Synthesis Of New Core Poly (Amidoamine) Dendrimers And Solubility Research Of Folic Acid

Dendrimer is a kind of spherical macromolecule with the special dendritic structureand nano-sized three-dimensional geometry. Dendrimers are widely used in chemistry andbiology fields due to their unique structural features such as high symmetry, definedmolecular structure, controlled molecular weight, a number of functional groups on thesurface, and various internal cavities. In the biomedical field, in particular, these featuresallow dendrimers to form drug delivery system by covalent bonding or physicalencapsulation of aqueous insoluble drugs, e.g. anticancer molecules. In this thesis, theresearch background, structural features, synthetic methods, and the physicochemicalproperties of dendrimer are introduced, and their applications are briefly summarized,highlighting in enhancement of drug solubility and cancer therapy.Polyamidoamine (PAMAM) dendrimers, which are the earliest developed and mostwidely studied dendrimer species, are extensively used in various applications such asanalytical chemistry, catalysts, and biomedical materials. The traditional polyamidoaminedendrimer has a small core unit which makes it relatively rigid and limits its potentials inbiomedical field. The performance of dendrimers in gene transfer and drug delivery tosome extent relies on their structural flexibility, which can be efficiently improved byenlarging the size of the core unit. We tried to synthesize PAMAM dendrimers withPEGDA, a molecule much larger than ethylenediamine, as the core, but failed according tothe experimental results. We then reacted ethylenediamine with excess PEGDA, in order toproduce a long branched unit containing PEG molecule. However, we didn’t obtain thedesired product since the reaction was complex and many by-products arose. Consideringthese unsuccessful experiences, we designed a new core unit containing primary amines atboth ends and an amide group in the structure. This compound was synthesized by reactingmethyl acrylate with excess ethylenediamine. G1~G4PAMAM dendrimer were preparedfrom this new core through repeating Michael addition and amidation reaction, and were characterized by FT-IR and1H-NMR. These synthetic compounds not only possess thestructural properties of traditional PAMAM dendrimer, but also have a larger core unit withan amide group presented. The increase of core unit may improve the flexibility ofdendrimer molecules and their capability to enhance the solubility of drugs insoluble inwater.In many cases, low aqueous solubility of drugs limits their practical applications.Folic acid is a member of the B vitamin family, and is an indispensable material for the cellgrowing. However, it has a very low solubility in water. In this thesis, folic acid was usedas a model molecule and its solubility in the presence of PAMAM dendrimers or a smallmolecule, i.e., ethylenediamine, was compared both under the acid and basic conditions.The effects of the type of end groups and the generation of dendrimers on the solubility offolic acid were investigated.1H-NMR technique was employed to analyze the mechanismof solubility enhancing provided by dendrimers. The results show that the ionization offolic acid dominates the solubilization process. Under the acidic condition, the degree ofionization is low, and dendrimers improve the solubility of folic acid mainly throughencapsulation. Under the basic condition, however, folic acid is totally ionized and thesolubility is largely enhanced due to the electrostatic interaction between folic acid and thesurface amines of PAMAM dendrimers. As for ethylenediamine, it exhibits an evenstronger solubilization effect on folic acid under the basic condition due to its“more-active” primary amines in the molecule. Under the acid condition, however, itdoesn’t show obvious solubility enhancing effect, which means the dendritic structure hasan advantage over the small molecule in this case.Finally, we investigated the solubility enhancing performance of the syntheticnew-core PAMAM dendrimers under the acidic condition, and compared the values withthose of the traditional dendrimers. The results indicate that with low generation, thenew-core dendrimer has a lower enhancing level because of the weaker encapsulationderived from the more open core structure. With high generation, on the contrary, thenew-core dendrimer shows a higher enhancing activity due to that its compact dendritic structure with a larger core cavity can provide better encapsulation capability for folic acid.