Synthesis And Inclusion Behaviors Of Folic Acid-Cyclodextrin Conjugates With Anti-tumor Drug Molecules

At preasent, targeted drugs is the important direction of tumor drug treatment,and the use of folic acid targeted therapy mainly depends on the folate receptor which is on surface of the target cells. Folate receptor is abundantly expressed in a large percentage of human tumors, but it is only minimally distributed in normal tissues. Folates entered cells via a receptor mediated endocytic process. The physiological process of folate conjugates entering into cells that mediates folate targeted drug delivery is identical to that for the free folate.Cyclodextrins, as the second generation of supramolecular host receptor, may form host-guest inclusion complexes or supramolecular systems with small-molecular drugs. This is an important method to improve the drug properties, however, this method is lack of specificity and targeting.Therefore, in this thesis, a type of functionalized folate-cyclodextrin conjugate composed of folate and cyclodextrin derivatives was synthetized. With the weak interaction of molecular recognition, folate-cyclodextrin conjugates/drug molecular inclusion system were prepared. Because of the specific binding of folic acid and folate, cyclodextrin inclusion complex can be targeted delivered to the target site to release the drug molecular. And the cyclodextrin inclusion complex will improve the targeted drug release and increase the solubility and stability of drug molecules.The major contents of this thesis are as follows:1. Several kinds of cyclodextrin derivatives were chosen and prepared,6-OTs-β-CD,6-I-β-CD, M-β-CD.6-en-β-CD.6-dien-β-CD and6-trien-β-CD. The structure of the products were determined by1H NMR spectroscopy.2. Folate-β-cyclodextrin ester conjugate (FA-β-CD) composed of folic acid and6-OTs-β-CD were synthesized. Several kinds of folate-β-cyclodextrin conjugates were prepared from folic acid and6-en-β-CD,6-dien-β-CD and6-trien-β-CD. The structure of the products were determined by1H NMR spectroscopy. The successful synthesis of this type of conjugate can provide a novel type of folate receptor-mediated targeted drug carrier.3. The inclusion complexes of folate-cyclodextrin conjugates and artemether (ATM) or5-fluorouracil (5-FU) were prepared. According to NMR, the inclusion mode involves the drug(ATM and5-FU) orientated in the folate-cyclodextrin conjugates cavity. The characterization of solid complex was studied by means of powder X-ray diffraction patterns (XRD), thermogravimetric analysis (TG) and differential scanning calorimetry (DSC).