The Synthesis Of Amphiphilic Block Copolymer And Its Preparation Of Antitumour Pro-drug

Cancer has become the greatest threat to human health.Drugs used in chemotherapy for cancer treatment,as paclitaxel,docetaxel,cabazitaxel,camptothecin ect.,all have defects such as poor water-solubility,nonselective distribution and so on.If used directly for treatment,it will lead to a variety of toxic side effects,and long-term use of drugs can induce the drug resistance of tumor cells.To prepare a polymeric pro-drug with adjustable drug-loading capacity,low-toxicity,and high drug-controlled release ability for paclitaxel,we have done the following research:(1)Lactide(LA)as raw materials,2,2-Dimethylol Propionic Acid(DMPA)as initiator,stannous octoate as catalyst,Polylactic acid with side carboxyl group was prepared by ring-opening polymerization.PLA was copolymerized with Polyethylene glycol with hexamethylene diisocyanate(HDI)as coupling agent.Thus,amphiphilic block copolymer with side carboxyl group was synthesized.A novel PLA-PEG-PTX pro-drug was prepared through the esterification reaction between the side carboxyl group on copolymer and hydroxyl group on paclitaxel.Its structure was characterized with 'H-NMR and FT-IR.The molecular weight and molecular weight distribution were determined by GPC.The results showed that amphiphilic block copolymer PLA-PEG with side carboxyl group was synthesized and paclitaxel was bonded to the PLA-PEG copolymer successfully.(2)Lactide(LA)as raw materials,2,2-Dimethylol Propionic Acid(DMPA)as initiator,stannous octoate as catalyst,Polylactic acid with side carboxyl group was prepared by ring-opening polymerization.With Succinic anhydride and DMAP as acylation agent,terminal hydroxyl of polyethylene glycol was carboxylated into a carboxyl.PLA was copolymerized with the carboxyl terminated Polyethylene glycol.Thus,amphiphilic block copolymer with side carboxyl group was synthesized.A novel PLA-PEG-PTX pro-drug was prepared through the esterification reaction between the side carboxyl group on copolymer and hydroxyl group on paclitaxel.Its structure was characterized with 1H-NMR and FT-IR.The molecular weight and molecular weight distribution were determined by GPC.The results showed that amphiphilic block copolymer with side carboxyl group was synthesized and paclitaxel was bonded to the PLA-PEG copolymer successfully.(3)Tetrahydrofuran as solvent,the pro-drug micelles of copolymer in aqueous were prepared by solvent evaporation method.The micelles were characterized by nano particle tracking analyzer and TEM,and the drug release properties were investigated by dialysis experiments.Nano particle tracking analyzer and TEM results showed that the pro-drug micelles from self-assembly are spherical with core-corona structure and particle size in 82?100nm.The critical micelle concentration of the micelles was between 10-2-10-3 g·L-1.Drug release research showed that micelles of PLA-PEG-PTX pro-drug released paclitaxel slowly and steadily without obvious burst release in buffer solution,and the cumulative drug release rate increased slowly over time,which indicated that the pro-drug micelles have a certain sustained-release effect.Moreover,the accumulative release rate in weak basic condition is higher than that in weak acid.The longer polylactic acid chain length or the longer polyethylene glycol chain length in the polymer,the higher the cumulative release rate is.