Design And Synthesis Of Functional Block-copolymer

Improving the therapeutic index of drugs is a major impetus for innovation in many therapeutic areas. The ideal drug is hoped to have some good properties, such as: high activity, low toxicity, good chemical and physical properties, and so on. But it is very difficult for a traditional drug to possess so many good characters by itself.With the development and cooperation of pharmacy, chemistry and polymer science, a new era of polymer therapeutics comes. Lots of good polymers have been used in drug research. The development of synthetic polymer drugs and therapeutics make it possible to construct a new chemical entity that can possesses all desired properties of drugs. In order to solve those problem, our group propose to synthesis a multifunctional drug entity which have desirable properties. The entity is composed of magnetic nanosphere and different functional copolymers. In this entity, good efficacy drugs and several different ligands with special functions are conjugated to one end of the block copolymers respectively, while the other end of the polymer are used to complex with Fe3O4 particles.In this paper, we are focusing on the synthesis of functional copolymers with different drugs and functional ligands. Basing on the former work, we choose PEG-b-PGA as the block copolymer, 5-fluorouracil as the modifying drug, galactose as the targeting ligand, and Tat (48-57) as cell penetrating peptide. At the beginning of research, we synthesized heterobifunctional PEG600 as one of the raw materials of the following research, which has bromide on one end and azide group on the other end.During the research, we designed two routes to synthesize drug conjugated block copolymers. One is to synthesize macromolecular initiator containing fluorouracil by click reaction first, and then using the initiator to synthesize 5-Fluorouracil- PEG-b-PGA by ATRP reaction. The other one is to synthesize furan protected Maleimido-PEG-b-PGA and thiol derivatives of 5-fluorouracil and galactose respectively. Then we can get Maleimido-PEG-b-PGA by deprotecting the furan ring. In the following step, we use different thiol derivatives to react with block copolymer, and can get 5-Fluorouracil-Maleimido-PEG-b-PGA, Galactose-Maleimido-PEG-b- PGA and Tat-Maleimido-PEG-b-PGA. We prefer to use the second route to synthesize functional block copolymer, because we can get different functional polymers by using the same copolymer and it can lessen the effect of molecular weight. During the experiment, the reaction process is monitored by HPLC and the structures of products are all identified by 1H NMR. The molecular weight of the final functional block copolymers is assessed by GPC.The results of GPC show that the molecular weights of functional PEG-b-PGA synthesized by ATRP reaction are controllable and have a narrow distribution. The magnetic nanosphere complexation with 5-Fluorouracil-PEG-b-PGA has been prepared and the stability of nanosphere has been investigated. Its water solution can stabilize more than half a year. The animal experiment will be developed soon.