Construction Of Supramolecular Prodrug Systems Based On Water-soluble Pillar[n]arenes And Evaluation Of Their Anti-tumor Effect

In order to maximize the efficacy of anticancer drugs,scientists are committed to the use of a variety of nanocarriers.The synthesis and purification of supramolecular nanocarriers based on non-covalent interactions are simple and high-efficient.Moreover,supramolecular nanocarriers also have good response to the external stimuli,especially the endogenous stimuli of the organism,thus supramolecular nanocarriers become a research hotspot of many researchers.Among them,supramolecular drug carriers are mainly constructed by the non-covalent interactions between macrocyclic hosts and small guest molecules.Macrocyclic molecules mainly include cyclodextrin,calixarene,cucurbit,and pillar[n]arenes.In this dissertation,we used water-soluble pillar[n]arenes as the macrocyclic host molecules,and we also designed and synthesized two kinds of novel prodrugs as guest molecules,and then based on the host-guest interactions the intelligent stimuli-responsive supramolecular drug carriers were constructed and applied to the target delivery and anti-cancer therapy.The specific research contents include the following two parts:In the first part,we first modified β-D-galactose unit on the both ends of water-soluble pillar[5]arenes,which was used as the host molecule GalP5,and we also designed and synthesized the camptothecin prodrug guest molecule G1.Subsequently,based on the novel host-guest self-assembled complexation,a supramolecular nanoparticle GalP5(?)G1 was successfully constructed.These nanoparticles could be stable for several months under the physiological conditions.Due to the low pH and high glutathione(GSH)concentration in the tumor microenvironment,the nanoparticles could be dissociated and quickly release the anticancer drug camptothecin(CPT).Cytotoxicity experiments also showed that the supramolecular prodrug nanoparticles GalP(?)G1 could identify HepG2 cells specifically.and then they had an obvious accumulation in the liver cancer cells through the receptor mediated endocytosis,which proved that the system had liver targeting characteristics.Therefore,this system could not only efficiently inhibit the proliferation of cancer cells but also could reduce the side effects to the normal cells.Therefore,it has a very bright potential application prospect in the fields of targeted drug delivery.In the second part,we used water-soluble pillar[6]arene(WP6)as the host molecule,and we also designed and synthesized a novel drug-drug prodrug guest G2.The two anticancer drugs,camptothecin(CPT)and chlorambucil(Cb),were connected by the disulfide linkage.In the special microenvironment of cancer cells,the disulfide linkage was destroyed under the stimuli of glutathione(GSH),thus the two anticancer drugs would be released to play a better synergistic effect.First,WP6 and G2 could self-assembled to form WP6(?)G2 supramolecular nanoparticles in aqueous solution,and then,under the stimulation of a high concentration of GSH,the vesicles were broken and the two anticancer drugs could released slowly.Cytotoxicity experiments also showed that the drug delivery system had an unparalleled effect compared with the single anticancer drug.Notably,it can not only effectively kill the cancer cells but also can greatly reduce the toxicity of anticancer drugs to normal cells.This study provides a new strategy for the construction of synergistic supramolecular nanocarriers and has a good application prospect in the fields of nanotherapy.In conclusion,two kinds of stimuli-responsive supramolecular drug delivery systems have been successfully constructed on the basis of assembly of water-soluble pillar[n]arenes in this dissertation.Also,we hope to provide some benefits and references for tumor treatment in future.