The Mechanism And Optimization Of Dendrimer Based Drug Delivery System

Dendrimers is a novel polymer with dendritic topological structure, which is different from traditional linear polymer and comb polymer. They have multiple surface functional groups and abundant relative hydrophobic cavities, the molecular weights and size can be controlled precisely, and are well mono-disperse, they are widely used in chemistry and biological fields, including host-guest chemistn light-catalysis, sensor, drug delivery, gene therapy, tumor diagnose and a lot of researchers have reported these, this thesis mainly analyzed and investigated the dendrimer based drug delivery system by NMR techniques, it aimed to establish the theory platform and modify the commercial dendrimer to provide the theoretic guide for further clinical use.The intcrmolecular and intramolecular interactions significantly influence the performance of dendrimer based drug deliver)" system, thus the study of physicochemistry of these system is of exceptional importance to the design and optimization of novel host-guest systems. However, the former studies only localized in macroscopic level, the particular information in the atomic level are cryingneed to supplement the whole research. In this dissertation, NMR analysis was applied to give insight in the interaction between dendrimer and drug molecules, electrostatic interaction, hydrophobic encapsulation and hydrogen bonding were proved to be the main interaction mechanisms in this system. Then, two dendrimers with different functional surface groups and the guests with different protonation abilities and space structures were chosen as the host and guest models, respectively. The influences of surface functional groups of dendrimer, molecular properties of guest such as protonation abilities and space structure hindrance to the interaction have all been analyzed and compared.The quantitative analysis of the interaction between dendrimer and guest has helped the study to a deeper level. Primary amine groups terminated PAMAM dendrimer and GMP, a base unit of DNA, were respectively chosen the host and guest model, quantitative calculation of the interaction was performed, obtainding the binding constant and number of binding sites, providing much deeper and more precise views for the dendrimer based gene delivery systemsBesides, the interaction behaviors between two opposite charged dendrimers with primary group and carboxylate group were investigated, the interaction model were analyzed by ITC method and UV technique, the pH dependence of the interaction mode was investigated, then the size and conformation of the aggregates were viewed by DLS and TEM techniques.In order to promote the clinical application, the modification of the commercialized dendrimers has been researched. The surfactant primary amine groups of PAMAM dendrimer were acetylated, and conjugated1,3-phosphate sultone to the tertiary amine in the internal cavities, transferring the functional groups to the dendrimer cavities successfully. The surface acetylated and interior funetionalized was obtained, it is much more safe and higher efficient. This method provides an original thought of the dendrimer clinical application.This dissertation gives a systematical analysis of the dendrimer based drug delivery system through NMR methods. Nowadays, dendrimer is widely used in the biomedical engineering, especially showed obvious advantages. The interactions between drug molecules are of great significance to the pharmacokinetics and pharmacodynamics when used as the drug carrier, the conclusions in the dissertation provide powerful support to the practical application.