The New Method Of PEGylated Chemical Drugs And The Studies Of PEI-g-PEG Copolymers

The emphases of the dissertation include two partions. 1. Small molecule drugs were modified by PEG with the high water-solubilization and biocompatibility by new method, and the products were characterized. 2. Two routes of synthesis for PEI-g-PEG copolymers have been described in the literature. The molecular structure of the resulting copolymers was evaluated spectroscopically (IR, NMR). Calorimetric analysis (DSC) verified the successful formation of the copolymers. At the same time, the graft copolymers were used to modify diethylenetriaminepentaacetic acid (DTPA) to produce macromolecular ligands in order to improve the relaxivities of gadolinium complexs. In this paper, the studies are summarized as follows:Nicotinic acid, which has been applied in clinical, benzoic acid and p-nitrobenzoic acid were used as the model drugs. Small molecular drugs with carboxyl were PEGylated via degradable ester bonds by two-step process. The yield of products were 80～85%. The small molecule drugs will be released by the degradation of ester bonds. The macromolecular prodrugs were characterized with IR, ¹H-NMR, DSC and GPC. The results suggested that small molecule drugs were conjugated to PEG. Products were dissolvable in most organic solvents such as CH₂Cl₂, CH₃CH₂OH, THF, C₆H₆, DMF and DMSO. The solubilization of products has been increased in water. PEG is relatively inexpensive for large scale processes. A facile method of synthesis was created for the preparation of macromolecular prodrugs.The vectors of PEI-g-PEG were prepared by two different new methods. â‘ .The process is simple and the time of the reaction was shortened. â‘¡. PEG was conjugated to PEI via degradable amide bonds. There are a variety of PEIs and the price of the precursors is low. The two benefits of the vectors of the graft copolymers were that A.they can be used more effective gene delivery vehicles because PEGylation of PEI carries advantages such as introduction of increases polymer solubility, biocompatibility and reduction in toxicity, B.the graft copolymers of PEI with a lot of amines have emerged as a potential candidate for drug-modifying.The new graft-copolymer ligand (9) was prepared. Ligand (9) has important function: (9) can complex with Gd³⁺ ion to prepare macromolecular contrast agent. In this paper, the macromolecular contrast agent (16a) of ligand (15a) , (16b) of ligand (15b) were synthesized and the relaxivity of (10),(16a) and (16b ) was studied. It proved that, the relaxivity of (10) was 12.73 (mmol/L)^-1·s^-1. Compared to Gd-DTPAcontrast agent, the relaxivity of (10) showed an approximately 142% increase in R₁. (16a) was 11.54 (mmol / L)^-1·s^-1. Compared to Gd-DTPA contrast agent, the relaxivity of (16a) showed an approximately 119% increase in R₁. (16b) was 11.35 (mmol / L)^-1·s^-1. Compared to Gd-DTPA contrast agent, the relaxivity of (16b) showed an approximately 115% increase inR₁.The new polyoxyethylene carboxyl derivative (11,17) were prepared. (11) has the flexible C-terminal, so it is easy to modify the amino derivative. (11) was used to modify PEI, which suggested it has perfect application to modification.