Preparation Of Amphiphilic Alginate Derivatives And Their Loading With Drug Delivery

Alginate and its derivatives are widely used in biomedical applications and pesticides,owing to the advantages of their unique properties of renewability,biocompatibility and nontoxicity.In this article,alginate was selected as the research object to synthesize amphiphilic alginate derivatives by bimolecular nucleophilic substitution reaction（S_N2）and Ugi reaction.The amphiphilic derivatives could be used as novel drug delivery in hydrophobic drugs,which could load with hydrophobic cyhalothrin or ibuprofen to prepare the drug-loaded Pickering emulsion or drug-loaded micro-nanocapsules.Meanwhile,the sustained-release properties of the as-prepared pharmaceutical preparations were studied.This paper contains three experimental systems involved in the above chemical modification methods:（1）Benzyl alginate derivative（BAD）was prepared by S_N2 reaction and characterized by means of FTIR,¹H NMR,UV and fluorescence spectrum（FM）.The reaction exhibited the high reactivity and no regioselectivity without the aid of the catalyst for the reaction,which could synthesize BAD with the degree of substitution similar to the initial charge ratio.The critical aggregation concentration（CAC）of BAD was 0.50 g/L.In addition,BAD could form stable BAD/Ti O₂ nanoparticle complex with Ti O₂ nanoparticles in aqueous solution with p H6.61 and without Na Cl.The structure of complex was characterized by FTIR and TGA,and its morphology was observed by SEM and TEM.The results showed that BAD adsorbed on the surface of Ti O₂ nanoparticles by hydrogen bonding,which improved the dispersion stability and the interfacial emulsification properties of Ti O₂ nanoparticles.Meanwhile,using the BAD/Ti O₂ nanoparticle composites as the solid emulsifier,the O/W Pickering emulsion loaded with cyhalothrin was prepared via the emulsion method,which had good stability and could form spherical emulsion droplets,and the drug release profile was fitted well with the Non-Fickian diffusion model.（2）Hexyl alginate derivatives（HAD）,octyl alginate derivatives（OAD）,decyl alginate derivatives（DAD）and lauryl alginate derivatives（LAD）were respectively prepared by S_N2reaction using halogenated alkanes with different carbon chain lengths as the hydrophobic modifiers,and characterized by means of FTIR,¹H NMR,TGA,XRD,FM and dynamic light scattering（DLS）.The results showed that the degree of substitution of HAD,OAD,DAD and LAD were all about 40%.After grafting modification,the initiating decomposition temperature of them decreased,the crystallite structure of them changed,the intramolecular hydrogen bond of them were destroyed and the molecular chain flexibility of them were enhanced.However,the length of the alkane chain had little effect on their structures.In the fluorescence test,as the alkane chain became longer,alkyl alginate derivatives could be more easily self-aggregation and the CAC value gradually decreased.Meanwhile,the relationship of pyrene fluorescence intensity ratios（I₁/I₃）,the ratio value of the fluorescence intensity of the first peak at 373 nm（I₁）to the third peak at 383 nm（I₃）,with the concentration of OAD,DAD and LAD revealed the dual platform curves,which were similar to that of the traditional surfactants.As the alkane chain became longer,the hydrophobic interaction became stronger and formed tighter micelle self-aggregates,so that the hydrodynamic particle size（d _H）tended to became smaller,and the exposed anion of-COO^-increased,which led to the reduction of zeta potential.All above results showed that HAD,OAD,DAD and LAD had good amphiphilic properties and colloidal interfacial activity.Taking OAD as an example,it could be observed by TEM and AFM that OAD could self-assemble in aqueous solution to form spherical micelle structures with different sizes.Furthermore,the drug-loaded micro-nanocapsules were prepared by using HAD、OAD、DAD和LAD loaded ibuprofen and the results showed that the sustained release performance were enhanced,whose sustained release time became longer.Moreover,the length of the alkane chain of the hydrophobic side groups had little effect on their drug release profile and their drug diffusion,all of which were fitted well with the Non-Fickian diffusion model.（3）Without changing other conventional components,a kind of alginate derivative（Ugi-Alg-1）was synthesized by Ugi reaction using p-Toluenesulfonylmethyl isocyanide instead of cyclohexyl isocyanide for the first time,and the other alginate derivative（Ugi-Alg-2）was also synthesized by Ugi reaction using propionaldehyde instead of formaldehyde.Their structures and properties were characterized by means of FTIR,¹H NMR,EA,TGA,XRD,FM,surface tension（SFT）,DLS and TEM.The results showed that the degree of substitution of Ugi-Alg-1 and Ugi-Alg-2 were 18.79%and 10.25%,respectively.After grafting modification,the intramolecular hydrogen bonds of them were destroyed,the initiating decomposition temperature of them decreased,the crystallite structures of them were changed and the molecular chain flexibility of them were enhanced.The I₁/I₃ value and the SFT value gradually decreased with the increase of the concentration of Ugi-Alg-1 and Ugi-Alg-2.Meanwhile,both of them exhibited spherical-like micelle structure with different sizes in aqueous solution,and the micelle size of Ugi-Alg-1 was larger than that of Ugi-Alg-2,which was consistent with the the hydrodynamic particle size（d _H）in the DLS test.Furthermore,the zeta potentials of Ugi-Alg-1 and Ugi-Alg-2 were respectively-54.6 and-60.8 m V,whose absolute values were higher than 30 m V.All of above results showed that the Ugi-Alg-1 and Ugi-Alg-2 had certain colloidal interface properties.Finally,the drug-loaded micro-nanocapsules were prepared by using Ugi-Alg-1 and Ugi-Alg-2 loaded ibuprofen.The drug release studies showed that the sustained release performance were enhanced,which sustained release time became longer,and the drug release profile were fitted well with the Class II Fickian diffusion model and the Non-Fickian diffusion model,respectively.Compared with the micro-nanocapsules that were prepared in the process（2）,the sustained release time of their pharmaceutical preparations were similar,and the drug diffusion model of Ugi-Alg-2 micro-nanocapsules was to the same as that of HAD,OAD,DAD和LAD micro-nanocapsules.