Modification Of Anticancer Drugs For Their Controlled Release

Cancer is one of the major diseases that seriously threaten human life.Traditional chemotherapy drugs often have poor water solubility,severe side effects and low bioavailability,which limit their clinical applications.Controlled drug release systems have been developed to overcome these constraints.Researchers found that modification of carrier materials or/and drugs in controlled drug release system can further increase their therapeutic effects,such as introducing functional groups into carrier materials or/and preparing prodrugs.It's worth noting that prodrugs could not only be designed to improve their loading efficiency,but also provide the possibility for responding to environmental stimuli.In the first chapter of this thesis,development of controlled drug release system was briefly reviewed,with the emphasis on the modification of carrier materials and drugs in controlled drug release system.In chapter 2,biodegradable block copolymer mPEG-b-P(MAC-co-DTC)was successfully synthesized by enzymatic ring-opening polymerization.The resulting copolymers could self-assemble to form nano-sized micelles in aqueous solution.Stable multiple hydrogen-bond interactions could be formed between thymine and 2,6-diaminopyridine(DAP)groups of MTX molecules to change the aggregation state of MTX molecules,which resulted in higher drug loading of MTX and pH-sensitive drug release behavior.MTT assays indicated similar cytotoxic activity against HeLa cells between MTX loaded micelles and free MTX.In chapter 3,a novel Camptothecin(CPT)prodrug was successfully synthesized by conjugating CPT to adamantanecarboxylic acid(AD)via a clickable disulfide linkage.The resulting CPT-ss-AD prodrug could act as a low molecular weight gelator to form gels in water/water-miscible organic solvent mixture by a heating-cooling process.Meanwhile,biodegradable amphiphilic block copolymer mPEG-b-P(MAC-co-DTC)was also employed as an organic framework together to form gel structure.CPT-ss-AD/mPEG-b-P(MAC-co-DTC)two-component gel exhibited less compact molecular arrangement but much more stability than CPT-ss-AD single-component gel.Both the two kinds of gels could effectively release the original CPT under reductive condition at a near-constant rate without any initial burst.As compared to CPT-ss-AD single-component gel,CPT-ss-AD/mPEG-b-P(MAC-co-DTC)two-component gel had a significantly higher release rate of CPT,while MTT assays also indicated highly potent cytotoxic activity against HeLa cells.In chapter 4,CPT-ss-AD/mPEG-b-PAC-CC-crosslinking two-component gel based on CPT-ss-AD gelator was successfully prepared.Biodegradable amphiphilic block copolymer mPEG-b-PAC was first synthesized in toluene using IPPL as the catalyst.Then mPEG-b-PAC and CPT-ss-AD were dissolved in ethanol/water mixed solvent to form CPT-ss-AD/mPEG-b-PAC gel by a heating-cooling process.CPT-ss-AD/mPEG-b-PAC-CC-crosslinking gel could be finally obtained through in situ photocrosslinking by UV radiation.As compared to CPT-ss-AD gel,CPT-ss-AD/mPEG-b-PAC-CC-crosslinking gel showed much more stability.The in vitro release studies also showed more sustained drug release behavior without an initial burst,which could be accelerated under reductive environment to release the original CPT.