Preparation Of Different Dimensional Multifunctional-Nanocomposites And Their Application In Drug Delivery

Multifunctional nano drug delivery systems?MNDDS?are widely used for experimental and clinical delivery to enhance the in vivo efficiency of many drugs and drug administration protocols,such as longevity,targetability,stimuli-sensitivity,magnetic properties,stability,safety,encapsulated nano gas,and others.With the advancement of medicine and the advocating of precision medicine,the nanocomposites are often needed to combine several of the listed properties.At present,the preparation of multifunctional nanocomposites is troublesome,and the functions are too immobilized to flexibly adjust.It is need to do more work to make those nanocomposites having widely used in various fields due to lack of variation.And the integration of functions of the nanocarriers from dimensionality,shape,size and even dimension of nanocarriers are still neglected.The dimension-shifting of nanocomposites has led to a rapid growth of design and fabrication of next generation functional materials on the micron scale.Exerting control over dimension-shifting is particularly significant as it can influence arrange and packing,and contributes to structural complexities and functional varieties.At the same time,the different of the dimension is of high importance because it significantly affects the pharmacokinetics and pharmacodynamics of the anticancer drug.Currently,multifunctional nanoparticles are assembled into nanocomposites of different dimensions for research in the field of medicine,such as one-dimensional nanochains,nanofibers and nanorods;two-dimensional nanosheets and grapheme;three-dimensional nanogels and nanofoams,etc.For the past few years,it have been proved that different dimensions have different effects and tremendous research effort has been aimed at changing the dimensions of the nanocomposites.But those methods are complicated and may have an effect on biocompatibility.Therefore,it is extremely important to prepare a multifunctional and biocompatible MNDDS by dimension conversion.In the first place we have prepared uniform Chitosan/poly lactic-co-glycolic acid nanoparticles?CS-PLGA NPs?loaded with Fe₃O₄ by emulsion–solvent evaporation method and applied Perfluoro-15-crown-5-ether?PFC?as release reservoir of oxygen delivery.We have modified the surface of PLGA nanoparticles with CS through the electrostatic force.The hysteresis loops showed negligible coercivity and remanence at 300 K,indicating the superparamagnetic nature of the the CS-PLGA NPs.The magnet adsorption experiment proved that Fe₃O₄ has been encased and the content was about 6%.Comparing to H₂O and PFC,CS-PLGA NPs displayed a more sustained oxygen release properties owing to the diffusional barrier and high polymer structure of CS-PLGA NPs.Homogeneous Chitosan/calcium carbonate-carboxymethyl chitosan nanoparticles?CMC-CA-CS NPs?with pH-response were prepared by ion exchange method.In the first step,the CMC-CA NPs acting as pH-responsive core were synthesized,and then CMC-CA-CS NPs were constructed by the charge traction of CMC-CA NPs and CS which were adsorbed on the surface of CMC-CA NPs to form a stable core-shell structure.Scanning electron microscopy showed that the nanoparticles were spherical and the surface was rough,and a fine mesoporous structure was observed under transmission electron microscopy.The composition,superparamagnetism and pH-response of the nanoparticles were analyzed by FTIR,Zeta potential instrument,particle size analyzer and fluorescence spectrophotometer.As previously mentioned,we have prepared the uniform CS-PLGA NPs and CMC-CA-CS NPs and those nanoparticles were employed as structure directing modules to drive the supraparticular assembly.To investigate the linear arrangement of nanoparticles under external magnetic field,the nanochains with different CS-PLGA NPs to CMC-CA-CS NPs ratios?R?were handled under an ultra-low magnetic field?5 mT?.Initially,both nanoparticles were homogeneously dispersed in water,while they were deposited under an ultra-low magnetic field,those were induced to arrange linearly along the direction of magnetic field.The linear trends exhibited more obvious and the spacing of nanochains is getting wider as magnetic field increased.The dimension between the nanochain and the structural unit is reversible.The linear assemblies could be re-dispersed easily in aqueous solution to recover to single nanoparticles only by slightly shaking on removal of the ultra-low magnetic field.The fine structure of the nanochains can be seen under SEM and those linear assemblies were composed of composite nanoparticles from several to numerous.The average hydrodynamic diameter of the nanochains were up to¹00?m,i.e.,much larger than the initial singular nanoparticles by optical microscope.Besides,we also successfully prepared three-dimensional nanogels assembled by 0D nanoparticals.We mixed CS-PLGA NPs and CMC-CA-CS NPs to ensure that all particles were negatively charged and homogeneously mixed.We then introduced glucono delta-lactone?GDL?as an acidifer which upon decomposition decreased the pH gradually from?11 to below the isoelectric point?IEP?of CS-PLGA NPs?pH?7.5?.As a consequence,the net charge of CS-PLGA NPs changed from negative to positive,thereby triggering self-assembly between oppositely charged CMC-CA-CS NPs and CS-PLGA NPs nanoparticles.The formation mechanism and porous microstructure of the nanogel were observed by CLSM and TEM,and the mechanical properties of the nanogel were also tested by rheometer.Strikingly,the composite gels prepared with different ratio of nanoparticles were not only injectable and moldable,but also obviously displayed a shear-thinning behavior and shape recovery properties.The anti-proliferation activities of different dimensions of nanocomposites on L929 cells HEI-OC1 were determined through MTT assay and these results revealed that the 0D,1D and 3D nanocomposites all have good biocompatibility.At the same time,the three-dimensional composite gels were cytocompatible by supporting attachment and continuous proliferation of L929 cells and HEI-OC1 in 3D in vitro culture conditions.Both Curcumin and Tanshinone IIA have therapeutic effects such as anti-tumor,scavenging free radicals,and others.The two drugs are loaded into the nanoparticles to improve the water solubility and stability of the drug.The drug loading and encapsulation efficiency of Curcumin and Tanshinone IIA were determined by HPLC.In vitro release results showed that different dimensions nanoparticle drug delivery systems also differ in drug release.In summary,the results of this study indicate that the multifunctional drug delivery systems of different dimension has retain some unique properties of nanoparticles,such as biological compatibility,pH responsiveness,magnetic properties and oxygen delivery capabilities,these properties may give these new nanomaterials a good application prospect.It is expected to become a new type of traditional Chinese medicine compound multi-component nano-drug carrier with potential clinical application value.Such transformational dimension between the zero-,one-and three-dimensional nanocomposites will contribute to giving full play to the functions of the material.