfully and they showed good morphology.The in vitro drug release test is same as Chapter 2 showed less than 16% of drugs released in HCl medium,but the drugs could be released gradually for over 72 hours in PBS.Cell viability tests indicated that Roses Bengal could be activated by light to kill the colon cancer cells,Caco-2 with selective effects.And the combination of Rose Bengal and Carmofur in the fibers showed better anti-cancer effects.Furthermore,we used the colon tissues from rats to test the mucoadhesive property in vitro.Results showed the core layer of the fibers could be effectively sticky to the colon wall for at least 4 hours because of the existence of HPMC in the fibers.These results demonstrated the potential of this drug-loaded core-shell nanofibers applied as targeted colon cancer therapy.The second section of this work is from Chapter 4 to 6,mainly studying the synthesis of two kinds of thermosensitive polymers and trying to fabricate them into nanofibers.We explored the advantages of the thermosensitive nanofibers as drug release system and wound dressings.Also,we compared the differences of the applications of the two polymers.The prepared nanofibers have both of thermosensitivity and nanofibrous structure.They could be applied as thermosensitive drug delivery system to achieve the drug release controlled by temperature.Moreover,thermosensitive polymers could effectively control the interaction between cells and materials by adjusting the temperature.So,they could be applied as wound dressing to reduce the secondary injures while replacing the dressings from the wounds.In Chapter 4,two kinds of thermosensitive polymers were synthesized by using relatively simple and effective method.By using temperature controlled ultraviolet spectrophotometer,the LCST of the two polymers could be seen,which are close to human body temperature,thus having good application prospects as biomaterials.Cell viability tests showed PDEGMA had better cyto-compatibility than PNIPAAm.Moreover,these two polymers were attempted to be fabricated into nanofibers via electrospinning.We finally used HFIP as solvent to create the nanofibers and concluded PNIPAAm had better spinnability over PDEGMA.Based on the conclusions of Chapter 4,we blended the two thermosensitive polymers with another polymer,EC to improve the spinnability,bring about the stability and decrease the cost in Chapter 5.By exploring the best spinning parameters,the blended nanofibers with good morphology were prepared.The thermosensitivity of the fibers were studied by temperature-controlled contact angle test.It was found that the fibers could become hydrophobic from hydrophilic when the temperature increased over LCST.The KET release rates and final ratios were higher at 25 ? than that of 37 ?,indicating its promising temperature-responsive drug release behaviors.They also showed gradual release properties because of the existence of EC in the fibers.In addition,cell tests verified that the fibers based on PDEGMA had better biocompatibility than those based on PNIPAAm.Therefore,we believe these blended thermosensitive nanofibers own the advantages and potential as ideal drug gradual and controlled release system.In Chapter 6,we picked PDEGMA from these two thermosensitive polymers as its better biocompatibility to apply into eletrospinning to produce the nanofibers wound dressing materials.Same as Chapter 5,we used another polymer to blend with PDEGMA for the same purposes.In this work,PLCL was chosen rather EC,as it has better mechanical property and more extensive applications than EC.After spinning with correct parameters,PDEGMA/PLCL composite nanofibers with good morphology were prepared successfully.Besides,one antibiotic,CIF was loaded to the fibers to bring about antibacterial property for the fibers.CIF could be released from the fibers for more than 72 hours gradually.The antibacterial test indicated CIF-loaded fibers could inhibit the growth of microorganisms for 72 hours.In vitro cells tests showed that L929 fibroblasts could proliferate on the fibers.Moreover,they could also be detached from the fibers by changing the culture temperature(25 ?)and the detached cells still had good cell viability.These verified the fibers could be potentially applied to reduce the secondary injuries as dressing materials.To confirm the good healing performance,the in vivo test on rats was conducted.During the test process,the thermosensitive nanofibers could be removed from the wounds easily after the treatment with cold saline.These accelerated the healing process of the wounds.Afterwards,H&E staining and Western blotting test further demonstrated the better healing performance of PEDGMA/PLCL thermosensitive nanofibers than all the control groups.In the third section,which is Chapter 7 in this work,we tried to combine the previous sections to prepare the dual-responsive nanofibers and apply them as dual-responsive drug release system.This work successfully combined the dual-sensitivity and electrospinning,dealing with problem about the high-cost and complicated preparation of dual-sensitive materials.In this chapter,we adopt relatively simple and effective blending electrospinning to prepare the dual-sensitive nanofibers.This is more effective and less cost than the normal method to produce the similar products.We chose the pH-sensitive Eudragit L100-55 and thermos-sensitive PDEGMA,which all have been studied in previous sections as the materials.For the thermosensitive polymers,we chose PNIPAAm rather PDEGMA,because PNIPAAm has better spinnability.For PDEGMA,it was difficult to be blended with Eudragit L100-55 to prepare the spinning solutions.Eudragit L100-55/PNIPAAm could be fabricated by blending spinning.Also,KET was loaded.The resultant fibers showed dual-responsive drug release behaviors during the drug release test at different temperatures and in different medium.The KET release could be faster in higher pH or at lower temperature.Besides,the fibers are non-toxic to cells.So this work provides a good example for producing the multi-sensitive drug release system.In conclusion,we successfully fabricated pH and thermo-sensitive polymers into sensitive nanofibers via electrospinning and achieve the combination of their advantages.By optimizing the spinning technology,we prepared a series of sensitrive nanofibers effectively,which have applied as sensitive drug release system,cancer therapy formulation and wound dressings.They demonstrated that it possible to apply the thermosensitive polymers into sensitive nanofibers by using electrospinning.Moreover,the application purposes were ascertained and a serial of modern tests could support their applications values.We believe this work could provide guide and reference for preparing more sensitive nanofibers with high values in the future.