| Drug delivery refers to the method to achieve the expected therapeutic effect safely and effectively by means of formula strategy,encapsulation technology,targeted method and other means according to specific needs in the process of transporting therapeutic drugs in vivo.In recent years,drug delivery methods using supramolecular chemistry have shown broad prospects.The advantage of supramolecular chemistry lies in the use of specific,dynamic and adjustable non-covalent interactions to improve solubility,reduce irritation and side effects,and improve drug efficacy.Through reasonable design,it can further endow drugs with precise delivery,controlled release and collaborative treatment functions.Supramolecular drug delivery systems provide a new perspective to improve the depth,breadth and precision of drug application,especially their application in "intelligent" therapy and precision medicine in emerging fields.In this paper,two macrocyclic molecules,acyclic cucurbit[n]uril and cyclodextrin,are used as drug carriers to improve the water solubility,reduce toxic and side effects,and improve the efficacy of capsaicin;And construct a bifunctional drug delivery system with tumor-targeting and glutathione stimulation response.The main contents of this paper are as follows:The first part is to use the excellent recognition ability of acyclic cucurbit[n]uril to encapsulate capsaicin molecules,so as to improve the water solubility of capsaicin,mask its strong irritation,and improve its protective effect on gastric mucosa.Three kinds of inclusion complexes of acyclic cucurbit[n]uril(M1-3)and capsaicin were prepared,and their inclusion behaviors were systematically studied by fluorescence spectra,XRD,FT-IR,SEM,TGA and NMR.The 2:1 host-guest inclusion complex with a strong binding constant were formed,and the encapsulation rate is up to 42.30%.The water solubility of capsaicin after inclusion can be increased by 12076 times.In vitro experiments showed that the encapsulation strategy based on acyclic cucurbit[n]uril effectively inhibited the expression of NO and IL-1β.and the antioxidant activity,antiinflammatory activity and preventive effect on ethanol-induced gastric mucosal injury were significantly improved,while the irritation to normal cells was significantly reduced.Laser confocal images showed that the inclusion complexes could be effectively internalized by GES-1 cells and located in the cytoplasm.In vivo mouse model,these inclusion complexes also showed great biosafety.The second part is to combine the advantages of functionalized cyclodextrin with traditional drug delivery platforms to build a bifunctional supramolecular drug delivery system with active targeting and stimulation response.Taking CAIX specifically expressed on tumor cells as the target,a supramolecular host(L-CD)with targeted function was designed and synthesized based on the β-cyclodextrin skeleton.It can form an amphiphilic inclusion complex with adamantane/disulfide modified methotrexate prodrug(MTX-SS-Ad),which can further self-assemble in water to form supramolecular nanoparticles(SNPs)of moderate size.The sulfanilamide group exposed on the surface of nanoparticles can preferentially deliver SNPs to tumor tissue,and the disulfide bond breaks under the promotion of high glutathione environment after entering the cell,realizing the disintegration of SNPs and drug release.The hostguest interaction was studied by various characterization methods.The self-assembly size and morphology of SNPs were determined by DLS and TEM,which shown that SNPs existed as spherical vesicles with a particle size of 77.93 nm and could be released rapidly under the stimulation of glutathione.Molecular docking,in vitro inhibition experiment and Western blotting showed that SNPs had great inhibition effect of CAIX in and out of cells.This strategy not only effectively inhibits the proliferation of cancer cells,but also does not cause additional toxic side effects on normal cells. |
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