| The main treatments of malignant tumors are drug(gene)treatment,radiation therapy and surgical treatment,at present,clinical drug therapy is the most popular.Unfortunately,due to the low water solubility,limited stability,non-targeting and other defects of anticancer drugs in human body,resulting in the treatment of existing clinical anticancer drugs is not satisfactory.In view of the shortcomings of drug treatment,scientists are committed to developing a variety of drug delivery systems.The newborn drug delivery system should have performances of improving water solubility,circulation stability and reducing side effects of anticancer drugs.Supramolecular drug delivery system become one of the research hotspots of drug delivery based on its simplicity,stimulating release,cancer targeting and other advantages.Supramolecular vesicles constructed based on host-guest recognition of macrocyclic compounds,possess closed bilayer membrane structure which is similar to cell membrane,and the internal water chamber of supramolecular vesicle could be used to load drugs.It is achieveable to reduce side effects and improve curative effect of anticancer drugs by introducing functional groups and targeting ligands into the building block of supramolecular vesicles to stimuli-responsive controlled release.Pillararenes are a new type of macrocyclic compounds developed in recent years,with symmetrical cylindrical cavity-like rigid structure,and easy to modify.The main differences between pillararenes are the cavity size and synthetic yield,and the yield of pillar[5]/[6]arene(PA[5]/[6])is the highest.But the cavity size of PA[6]is larger than PA[5],which leads to PA[6]have a wider selectivity of guest molecules.PA[6]modified with water-soluble groups have been assembled into supramolecular vesicles with a variety of guest molecules,but there only a few guest molecules have high binding affinity with PA[6].Based on the research of stimuli-responsive host-guest and PA-based supramolecular vesicular drug delivery system,the main research work of this paper is divided into the following two parts:1.Host-Guest Interactions and Stimuli-Responsive Performances of CarboxylatedPillar[6]arene and Benzimidazolium CationThe supramolecules are formed based on non-covalent interactions between molecules,for instance,electrostatic interaction,charge transfer,hydrogen bonding,π-π stacking and hydrophobic interaction,and could be destroyed under external stimuli to achieve stimuli-responsive performances.The water-soluble carboxylated PA[6](CPA[6])was synthesized by modifying the carboxyl groups on both sides of the PA[6]ring,and interacting with the benzimidazolium cation in aqueous solution through host-guest interactions to form the inclusion complex,and the presence of stable inclusion complex was confirmed by nuclear magnetic technique(NMR).The inclusion complex could be dissociated in the presence of cancer tissue acidic species(pH),carbon dioxide(CO2)of metabolic acidosis,abnormal accumulated zinc ions(Zn2+)of special diseases and metabolic bio-polyamine analog hexamethylene diamine(HDA)was verified through NMR.Besides,the pKa of fully protonated CPA[6](CPA[6]H12)was predicted by integrating experiment and software prediction,and host-guest interactions between CPA[6]and benzimidazolium cation in aqueous solution were weakened by saturated aqueous solution of CO2 was explained.pH,CO2,Zn2+and HDA stimuli are all associated with cancers or specific disease,so that the inclusion complex have promising application in construction of supramolecular drug delivery carrier.2.Supramolecular Vesicles Coassembled from Carboxylated Pillar[6]arene andBenzimidazolium Cation Amphiphile and Quintuple-Responsive Drug ReleaseSupramolecular vesicles and liposomes both could be used as carriers of anticancer drugs,the difference is that liposomal drug preparations are mainly sustained-release drugs,however,supramolecular vesicles could respond to endogenous or exogenous stimuli,so that could realize drug controlled release.Novel host-guest based supramolecular vesicles were co-assembled from carboxylate-substituted CPA[6]and disulfide-linked benzimidazolium cation amphiphile.The supramolecular vesicles showed almost no cytotoxicity and quintuple-stimuli-responsive controlled drug release upon trigger of glutathione,pH,CO2,Zn2+,and HDA through cleavage of disulfide bonds,protonation of carboxylate groups,metal chelating,and competitive binding.The CO2-mediated and biogenic amine-triggered controlled drug releases from pillararene-based supramolecular vesicles were reported for the first time,respectively.Moreover,this is the first case that one smart pillararene-based supramolecular vesicle was integrated with quintuple-stimuli-responsive performances to meet diverse requirements of controlled drug release.Importantly,each of the five stimuli is closely related to microenvironments of tumors and diseases of human body.The microstructure of supramolecular vesicles was described for the first time by means of molecular calculation and freeze drying,which is helpful for understanding and designing supramolecular vesicles.The smart stimuli-responsive supramolecular vesicles have promising applications in drug therapy of tumors and relevant diseases. |
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