| In order to improve the drug loading and effectively avoid burst release,nanoporous materials which could be designable and modificative is gradually used as drug carriers.The drug release profiles couldn't be predicted and cotrolled accurately,so the drug daily release amount and release rate can not be adjusted based on the patient individual.Therefore,the development of new nano-drug delivery systems which could realize "programmable" release and tune drug delivery precisely is a very valuable and prominsing research,and it provides a new direction to achieve individualized and customized medical therapy.The host-guest interaction is the kinetic basis for drug release.The reason for drug uncontrollable release kinetics is that the activation energy of the host-guest interaction is usually discrete and can not be continuously regulated.In this paper,the metal-organic frameworks(MOFs)were used as novel carriers for guest molecules,and a variety of different functional groups were introduced to construct multivariate metal-organic frameworks(MTV-MOFs).Because the host-guest interaction between functional groups and guest molecules can be quantified separately,the host-guest interaction between MTV-MOFs and guest molecules can be controlled by adjusting the combination and proportion of different functional groups in the frameworks.And the drug release rate can be tuned in a wide range.Further,the host-guest interaction is also be quantified in some extent.It provides a new method for studying the host-guest interaction,especially for weak interactions(such as static electricity,hydrogen bonds,?-?,van der Waals forces,etc).Through regulating the pore chemical environment at the molecular level,the drug release was dialed-in.And it is worth mentioned that this method is not only applicable to control single drug molecule release,but also to adjust drug co-loading system,so that,the drug release curve could be "programmed"precisely based on the patients actual needs.(1)A series of MTV-MIL-101(Fe)s materials were synthesized by controlling the proportion of terephthalic acid,2-aminoterephthalic acid and 1,4-naphthaleic acid.The consistency of the structure of MIL-101(Fe)s with the reported one is confirmed by X-ray powder diffraction(PXRD),scanning electron microscopy(SEM),transmission electron microscopy(TEM),nitrogen adsorption and EDS.The morphology of the samples is octahedral and the particle size is about 300 nm.The MIL-101(Fe)s show high the Brunauer-Emmett-Teller(BET)surface areas,and the distribution of the two ligands in the feamework is homogeneous.So MTV-MOFs are not the physical mixture of the single linker MOFs which come from two different kinds ligands.(2)The activated MTV-MIL-101(Fe)s were added to the ethanol solution of guest molecules(ibuprofen,rhodamine B and doxorubicin),and the guest molecules were single/co-loaded.The ibuprofen and rhodamine B were loaded into MIL-101(Fe)-(NH2)x,MIL-101(Fe)-(C4H4)x,MIL-101(Fe)-(NH2)x(C4H4)1-x respectively and doxorubicin was single loaded into MIL-101(Fe)-(NH2)x(C4H4)1-x.At last,ibuprofen/rhodamine B or ibuprofen/doxorubicin were co-loaded to MIL-101(Fe)-(NH2)x(C4H4)1-x.All samples were wrapped with hyaluronic acid after loading guest molecules.The complex was digested by NaOH solution,and the capacity of guest molecules was determined by HPLC and fluorescence spectrophotometer.(3)After wrapped by hyaluronic acid,the compounds with guest molecules were added to the dialysis bags to detect the release profiles in HEPES buffer solution.The release medium was exchanged by fresh buffer solutions at specific time intervals,and the amount of guest molecule in the solution was determined by HPLC or fluorescence.In the single-loading system,it was found that the release of ibuprofen increased with 1,4-naphthalene dibenzoic acid ratio adding,while with the ratio of the-NH2 functional group increasing,the release slowed down.From the ibuprofen release kinetics,the order of the interaction between these three ligands and ibuprofen was obtained,2-aminoterephthalic acid>terephthalic acid>1,4-naphthalene dibenzoic acid.And for rhodamine B single loading system,the release law was adverse with ibuprofen.Faster release was observed as the ratio of 2-aminoterephthalic acid linkers increasing,while the release slowed down when more terephthalic acid linkers were present.In contrast,for MIL-101(Fe)-(C4H4)x,the increase of terephthalic acid linker ratio leaded to faster rhodamine B release,while the presence of 1,4-naphthalene dibenzoic acid linker slowed down the release process.From these phenomena,the order of the interaction between these three ligands and rhodamine B was obtained,1,4-naphthalene dibenzoic acid>terephthalic acid>2-aminoterephthalic acid.For the doxorubicin single loading system,the release law is the same with rhodamine B.When the content of-C4H4 increased in the framework,the release slowed down;when the ratio of-NH2 functional group increased,the release was accelerated accordingly.So the drug release was dialed-in by adjusting the ratio of linkers in the frameworks.For the co-loading system of guest molecules,the release laws were consistent with the single loading systems.In the system of ibuprofen and rhodamine B,the release of ibuprofen was accelerated,while the release of rhodamine B slowed down when the content of-C4H4 increased in the framework.With the-NH2 functional group increasing,the release of ibuprofen became faster and the release of rhodamine B became slower.For the ibuprofen and doxorubicin co-loading system,the release behavior of ibuprofen maintained and the release of doxorubicin was same with rhodamine B.So the "programable" co-delivery of two kinds of drugs were realized.(4)Based on the diffusion theory,the Weibull model is derived and the actual physical meaning of the parameters is given in the model:k is a parameter which is relevant with host-guest interaction and n is a parameter which is relevant with guest-guest interaction and pore confinement.The Weibull model was used to fit the release curve of guest molecules,and the fitting results were consistent with the experimental ones.Combining the Weibull model with the Arrhenius equation,a linear coorelation between the In k value and the ratio of ligands in the framework is found.So the host-guest interaction is related to the ratio of linkers.And the drug release could be dialed-in by tuning the linker proportion in metal-organic frameworks.The Weibull model is also used to predict the release kinetics of guest molecules.And the predicted profiles were consistent with the experimental ones,which proved the applicability of the Weibull model in these system.Through idealizing the carrier model,the maximum release amount of guest molecules is calculated.In the MTV-MOFs system,the time of the maximum release amount is related with the proportion of ligands in the framework,and can be adjusted by changing the proportion of ligands.In contrast,for the physical mixture system of single ligand MOFs,two kinds of maximum release peaks appear which correspond to two different MOFs frameworks,respectively.When the ratio is changed,the intensity of peaks changes,but the time of peaks is invariant.So the physical mixture can not adjust the time of the guest molecules maximum release amount.These results are also proved in experiments.In the case of doxorubicin loading MIL-101(Fe)-(NH2)x(C4H4)1-x,the time to achieve the maximum release amount was shifted up to 12 days,from the 17tth to the 29th day over a 40-day release period.Such flexibility is not observed in the physical mixture of the single-component MOF counterparts.MTV-MOFs as a drug carrier can tuned the guest molecules release behavior,the release rate and the daily release amount.And it shows a great research value and application prospect in individualized and customized medical therapy. |
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