| The most prominent challenge in drug delivery is the ability to deliver the therapeutic agent to target site of action in a safe,effective and efficient way to elicit its pharmacological effect with minimal side effect.In line with this,several novel design and formulations have been proposed of which some are already available in the market.A huge variety of carriers have been proposed,as they can effectively modify the physicochemical properties of a drug,masked unpleasant taste,minimize side effect by promoting active agent in desired target site and target specific cells.However,large chunk of the proposed delivery carriers is made from toxic components making them relatively unsafe for in vivo application.Considering the adverse effect of these materials,its necessary to adopt safe and efficient strategy for drug delivery purposes.Consequently,the distribution of carriers within vessel cross-sections plays an important role,since binding of carriers is only possible in case of direct particle-wall interactions.In this context,?-cyclodextrin based metal-organic frameworks(CD-MOF)are biocompatible highly-ordered nanoporous material with unique properties and potential applications in wide areas,including drug delivery.Similarly,particle morphology and geometry play a crucial role for nanoporous materials intended for ocular drug delivery Moreover,there are so many works that proved the significance of particle shape,morphology and geometry that influence their diffusivity,biological interaction,enhanced surface binding,enhanced in vivo circulation time,and ability of control releaseIn this work,for the first time a two-dimensional nanosheet y-cyclodextrin based metal-organic frameworks(CL-NS-MOF)was synthesized through a facile green chemistry approach intended to deliver and improve ocular bioavailability of dexamethasone in the eye.The size of the carrier was well tailored by altering the reaction parameters.Its stability in water improved by polymerization reaction via cross-linking of ?-CD in NS-MOF by a carbonate bond using a diphenyl carbonate(DPC)as a crosslinking agent to prepare cross-linked MOF(CL-Ns-MOF)and dexamethasone was loaded in to its cavity.The particles and their inclusion complex were characterized by PXRD,TGA,SEM,BET,FTIR,and molecular docking.At the same time,a 3D-cubic shaped CL-CD-MOF already synthesized and reported in our lab,of similar specification in term of particle size(5 ?m)was also loaded with same quantity of DXM.These two loaded carriers were deployed as eye drop suspension and there potential as ocular drug delivery carrier was studied in vivo.The detailed research contents and results of this paper are as follows1.Facile synthesis,characterization and particle size control of two-dimensional cyclodextrin metal-organic frameworks nanosheetHerein,a 2-dimentsional nanosheet cyclodextrin based metal-organic framework was synthesized and stably isolated through a facile green chemistry approach by the coordination of y-cyclodextrin and potassium carbonate in water without vapor diffusion of alcohol as known conventionally.The crystal was confirmed by its morphological features from scanning electron microscopy(SEM)having a particle size up to 60 ?m and a nanometer thickness.Its crystallography,counterion-CD nature of the complexation and porosity was further characterized by investigating its crystallinity using powder X-ray diffraction PXRD+.The BET analysis pattern was classified as Type 1B,an indication of substantially microporous materials.NS-MOF depicted Reversible Type I isotherms which are given by microporous solids having relatively small pore volume.The size was modulated by altering the reaction temperature and introduction of acetone.It was observed by altering the reaction temperature(from 25?-0?)the nucleation rate can over power the rate of the crystal growth causing drastic decrease in particle size from 60 ?m to under 10 ?m.Furthermore,a smaller crystal particle below 5 ?m was achieved by employing anti-solvent strategy to further control and reduce the crystal size of the NS-MOF,deploying acetone as the antisolvent.It's observed that addition of 5%acetone control the size to 5 ?m and further increasing the solvent proportion up to 15-20%resulted in smaller particle of size 2.5 ?m,however,the lateral thickness of the nanosheet remained unchanged.The statistical analysis of the particle size distribution was conducted and it further proved that the particles were uniformly distributed and well controlled.2.Two-dimensional NS-MOF transformation behavior to 3D CD-MOFNS-MOF can undergo post-synthesis transformation,when dispersed in methanol it completely breaks in to cubic shape crystals after subjecting the mixture to sonication force The process was monitored by microscopy.Initially,the solvent penetrates through the crystal pores thereby wearing out the cemented surface and the crystal edge,causing the nanosheets to break either horizontally or vertically followed by further breaking and growing in to cubic form crystals.In another parallel experiment the NS-MOF dispersed in ethanol still retained its nanosheet morphology.This highlight energy supplied by the sonicates isn't the only prerequisite for the crystal transformation and affirmed the significance of methanol.PXRD peak of those samples dispersed in methanol confirm that the patterns are similar to CD-MOF proving the crystal transformation from 2D-nanosheet to cubic structureAfter subjecting the sample to non-ionizing radiation of microwave at a frequency 250 Hz and temperature of 50?,the morphology of the crystals was observed under microscope.The particle size maintained the normal range of 400 nm-1 ?m ruling out the possibility of extending the time duration in particle size reduction.However,we speculated that by increasing the frequency it' s possible to obtained much smaller nano size cubic CD-MOF3.Application of NS-MOF carrier to deliver dexamethasone to the anterior segment of the eyeParticle geometry and the shape of nanoporous materials has shown to have significant effects on their pharmacokinetics in the body.NS-MOF carrier was constructed using the safest solvent-water system in a simple one-pot reaction involving y-cyclodextrin and potassium carbonate.Particle size optimization was achieved by adjusting the reaction temperature and the introduction of crystal growth suppressor(appropriate proportion of acetone).The NS-MOF stability in aqueous medium was improved by polymerization reaction into cross-linked CD-MOF(CL-CD-MOF)without blocking its cavity for drug loading.3D-cubic shaped CL-CD-MOF loaded with the same quantity of dexamethasone(DXM)as that for 2D CL-NS-MOF and the pharmacokinetics of these carriers in tear fluid and aqueous humor to deliver DXM was studied in rabbitsThe concentration of the formulations:DXM@CL-NS-MOF and DXM@CL-CD-MOF were measured in the aqueous humor of a rabbit following instillation of 40 ?L with the currently marketed dexamethasone eye drop suspension(Maxidex).The pharmacokinetics parameters of the formulations in the aqueous humor were elucidated.The result showed that DXM@CL-NS-MOF deliver higher concentration of DXM in to aqueous humors in vivo than the other two formulations,it attained Cmax which was 270%and 50%increases over the Cmax of DXM@CL-CD-MOF and Maxidex,respectively.Similarly,the formulation of DXM@CL-NS-MOF achieved the best AUC among all three formulations and 70%increase in MRTs over Maxidex.Therefore,DXM@CL-NS-MOF formulation proved to have improved residence time significantly and prolonged DXM bioavailability in conjunctival sac,this will considerably reduce the amount of dose given and frequency.The results clearly proved the superiority of DXM@CL-NS-MOF over DXM@CL-CD-MOF which highlight the significance of particle size and geometry in drug delivery and further confirmed the great potential of NS-MOF in biopharmaceutics. |
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