Construction Of Two Glyconanoparticles Based On Pillar[5]arene And Their Application In Targeted Drug Delivery

Chemotherapy is one of the principal means to treat cancers.However,chemotherapy kills cancer cells,but also has serious toxic and side effects on normal cells.The targeting or stimulating responsive glyconanoparticles of nano-drug delivery systems have a nano-effect,depending on the difference in the composition of the cell membrane on the surface of the normal cell and the cancer cell or the difference in the microenvironment between the two kinds of cells,which can help the loaded drug released in the cancer cell but not released or released slowly in the normal cell,thus reducing the damage to the normal tissue caused by the use of the drug.In order to target killing of hepatocellular carcinoma and breast cancer cells,in this study by using a fifth-generation macrocyclic molecular pillar arene,combing with small molecular saccharide and triphenylphosphine,both of which have targeting characteristics,and protein Con A which is degradable under acidic conditions,two new dual-functional glyconanoparticles were constructed and their application in drug delivery were studied:1.Double targeting drug delivery glyconanoparticles was developed based on galactose modified pillar [5] arene and triphenylphosphine derivatives.Galactose modified pillar [5] arene(GALWP5)and triphenylphosphine derivatives(D-TPP)were used as subject and object,a double targeting supramolecular saccharide vesicle(GALWP5(?)D-TPP)was successfully constructed.The galactose GAL unit and triphenylphosphine TPP unit of the vesicle have double targeting potential(Hep G2 cell and mitochondria are targeted respectively).The results of cell experiments in vitro showed that the dual targeting saccharide vesicles had negligible cytotoxicity and good mitochondrial targeting.GALWP5(?)D-TPP loaded with doxorubicin hydrochloride(DOX)not only targets to Hep G2 cells overexpressed with ASGP-R,but also has good mitochondrial targeting,the system contributes to the enrichment of drugs in mitochondria after entering cancer cells.At the same time,the drug loading system not only improves the anticancer efficiency of the drug on cancer cells,but also effectively reduces the side effects on normal cells.This work provides a good example of the rational design of effective cellular and subcellular double targeting delivery systems,and also has potential application in accurate chemotherapy.2.p H response and targeting drug delivery glyconanoparticles was developed based on mannose modified pillar [5] arene and protein Con A.The novel water-soluble mannose pillar arene MANWP5 was synthesized for the first time by attaching the modified mannose to both ends of the pillar [5] arene by a click reaction.The interaction between protein Con A and water-soluble mannose pillar arene MANWP5 was further detected by circular dichroism.By virtue of the good targeting effect of mannose on MCF-7 of breast cancer cell and p H responsiveness of protein Con A to degradation under acidic conditions,This study successfully constructed p H-responsive targeting supramolecular saccharide vesicles(MANWP5@Con A)by combining the water-soluble mannose pillar arene MANWP5 and protein Con A.The results of cell experiments in vitro showed that all the components of the system had negligible cytotoxicity to normal cells 293 T.Subsequently,this study investigated the cytotoxicity of the loading system to the three subjects(293T,MCF-7,Hep G2)and found that it could improve the anti-cancer efficiency of drugs and effectively reduce the toxic and side effects on normal cells.More importantly,after the MANWP5@Con A drug loading system was dispersed in cancer cells,its constituent compound MANWP5 can still play an anti-cancer effect and achieve a synergistic effect.All these results indicate that the MANWP5@Con A loading system is a biocompatible,p H-responsive targeting glyconanoparticles that can be used for responsive drug release and targeting cancer treatment.In summary,two novel dual-functional nanoparticles based on pillar [5] arene were constructed for the first time in this study.The dual-functional nano-loading systems have the advantages of excellent biocompatibility,obvious targeting and drug controlled release.Meanwhile,these two kinds of dual-functional nano-loading systems successfully reduced the toxic and side effects of drugs on normal cells and enhanced the targeted killing of drugs on cancer cells.It is of great significance for the improvement of chemotherapy process to achieve the purpose of robust treatment of cancer.