Study On Supramolecular System Of Polyamine-Modified Yclodextrin And Three Antitumor Compounds

Docetaxel(DTX),hydroxycamptoacine(HCPT)and etoposide(EPEG)are representative anti-tumor drugs with wide anti-tumor spectra and significant anti-tumor activities against prostate cancer,non-small cell cancer,lung cancer,liver cancer,leukemia,lymphoma,etc.However,they are drugs with low solubility and low permeability,which limit their clinical application.Cyclodextrin(CD)and its derivatives have hydrophobic cavities and hydrophilic surfaces,which includ with hydrophobic drugs and improve the solubility,dissolution rate,stability,bioavailability and other physicochemical properties of the drugs.The polyamine-modified CD can significantly increase the recognition sites and water solubility compare with natural CD,which significantly improves the solubility,dissolution rate,stability,bioavailability and other physicochemical properties of the drug.In this paper,three kinds of polyamine-modified?-CD were synthesized,and the inclusion complexes of the?-CD with three kinds of antitumor compounds were prepared and characterized.The water solubility,antitumor activity and in vitro release of the inclusion complexes were studied.A kind of drug-loading cyclodextrin polyrotaxane was synthesized and its characterization and properties were studied.The main work is as follows:1.Three kinds of polyamine-modified?-CD were synthesized using ethanediamine,diaminopropane and butanediamine,which were characterized by ~1H NMR,MS,FT-IR.2.Nine new inclusion complexes of H1-3 with DTX,HCPT and EPEG were prepared,which were characterized by NMR,SEM,XRD,FT-IR.The possible binding mode of inclusion complexes were deduced by 2D ROESY.The inclusion ratio of host and guest was determined to be 1:1 by phase solubility method.In terms of the host,the order of their stability constants is H3>H2>H1.On the other hand,for the guest the order of the stable constants is DTX>HCPT>EPEG.The molecular recognition mechanism of polyamine-modified?-CD in the matching relation between host with guest and hydrogen bond interaction on the stability of inclusion complexes was discussed.3.The water-solubility of inclusion complexes was detected by saturated aqueous solution method,which indicated that the water-solubility of guest increased84.91-252.63 times after forming inclusion complexes with H1-3.The MTT study showed that the cytotoxic activity of H1-3/DTX inclusion complexes against three tumor cells was stronger than that of free DTX,and the toxicity of the H1/DTX inclusion compplex against normal cells was about 5 times lower than that of free DTX.In vitro release study was carried out by ultraviolet spectroscopy.The results showed that the inclusion complexes could be released slowly within 8 hours in two buffer solutions of NaCA/HCA(pH=5.0)and PBS(pH=7.2),and the accumulating released percentages were more than 80%.4.DTX-PR1 was synthesized,which was characterized by ~1H NMR,SEM,XRD,FT-IR.The water-solubility of DTX increased 484.21 times after complexing with PR1.The accumulating released percentages of DTX in NaAc/HAc and PBS buffer solutions were less than 17%,while the accumulating released percentag in FBS was more than 50%...