| Background:Supramolecular chemistry is mainly focused on molecular polymers with regular structures and special functions based on weak non-covalent molecular interactions,which correlate different scientific fields including Chemistry,Materials Science and Life Sciences.Cyclodextrin?CD?is one of the hot issues in supramolecular chemistry,which has been widely applied in the medical field.The poor solubility and low bioavailability are key barriers for insoluble drugs in preparations development and clinical applications.CD can form different supramolecules with progressive structures which can be used for insoluble drug delivery in distinguishable ways according to different spatial structures.As for single molecules,CD presents a cylindrical hollow structure and can be used to form inclusion complex with drug molecules based on host-guest interactions to efficiently enhance drugs solubility and modify the druggability.Relying on coordination with metal ions,CD can be regularly assembled to form spatially porous metal-organic frameworks?CD-MOF?.Due to different spatial structures from single CD molecules,CD-MOF possibly shows a super capacity of loading drugs to improve drugs solubility and bioavailability.Furthermore,the structure of CD-MOF can be functionally modified to show the ability to release drug in a stimuli-responsive way,which can be applied in targeting drug delivery.According to the designs and evaluations of CD-based supramolecular systems with different structural orders,CD can be applied in insoluble drugs delivery for diverse demands.In this research,based on characterizations of CD-based supramolecular systems with different structural orders,three insoluble drugs with different drug delivery demands,including NLG919,folic acid?FA?and cilostazol?Cil?,were focused on to overcome the challenges in their delivery.Methods:?1?The stirring method is applied to prepare supramolecular drug-loading systems of NLG919/CD,FA/CD-MOF and Cil/BRAP-MOF.?2?Scanning electron microscopy?SEM?,Dynamic light scattering analysis?DLS?,Differential scanning calorimetry?DSC?,Nuclear magnetic resonance spectroscopy?1H-NMR?,Fourier transform infrared spectroscopy analysis?FTIR?,Powder X-ray diffraction?PXRD?,Small angle X-ray scattering analysis?SAXS?,N2 adsorption and molecular simulation are used to characterize BRAP,BRAP-MOF,NLG919/CD,FA/CD-MOF and Cil/BRAP-MOF to illustrate drug loading process and underlying mechanisms.?3?Cell experiments are used to evaluate the bio-safety and bio-efficacy of NLG919/CD and BRAP-MOF.Oral bioavailability study in rats is carried out to evaluate the function of CD-MOF in FA bioavailability enhancement.Tumor inhibition tests in tumor-bearing mice are applied to research the anti-tumor efficacy of NLG919/CD combined with paclitaxel?PTX?.Results:?1?Several CDs were demonstrated to improve the solubility of NLG919 in different ways,and HP-?-CD was confirmed to be the most promising carrier for NLG919 delivery in an intravenous formulation.The drug loading mechanism of NLG919/HP-?-CD involving the cyclohexyl and substituted ethanol moiety of NLG919 embedded into the cavity of HP-?-CD,leaving the imidazo-isoindole group exposed to the solvent,was verified by the results of DSC,PXRD,1H-NMR and molecular simulation.The cell-based IDO-1 assays showed that IDO-1 inhibiting activity of NLG919 would not be influenced after NLG919/HP-?-CD inclusion formation.The cell cytotoxicity experiments indicated that NLG919/HP-?-CD complex could significantly improve the activity of PTX in growth suppression of HeLa cells and 4T1 cells.Furthermore,the combination of PTX with NLG919/HP-?-CD in intravenous formulation presented stronger anti-tumor activity,compared with PTX?i.v.?or PTX?i.v.?plus free NLG919?p.o.?.It showed that NLG919/HP-?-CD could improve PTX chemotherapy in tumor-bearing mice.?2?CD-MOF was demonstrated to significantly enhance FA solubility?1450times?better than single?-CD molecules,and to meaningfully improve FA bioavailability in rats.Furthermore,the underlying super-loading mechanism of FA by CD-MOF was demonstrated by several methods comprising of SEM,PXRD,FTIR,SAXS,N2 adsorption and molecular simulation:FA preferred to distribute in dual CD pairs at low loading molar ratio?1:2?,and then entered into the inner cavity of CD-MOF with the increment of FA loading content.The FA nanoclusters formation inside CD-MOF at high FA/CD-MOF molar ratio was demonstrated to be a key part contributing to the super-loading mechanism of FA/CD-MOF.?3?The synthesized BRAP-MOF with sensitive group was characterized to be amorphous nano-particles with negative charges and sensitive in H2O2 condition by methods including SEM,DLS,PXRD,IR and 1H-NMR.And BRAP-MOF presented the ability to load Cil,and was further demonstrated to release Cil in H2O2-concentration-dependent way.In cell tests,BRAP-MOF presented good biocompatibility and effects in protecting cells against H2O2 activition.Conclusions:In this research,relying on CD-based supramolecule systems with structural orders,the relationships between structurally different CDs and their versatile applications in drug delivery were studied to deliver insoluble drugs in multifunctional ways.In single CD supramolecular level,the solubility of NLG919was significantly enhanced based on host-gust interactions,to achieve an intravenous preparation of NLG919,and the combination of NLG919/HP-?-CD inclusion evidently improved the anti-tumor efficacy of PTX in mice.Based on the regularly assembled porous structure of CD-MOF,the solubility and bioavailability of FA were both significantly improved after the super-loading of FA by CD-MOF.And the drug loading mechanism of FA/CD-MOF was sufficiently demonstrated to further clarify the molecular mechanism of drug delivery underlying the special supramolecular structures of CD-MOF with dual cavities.Finally,the structure of CD-MOF was functionally crosslinked to synthesize a novel H2O2-sensitive supramolecular system?BRAP-MOF?for thrombus-targeting drug delivery in vivo. |
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