Preparation And Characterization Of Supramolecular Polymer Prodrug Micelles

Cancer has become a major threat to human health.Chemotherapy is one of the main approaches to fight against cancer.However,conventional chemotherapeutic drugs have many disadvantages such as poor selectivity,short half time in blood circulation,numerous adverse side effects and so on.Recently,polymeric anticancer prodrugs synthesized by attaching drugs to polymer chains via stimuli-responsive covalent bonds have been widely investigated.Anticancer nanodrugs can be prepared by these polymeric prodrugs through nanotechnology,which can greatly improve circulation time,targeting ability and bioavailability of conventional anticancer drugs.Nevertheless,all polymers have certain molecular weight distribution,and it’ s very difficult to precisely control the bonding sites and bonding efficiency.As a result,the chemical composition of polymeric prodrugs is complex,which greatly limits their potential clinical applications.In order to solve the problem of chemical purity of polymeric prodrugs,we designed and synthesized supramolecular polymeric prodrugs(SPP)based on host-guest interaction.First,a small molecular prodrug containing two adamantyl groups and one camptothecin moiety was synthesized,which has specific chemical composition and molecular structure.And at the same time,a poly(ethylene glycol)derivative containing two β-cyclodextrin units was synthesized.Then,amphiphilic SPP was prepared through the host-gust interaction of adamantane and β-cyclodextrin units by simply mixing the two precursors with 1:1 molar ratio,which can self-assemble in aqueous solution to give nano-sized supramolecular polymeric prodrug micelles(SPPM).Three kinds of SPPM with different PEG chain length were prepared,which are denoted as mPEG1K-2CD/2 Ada-SS-CPT,mPEG2K-2CD/2Ada-SS-CPT and mPEG5K-2CD/2Ada-SS-CPT.The critical micelle concentration(CMC)of the three kinds of SPPM are 0.0155 g/L,0.0243 g/L and 0.0302 g/L respectively,which slightly increased with the increasing of PEG chain length.The low CMC of the SPPM indicates that they could maintain the self-assembled nanostructures during the blood circulation.2Ada-SS-CPT was formed by connecting Ada and CPT through a redox-responsive disulfide bond,which makes it possible to recover CPT molecules in cancer cells with high reduction potential.The CCK-8 experiments showed that the IC50 of the three kinds of SPPM against HepG2 cells were 0.78 μg/mL,0.60 μg/mL and 0.28 μg/mL respectively,demonstrating their high efficiency to kill cancer cells.The cell uptake and internalization of the SPPM were observed by confocal laser scanning microscopy(CLSM)using nile red as a fluorescence probe.The results indicate that the SPPM can be easily taken by HepG2 cells and the incorporated nile red molecules can be rapidly released in response to the reductive intracellular microenvironment,which can recover CPT molecules and lead to the disassembly of SPPM.The novel SPP we reported in this work can combine the general advantages of polymeric prodrugs and small molecular prodrugs,which should have a bright future in clinical chemotherapy.