Development And Application Of Drug Delivery System Based On Bioactive Ionic Liquid

Drug delivery systems mainly include oral,injection,and transdermal administration,among which oral administration is widely used for its advantages of painlessness,self-management,and high patient compliance;injection administration has accurate dosage,and bioavailability The advantages of high and fast reaching plasma levels;the biggest advantage of transdermal administration is to avoid the first-pass effect of the liver,which is convenient for patients to self-administer.Therefore,oral administration,injection administration,and transdermal administration are currently the most used clinical drug delivery systems.However,the existing drug delivery carriers have many shortcomings,such as poor controllability of drug carriers,small drug loading,poor biocompatibility,weak targeting,and high toxicity,which hinder their clinical application.Therefore,there is an urgent need to develop new drug carriers with good controllability,large drug loading,good biocompatibility,strong targe ting,and low toxicity.Ionic liquids（ILs）are molten salts that are liquid at room temperature and have the advantages of designability,green non-toxicity,high stability,high solubility,and specific biological activities.They are widely used in green solvents,drug delivery,and drug synthesis and other fields show great application prospects.Therefore,this thesis developed four bioactive IL drug delivery carriers through rational design and modification of biologically active ILs and studied the toxicity and biocompatibility of IL drug delivery carriers in vitro experiments.The feasibility and efficacy of IL drug delivery carriers were studied through in vivo experiments.The main research work and contents are as follows:Using L-（-）-carnitine（Car）or betaine（Bet）as the cation precursor and taurine（Tau）with antitumor activity as the anion precursor,the taurine-based IL[Car][Tau]（ILs generated by L-（-）-carnitine and taurine）and[Bet][Tau]（ILs generated by betaine and taurine）were prepared by the ion-exchange reaction.Both ILs exhibit good fluidity,stability,biocompatibility,and non-toxicity at room temperature.Among them,[Car][Tau]can effectively transdermal deliver insulin and dextran,with the cumulative transdermal amounts of 54.97%and 47.38%,respectively;which were 3.59-fold and 4.45-fold higher than those of the phosphate buffer saline（PBS）,respectively.In addition,after co-incubating[Car][Tau]with tumor cells for48 h,the cell survival rate was 8.29%.With the increase of the concentration,the apoptosis of tumor cells also gradually increased;when the concentration of[Car][Tau]was 200μg m L^–1,the inhibition rate of tumor cells was 92.56%.[Car][Tau]combined with chemotherapeutic drugs（doxorubicin,DOX）could improve the efficacy of drugs and reduce their side effects of drugs.Using L-（-）-carnitine as the cation precursor and malic acid（MA）or citric acid（CA）as the anion precursor,MAC（abbreviation for the formation of IL from malic acid and L-（-）-carnitine）and CAC（abbreviation for citric acid-L-（-）-carnitine IL）were prepared by a combination of density functional theory calculations and experimental studies,respectively.An IL-in-oil-based microemulsion（MME）was developed using isopropyl myristate,Tween-80/Span-20,and MAC.The pseudo-ternary phase diagram results show that the MME has a larger microemulsion region,smaller nano-droplets,and stability at room temperature than the conventional water-in-oil microemulsion.Compared with water,the solubility of rosiglitazone and bezafibrate in MME were increased by 49.28 folds and 61.11 folds,respectively.MME transdermal delivered insulin approximately 1.22 folds more than MAC.In addition,after co-incubation with mouse embryonic fibroblast cells and human colorectal adenocarcinoma cells for 4 h,the fluorescence intensity of the MME group was stronger than that of the free PBS group（1.25 and 1.99 folds）.The cell viability of MME was 97%,indicating that MME has lower cytotoxicity as a drug carrier.Few-layer IL-Ti₃C₂T_x MXene composite nanomaterials with an average lateral dimension of less than 200 nm and an average thickness of 1–4 nm were prepared by fluorine-containing imidazolium-based ILs via a"one-step"-assisted Ti₃Al C₂MAX phase exfoliation,intercalation,and surface modification.The composite nanomaterials can be uniformly dispersed in water,PBS,saline,and culture media,and the composite nanomaterials in water were 164.5 nm;after the nanomaterials were stored in solution for 30 days,their nanosheets and polydispersity index have not changed significantly,and the sheet-like structure remained.ILs can inhibit the oxidation of MXene nanosheets,enabling them to have better stability.Under 808nm laser irradiation,the IL-Ti₃C₂T_x MXene composite nanomaterials exhibited good photothermal stability,strong near-infrared absorption,and photothermal conversion efficiency as high as 63.91%.In addition,IL-Ti₃C₂T_x MXene@DOX composite nanomaterials can promote drug release under acidic and 808 nm laser irradiation.In vitro and in vivo experiments showed that IL-Ti₃C₂Tx MXene composite nanomaterials exhibited obvious antitumor effects on mouse breast cancer cells under laser irradiation,and had a good photothermal and photoacoustic imaging at the tumor site.A poly（ionic liquid）（PIL）-based block polymer（P-3）containing targeting ligands,light,and p H responsiveness was prepared using a radical polymerization method.The polymer P-3 can self-assemble into nanoparticles with a particle size of 40 nm in an aqueous solution,and its particle size and polydispersity index did not change significantly after 10 days of storage at room temperature.The nanoparticles can be uniformly dispersed in water,PBS,and culture medium.The particle size of P-3@DOX was 60 nm,which makes it have a high drug loading capacity of approximately 70%,achieving controlled drug release under acidic and light irradiation.In vitro experiments showed that P-3@DOX could effectively kill more than 90%of human breast cancer cells and mouse breast cancer cells at a concentration of 100μg m L^–1.In vivo experiments show that the PIL-based drug-loaded nanoparticles have good targeting and accumulation capabilities at tumor sites,and can effectively inhibit the growth of tumor cells.