Synthesis Of Amphiphilic Block Copolymers And Construction Of Drug Delivery Systems

At present,it has been confirmed in clinical that combination therapy is an effective method for improving efficacy and relieving tumor’s drug resistance.Drug carriers offer the possibility of achieving synergy of multidrug combinations and reducing toxic side effects in humans.However,the large difference in the solubility of the hydrophilic/hydrophobic drugs makes it difficult to achieve balanced loading and releasing on the same carrier.At the same time,the linear structure of the nanocarriers has the advantages of longer in vivo circulation time and larger drug loading,and a new type of drug carrier is designed and synthesized by utilizing the characteristics that amphiphilic asymmetric block copolymers self-assemble in aqueous solution.Asymmetric mPEG-PLA-mPEG with different molecular weights mPEG at both ends,self-assembled to form linear nanotubes and encapsulate both hydrophilic/hydrophobic drugs at the same time,in order to reduce the toxicity of anti-cancer drugs and improve the therapeutic effect of drugs.This study focused on the research on the synthesis of amphiphilic block copolymers and construction of drug delivery systems.Amphiphilic mPEG-PLA diblock copolymers and asymmetrical mPEG-PLA-mPEG triblock copolymers were synthesized.The self-assembly of diblock and triblock copolymers yielded filomicelles and nanotubes,respectively.The biocompatibility of filomicelles and nanotubes was evaluated from the aspects of hemocompatibility,cytocompatibility and histocompatibility.Finally,mPEG-PLA self-assembled filomicelles loaded with a hydrophobic anticancer drug,cycloprotoberberine derivative A35,and mPEG-PLA-mPEG self-assembled nanotubes loaded with paclitaxel(PTX)and/or cis-diaminedichloroplatine(CDDP)were constructed.The inhibitory effects of drug loaded aggregates on tumor cells were studied.Lactide was first synthesized by polycondensation of lactic acid followed by cyclization under vacuum at high temperature.mPEG-PLA was synthesized by ring-opening polymerization of lactide using monohydroxyl poly(ethylene glycol)(mPEG)as macroinitiator under anhydrous and oxygen-free conditions.Secondly,mPEG-PLA was functionalized with terminal alkyne group,and mPEG was azido-functionalized.Asymmetrical mPEG-PLA-mPEG triblock copolymer was finally obtained through Cu catalyzed click reaction.The various mPEG-PLA diblock copolymers and mPEG-PLA-mPEG asymmetric triblock copolymers were used to prepare aggregates by using cosolvent evaporation method.The results showed that filomicelles and nanotubes were formed by self-assembly of mPEG-PLA and mPEG-PLA-mPEG,respectively.The biocompatibility of mPEG-PLA filomicelles and mPEG-PLA-mPEG nanotubes was evaluated in terms of in vitro hemocompatibility,cytocompatibility,and in vivo zebrafish embryo compatibility.All the results showed that the filomicelles and nanotubes present good cell compatibility,blood compatibility and embryo compatibility.Taking a hydrophobic anticancer drug,cycloprotoberberine derivative A35 as a model drug,drug delivery system was constructed from mPEG-PLA filomicelles.The drug loading,efficiency,drug loading content,cell uptake of drug-loaded filomicelles,and the inhibitory effect on tumor cell growth were studied.The results showed that self-assembled mPEG-PLA filomicelles have good biocompatibility,and exhibit strong tumor inhibitory effect on tumor cell growth.This indicates that drug delivery system of filomicelles has been successfully constructed.On the other hand,drug delivery systems were constructed from mPEG-PLA-mPEG triblock copolymers,taking hydrophobic anticancer drugs PTX and CDDP as model drugs.PTX single-loaded,CDDP single-loaded and PTX/CDDP dual-loaded nanotubes were obtained.The drug encapsulation efficiency,drug loading and drug release,cellular uptake of drug-loaded nanotubes,and the inhibitory effect on tumor cell growth were studied.The amounts of total released drugs and total drug loading of the dual-loaded PTX/CDDP nanotubes were significantly higher than those of single-loaded ones.The results also showed that blank nanotubes present no cytotoxicity,but dual-load PTX/CDDP nanotubes exhibit strong cytotoxicity to tumor cells.These results indicate that dual-loaded PTX/CDDP nanotube systems were successfully constructed,thus setting the basis for further clinical experiments.