The Mechanism Of Dendrimer-based Host-guest System And High Throughput Screening Of Drugs

Dendrimer is a new class of three-dimensional, hyperbranched polymers with excellent monodispersity, globular shape, interior cavities, nanoscale size, well-defined molecular weight and numbers of surface functionalities. These unique structural properties endow them with great potential in miscellaneous applications such as catalysis, sensor technologies, pharmaceutical industry, host-guest chemistry and life sciences. Nowadays, a great deal of attention has been given to dendrimer-based host-guest interactions and their studies, which becomes a fast-growing field and has a wide application prospect.In this thesis, multiple nuclear magnetic response (NMR) techniques are applied to investigate the host-guest interactions between dendrimer and guest molecules, the competitive binding of multiple drugs by a single dendrimer and high-throughput screening of dendrimer-binding drugs. These results propose a theory guide for the dendrimer-based host-guest system and application in the combination therapy, a new fast high-throughput screening method and a multiple functional nano-platform based on dendrimers and drug molecules. The research investigations and conclusions are outlined below.The host-guest interactions of cationic and anionic poly(amidoamine)(PAMAM) dendrimers with three ionic liquids were investigated by several NMR techniques such as1H and19F NMR, PFG NMR, and1H-1H NOESY. Anionic PAMAM dendrimer interacts with ionic liquids via ionic interactions. However, almost no interaction is observed between cationic PAMAM dendrimer and ionic liquids. Besides, no inclusion formation between the PAMAM dendrimers and the ionic liquids is observed based on NOESY studies. The interactions between dendrimers and ionic liquids are much different from that between dendrimers and surfactants or amphiphilic drugs. The results obtained from PFG and NOE studies provide new insights into dendrimer-based host-guest systems.The host-guest chemistry of dendrimer-drug complexes was investigated by NMR techniques consisting of1H NMR and1H-1H NOESY. Ethanol was used as an internal standard to simultaneously quantify dendrimers and drugs, as well as to estimate the binding ability of dendrimers toward different drug molecules. The results suggest that supramolecular structure of dendrimer-multiple drug complexes is formed based on electrostatic interactions and hydrophobic/hydrogen-bond interactions. Factors including hydrophobic properties, sizes, pKa values, charged groups, and spatial hindrance effects of the drugs influenced the localization of drug molecules on the surface and in the interior pockets. In a ternary host-guest system of dendrimer/mycophenolic acid/phenylbutazone, much more phenylbutazone localized in the inner pockets than mycophenolic acid, while more mycophenolic acid bound on the surface by ion-pairs than phenylbutazone. These results provide new insight into host-guest chemistry of dendrimer-drug complexes and the design/optimization of dendrimer-based drug delivery systems.Based on the competitive study, a high-throughput screening of dendrimer-binding drugs is investigated by NMR techniques including saturation transfer difference (STD) NMR and Hadamard-encoded nuclear Overhauser effect measurements. The screening results for insoluble drugs show that phenylbutazone and sulfamethoxazole prefer to localize in the interior pockets of dendrimer, while mycophenolic acid mostly binds on the dendrimer surface, and noncharged insoluble drugs like trimethoprim and primidone do not interact with dendrimers. In another path for soluble drugs, n-butanoic acid and dimethylformamide are screened as dendrimer-binding compounds from a screening pool containing eight soluble compounds by STD NMR. The screening of dendrimer-binding insoluble or soluble compounds can be finished within an hour.Highly efficient NMR tools provide us large amounts of detail information in dendrimer-based host-guest systems. Different host-guest behaviors for binary, ternary systems and a high-throughput screening of dendrimer-binding drugs are presented. On the other way, The NMR-based methods can not only be used to study dendrimer-based system, but also the host-guest systems base on other macromolecules. These results also give some important theoretical supports for the design of preparation formulation based on dendrimers.