The Preparation Of Novel Dextran Derivatives Self-aggregation Micelle And Application Of Anti-tumor Drug Delivery

The hydrophobically modified amphiphilic dextran copolymers tend to form core-shell-type nanosized micelles in an aqueous environment. These core –shell type micelles may be used as drug vehicles to prevent the potential di sadvantages of most anticancer drugs. In this study, biocompatible dextran were chosen as raw material, and three kinds of diaminecompound as connection arm, three kinds of hydrophobic acid were grafted to synthesize six amphiphilic copolymers and the corresponding micelles. We discussed micellar behavior, the capability of loading and releasing drug systematacially. Those studies provided a theoretical basis for developing novel p H-sensitive polymeric micellar drug carriers. Moreover, it provided new ideas for the deep processing of natural polysaccharide in the field of drug carriers. The main contents of this paper are as follows:Synthesised novel amphiphilic dextran derivates in three steps by solvothermal methods:1) Periodate oxidation reaction to gain polyaldehyde dextran in different oxidation degree. 2) Three diaminecompound(fat diamine hexamethylenediamine, aromatic diamine paraphenylenediamine and Hydrazine Diamine adipic dihydrazide) as connection arm graft from the molecular surface of polyaldehyde dextran, formation the diamine-dextran derivatives. 3) Three hydrophobic acid(12-carbon aliphatic carboxylic acids lauric acid, 18-carbon aliphatic carboxylic acid stearic acid and ring shaped fatty acids deoxycholic acid) hydrophobic modified for diamine-dextran derivatives gain six novel amphiphilic dextran derivates.The final amphiphilic dextran derivates were characterized by IR spectra, TG-DTA, 1H NMR and XRD to determine their composition and chemical structure. They are: lauric acid-paraphenylenediamine-polyaldehyde dextran(LA-PPD-Ox Dex), deoxycholic acid-paraphenylenediamine-polyaldehyde dextran(DCA-PPD-Ox Dex), stearic acid-paraphenylenediamine- polyaldehyde dextran(SA-PPD-Ox Dex), stearic acid- hexamethylenediamine-polyaldehyde dextran(SA-HMDA-Ox Dex), stearic acid- adipic dihydrazide- polyaldehyde dextran(SA-ADH-Ox Dex), deoxycholic acid- adipic dihydrazide- polyaldehyde dextran(DCA-ADH-Ox Dex).The solvent diffusion-ultrasonicator method was used to prepare micelles, and investigate the ability of micelle aggregation by fluorometry using pyrene as a probe. The result indicated the ability of micelle aggregation depending on the oxidation degree of polyaldehyde dextran, the type of diaminecompound and hydrophobic acid, which ranged from 0.07~0.18 mg/m L: Impro vement of the degree of polyaldehyde dextran, coupled with the decrease of diamine arm length and the increases of hydrophobic acid chain length, will enhance the aggregation ability of micelle. Inside, the aliphatic diamine and linear chain aliphatic carboxylic acid have better ability of micelle aggregation. Dynamic light scattering(DLS) was used to measure the particle size of different amphiphilic dextran derivates micelles. The result revealed the particle size of micelles were less than 500 nm, within the scope of nano. Besides, the stronger of micelle aggregation ability, the smaller of the micelles’ particle size. The morphology of micelles which were investigated by TEM and SEM measurement, revealed the self-assembled micelles are well dispersed as individual nanoparticles with regularly and air-cored spherical shape.Curcumin were loaded into the dextran micelle by dialysis method, we investigate the effect of the ratio of drug/carrier, the type of diaminecompound and hydrophobic acid to micelle drug-loading capacity. The result indicated that the addition of the ratio of drug/carrier lead to the in creasement of micelle drug loading rate, while the encapsulation efficiency was decrease. SA-PPD-Ox Dex has the strongest drug-loading capacity among those tested, the drug-loading capacity is 8.34%, while the ratio of drug/carrier is 4/20. In addition, the drug- loading capacity of three dextran micelle which diamine arm was consistent was DCA-PPD-Ox Dex(8.91%)>SA-PPD-Ox Dex(8.34%)>LA-PPD-Ox Dex(6.58 %).The condition of drug release indicated micelles have sustained release for model drug curcumin, and drug release condition was related with the properties of micelle material, the micelle drug loading rate and th e p H of release medium: the stronger of the drug-loading capacity and drug loading rate, the slower rate of vitro release, that is sustained release is more obvious. And the lower of the p H of release medium, the faster rate of vitro release, namely, the m icelle had a certain p H-sensitivity. The proliferative inhibition activity of micelle was testing by MTT assay.