Study On The Preparation And Cytotoxicity Of CDDP Supramolecular Micelles Based On β-Cyclodextrin

Supramolecular chemistry is a new discipline developed in the eighties of last century, the main study of it is about the fabrication of some ordered molecular aggregates with special structures or functions using noncovalently intermolecular interactions between two or several molecules. As one of the most important host molecules, β-CD has a wide application in supramolecular chemistry. Because of its special properties:a hydrophilic exterior surface and hydrophobic interior, β-CD can form inclusion complexes in aqueous solutions with a variety of substrates, including orgnic molecules, inorgnic ions and metal coordination compounds. In the last several decades, amphiphile cyclodextrins based on CDs have gained much attention. Amphiphile cyclodextrins prepared from CDs can be divided into two types:one is based on the amphiphilied CDs modified by covalent bond, and the other is based on the supramolecular amphiphiles from the complexes between CDs and hydrophbic guests. It is well known that adamantane units can form strong inclusions with β-CD, in this thesis, we investigate a series of supramolecular micelles as carries of CDDP, and studied the drug loading, stability, sustained drug release and cytotoxcity of CDDP supramolecular micelles anticancer drugs. The details are given as follows.Chapter1:IntroductionThe self-assembly of supramolecule can form various ordered aggregates through intermolecular interactions between molecules, such as micelles, otaxanes and hydrogels.Cyclodextrins (CDs), are cyclic oligosaccharides composed of D-glucose units that are joined by a-1,4-glucosidic linkages. They have hydrophiphilic outer surfaces and hydrophobic inner cavities, the most significant characteristic of the cyclodextrins is their ability to form inclusion complexes in aqueous solutions with a wide variety of substrates, such as organic, inorganic and biological macromolecules. A number of novel supramolecular assemblies have been designed, such as micelles, otaxanes and vesicles. Supramolecular micelles based on CDs inclusion complexes have gained more and more attention. They have potential applications to drug delivery and release, smart materials, bio-mimicry field.Chapter2:Fabrication of CDDP supramolecular micellesAlthough conventional medicines have good anticancer activities, the clinic use of these drugs is frequently limited by their poor water solubility, severely toxic side effects and so on. To enhance the therapeutic efficacy of anticancer drugs and the selectivity of drug delivery, thereby reducing their toxic side effects, they have been conjugated to macromolecular carriers. Firstly, per-6-amino-β-cyclodextrin with seven primary amino groups was used as initiator of the ring-opening polymerization of γ-benzyl-L-glutamate N-carboxyanhydride (BLG-NCA). Benzyl groups were removed by NaOH to obtain β-CD-PLGA. And then, The hydrophilic Ad-containing polymer mPEG-Ad was prepared by1-adamantanecarboxylic acid chloride and mPEG-NH2, the structural characteristics of these polymers were attested by means of1H NMR, GPC, IR measurements.Chapter3:Characteristic of CDDP supramolecular micelles and its cytotoxicityβ-CD and adamtantly group (Ad) has been mostly investigated due to their high association constant. They can form inclusion complexes in aqueous solutions, which result in supramolecular assemblies. Polymer β-CD-PLGA-CDDP containing β-CD was fabricated from β-CD-PLGA and CDDP. A hydrophilic Ad-containing polymer mPEG-Ad was prepared by1-adamantanecarboxylic acid chloride and mPEG-NH2. Driven by the inclusion interaction between the β-CD and Ad group. The supramolecular micelles were prepared by dialysis method. The formation of CDDP supramolecular micelles was confirmed by the methods of fluorescence spectrophotoscopy, ICP-AES, UV-vis, DLS and TEM. Drug could be released from (3-CD-PGL-CDDP/mPEG-Ad in a controlled manner.