Systhesis Of Novel Zirconium Phosphonates And Its Properties As Drug Carrier

In recent years, development of drug stability, nanoparticles and sustained and controlled release preparation, more and more attention is attraced to study on control of drug dosage, increase of bioavailability, decrease of toxicity and relief of patients pain, it is important to synthesize and apply a novel drug carrier for sustained and controlled release nanomedicine.Zirconium phosphate(phosphonate) has been extensively applied in the fields of ion exchange, intercalation, catalysis, optoelectronics, nano-materials, environmental protection and others due to its high thermal stability, strongly acid and alkali resistance, high surface areas, designable structutre and simple preparing process, which has layered structure with the interlayer distances of 0.7 nm-2.0 nm, the layered structure can be still remained after intercalation of guest. At present, but few study is in biomedical applications, so it is important to study on synthesis the new zirconium phosphate(phosphonate) for drug carrier. In this thesis, the specific research contents and results are as follows:(1)4-Aminobutanoic acid dimethylphosphonic acid(4-ABMPA),6-Aminohexanoic acid dimethylphosphonic acid(6-AHMPA) and 1-methyl-3-phenylpropylamine dimethylphosphonic acid(MPPAPA) were synthesized using 4-Aminobutanoic acid、 6-Aminohexanoic acid and 1-methyl-3-phenylpropylamine by Mannich reaction, the synthetic yields were 73.5%、76.1% and 77.9%, respectively. The structures of them were characterized by nuclear magnetic resonance(NMR)、fourier transform infrared spectroscope(FTIR)、thermogravimeteic-differential thermal analysis (TG-DTA), their molecular formulas were OOC(CH2)3NH+(CH2PO3H2)2·0.34H2O -OOC(CH2)5NH+(CH2PO3H2)2·0.43H2O and H20, respectively.(2) Novel zirconium phosphonates were synthesized by the organic phosphonic acids as raw material through precipitation method(HF method), hydrothermal method and HF-hydrothermal method, respectively. The synthetic yield by hydrothermal method was significantly higher than that of HF method, compared to the former two methods, the difference of HF-hydrothermal method was not significant. The structures of them were characterized by X-ray diffraction(XRD)^ scanning electron microscope(SEM), FTIR and TG-DTA. Their molecular formulas were Zr(O3PCH2)2N(CH2)3COOH-2.4H2O (4-ZABMP), Zr(O3PCH2)2N(CH2)5COOH-0.74 H2O (6-ZAHMP) and Zr(O3PCH2)2NCH(CH3)(CH2)2C6H5 (ZMPPAP). The result showed that the crystal morphology, crystal formation time and yield were influenced by HF concentration. Increase of HF concentration, the crystal type was better, but the yield and the generation of crystal decreased. Zirconium phosphonate has typical layered structure by HF method and HF-hydrothermal method, the crystal shape is regular, and the crystal size of former (0.3～0.5 μm) is bigger than the latter(0.1～0.2μm), the thermal stability is less than the latter. But zirconium phosphonate with lamellar structure could not be obtained by Hydrothermal reaction without HF.6-ZAHMP was easily obtained in good crystal type and high thermal stability by HF method, so it could be used as a drug carrier.(3) Two novel antibacterial agents(Ag@6-ZAHMP�'�Ag-Zn@6-ZAHMP) were prepared and characterized by XRD、SEM、FTIR and TG-DTA, it was confirmed that Ag+、Zn2+ got into the 6-ZAHMP interlayer or could be adsorbed on the surface of the carrier. Under reaction time of 5 h,40 ℃, pH7.0, CAgNO3=0.2 mol/L, Ag@6-ZAHMP contained the highest amount of Ag+(qAg= 20.22 mg/g); Under reaction time of 5 h,40 ℃, pH7.0, CAgNO3/CZn(NO3)2=1, Ag-Zn@6-ZAHMP contained the highest total amount of Ag+、Zn2+ (qAg=17.99 mg/g, qZn=51.21 mg/g). Two kinds of new antibacterial agents had strong ultraviolet light resistant ability and good release properties.Escherichia coli (ATCC 25922) and Staphylococcus aureus (CVCC 1882) as the test bacterias, two kinds of new antibacterial performance were studied in reference to the national standard method (GB15981-1995). The results showed that Ag@6-ZAHMP, Ag-Zn@6-ZAHMP had good antibacterial activity, the two kinds of antibacterial agents could kill 99.9% of bacteria at 1.25 mg/mL. At the same concentrations, Ag@6-ZAHMP antibacterial effect on Escherichia coli was stronger than Staphylococcus aureus; and Ag-Zn@6-ZAHMP for Staphylococcus aureus antibacterial effect is better than that of Escherichia coli.(4) 5-FU@6-ZAHMP were prepared by 6-ZAHMP as 5-fluorouracil (5-FU) carrier. By orthogonal experimental design, the optimal synthesis level of 5-FU@6-ZAHMP was A2(50 ℃), B1(pH2.0) and C2(0.5 mg/mL), the maximum loading dose is 97.29 mg/g. The structures of them were characterized by XRD, SEM, FTIR and TG-DTA,5-FU can be well combined with 6-ZAHMP. In vitro tests it is showed 5-FU@6-ZAHMP could be better located to release the drug in the colon, it was hardly release in simulated gastric fluid (pH1.2,2h), and released small amount of the drugs in simulated intestinal fluid (pH6.8,4h),5-FU@6-ZAHMP was placed to the simulate colonic fluid (pH7.5) about 49 h, the releasing dose of 5-FU was more than 80%.5-FU@6-ZAHMP has good characteristics in vitro release tests, it provides a theoretical basis in vivo.Above all, novel zirconium phosphonates were synthesized by the organic phosphonic acids as raw material through HF method, hydrothermal method and HF-hydrothermal method, respectively. Layered 6-ZAHMP could be use of drug carrier because of good crystal type and high thermal stability by HF method. Ag/-Zn@6-ZAHMP showed strong antibacterial effects due to good release properties and strong ultraviolet light resistant ability, and 5-FU@6-ZAHMP could be located to release the drug in the colon, not only improving the local therapeutic concentrations, but also decreasing the systemic absorption and toxicity. This thesis provides a new idea for the development of drug carrier.