Preparation And Characterization Of Polylactide-based Multifunctional Doxorubicin Prodrug

As a frontline anticancer drug,Doxorubicin(DOX)is has been widely used as the cytotoxic agent and can treat a broad spectrum of cancers,such as breast,stomach,and bladder cancer.However,due to the poor specificity,low utilization rate,short half-life in the blood stream and toxic dose-related side effects of DOX.To overcome the above disadvantages,it has been developed that polymer-based nanosystems loaded with DOX which were biocompatible and biodegradable aliphatic polyesters nanocarriers are becoming more and more popular.At the same time,due to the differences between tumor tissues or cells with normal,a controlled drug delivery systems,such as acid sensitivity,reductive sensitivity and enzyme sensitivity,have been developed.Furthermore,in order to realize the high specificity and efficiency of nanosystems,it has been designed that a new paradigm,theranostic nanosystems,with simultaneously integrating imaging probes,therapeutic agents,and tissue/cell specific targeting ligands.In this thesis,we designed a new class of biodegradable micelles for tumor theranostic.Amphiphilic block copolymer containing biotin was used as polymer carrier,and the polymers were chemical modificated by thiol-ene click reaction and esterification.Then,the functionalized polymers reacted with histamine and DOX using the nucleophilic click reaction,a novel prodrug of doxorubicin,Btn-m Oeg-His/ Dox,containing biotin and a side imidazole was developed.Btn-m Oeg-His/Dox then loaded with hydrophobic quantum dots through ligand exchange reaction and further dispersed in water to give a new class of micelles,QD-Btn-Dox-M,which combined the function of biodegradable and simultaneously with therapeutic and diagnosis micelles,.In vitro drug release of the prodrug demonstrated that the the amine bond can cleaveged in sub-acidity environment and DOX can successfully released.The MTT assays of Btn-m Oeg-His/Dox and QD-Btn-Dox-M to MCF-7 cells and A549 cells was used to value the in vitro cytotoxicity.The results revealed that the synthetic polymers are suitable to be a drug carrier,under the same conditions,QD-Btn-Dox-M showed pronounced cytotoxic effects.Confocal laser scanning microscopy(CLSM)results demonstrated that the QD-Btn-Dox-M was an excellent biolabeling probe,and that biotin group can promote the cell internalization of QD-Btn-Dox-M in MCF-7 cell lines.In this thesis we also designed biodegradable,targeting,and reductiveresponsive prodrug micelles.Amphiphilic block copolymer containing biotin as polymer carrier,hydroxyl functionalized polymers via thiol-ene click reaction,then reacted with dithiodipropionic anhydride and activated with N-hydroxysuccinimide,then the functionalized polymers reacted with DOX by the nucleophilic click reaction.A new class of biodegradable targeting reductive-responsive prodrug,Btn-m Oeg-SSDox,was developed.DOX release assay demonstrated that the prodrugs can effectively release DOX under high concentration of GSH.And MTT results showed pronounced cytotoxic effects.