| BackgroundCyclodextrins(CDs)are open at both ends,slightly conical hollow cylinder three-dimensional ring structure.Cavity was hydrophobic,and the external was hydrophilic.Due to the unique cylindrical structure,internal hydrophobicity and external hydrophilicity.Cyclodextrins can contain specific molecules,with the ability of binding host and guest molecules.Cyclodextrins are non-toxic and harmless,and their inclusion can enhance the stability of the drug molecule,increase the solubility of the drug,reduce the adverse reaction,improve the bioavailability and so on.Therefore,the cyclodextrin as a suitable drug carrier is widely used in the field of medicine.Nowadays,modified cyclodextrin has become a hot topic because of its solubility in water and inclusion capacity.Carboxymethyl-?-cyclodextrin(CM-?-CD)is one of the ?-cyclodextrin derivatives,which has low solubility in low pH solutions.However,it can be dissolved at any concentration and better self-mobility in the alkaline solution(pH>4),due to the dissociation of carboxyl.So,it has a good solubility in the intestinal environment.In addition,it has lower hemolysis.Recently,carboxymethyl-?-cyclodextrin has been used in drug-enxtended release formulations.Cell-penetrating peptides(CPP)are small peptides that are able to ferry much larger molecules into cells,and have transmissive transport capacity.Biomarkers have an important effect on the treatment of many diseases.However,due to first pass effect and cell barrier,macromolecules penetrate into the cell through the cell membrane difficultly,that makes the therapeutic value of biological macromolecules in the field of medicine applications limited.The discovery and application of cell-penetrating peptides undoubtedly solve this problem to a great extent.Cell-penetrating peptides,as a drug-loaded material in vivo and in vitro transport,have better advantages than other biological macromolecule,such as high transport efficiency,carrying more species,less toxic,and so on.Studies show that the guanidine is the key factor that affect the penetration ability of the membrane.Eight poly arginine(R8)are rich in guanidine,so it has stronger penetration ability.Insulin can promote cell uptake and utilization of glucose,and inhibit the decomposition of glycogen and glycogen mutation.And it can decrease the level of blood sugar.Hence,insulin is preferred treatment drug of type I and type II diabetes.But long-term injection of insulin has brought a lot of pain to the patients' body and mind,such as local skin allergies,swelling and fever,and even subcutaneous fat atrophy or hyperplasia.So many scientific researchers are committed to the study of insulin non-injection administration.However,insulin has been a great hindrance in the research and application of the non-injection administration,due to itself vulnerable to digestion and combined with the cell barrier effect.The combination of cyclodextrin and cell-penetrating peptides two drug can combine the advantages of both.It has an important application prospect for promoting the effective transport of drug macromolecules.AimResearch and develop novel drug carrier material:R8-CM-?-CD.synthesis the R8-CM-?-CD by chemical reaction,characterize the structure,and explore the feasibility of the inclusion.Finally,prepare R8-CM-?-CD/insulin inclusion and study its effect on enhancing insulin stability.Methods1.Synthesis and characterization of R8-CM-?-CD:The R8-CM-?-CD was successfully synthesized using R8 and CM-?-CD as raw materials and N,N-dimethylformamide(DMF)as solvent.The structures were characterized by IR,UV,XRD,DTA and MALDI-TOF-MS.2.Preparation of R8-CM-?-CD/insulin inclusion:Determine the best inclusion ratio by equal equimolar method,and prepare the inclusion according to the inclusion ratio.Identify the inclusion through thermal analysis(DTA,TGA).3.R8-CM-?-CD performance study:Study both penetrating ability in vitro and enzyme stability.Experiments include:determine insulin content through Caco-2 monolayer cells,observe insulin fluorescence signal strength by laser scanning confocal microscopy,as well as determine the remaining content of insulin in the chymotrypsin degradation.Results1.IR,UV,XRD,DTA and MALDI-TOF-MS results suggest that the R8-CM-?-CD is all successfully synthesized.2.DTA and TGA results show that R8-CM-?-CD/insulin inclusion are successfully prepared.Compared with CM-?-CD,inclusion of R8-CM-?-CD is stronger and the formation of inclusion is more stable by determining of inclusion constants.3.Penetrating ability experiment results.suggest that the R8-CM-?-CD has a better ability to penetrate the membrane.Enzyme stability experiment results show that R8-M-?-CD can effectively inhibit the degradation of insulin by chymotrypsin.ConclusionThe R8-CM-?-CD,as a drug carrier material,is successfully synthesized by chemical reaction.It has a stronger ability to include biological macromolecules and penetrate the membrane.It can also significantly enhance the stability of insulin and improve bioavailability.Therefore,the new drug-loaded material has important research significance and will have a broader prospect in the field of medical applications... |
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