Nanocarriers Based On Host-Guest Recognition Of Macrocyclic Molecules And Their Biomedical Research

Chemotherapy is one of the most effective tumor treatment methods in clinic.However,due to the poor water solubility and their non-specific accumulation,the chemotherapeutic performance of traditional medicine are unsatisfied.Based on the significant differences between tumor tissues and normal tissues,such as low pH,hypoxia condition,and over-expression of GSH,H2O2 and esterase in tumor tissues,many nano carriers based on the responsiveness of the tumor microenvironment have been reported.Host-guest interaction based supramolecular prodrug self-assemblies have drawn wide concern to develop various stimuli-responsive systems with high drug-loading efficiency.As a new type of macrocyclic host molecules,pillar[n]arene has been extensively utilized to construct supra-amphiphiles for the encapsulation and delivery of hydrophobic chemical drug.Herein,the water-soluble pillar[6]arene(WP[6])was utilized to include Cb-based prodrug to prepare supramolecular prodrug nano-carriers for the enhanced chlorambucil-based chemotherapy.(1)The abundant cellular GSH in cancer cells have been reported to be responsible for the reduced chemotherapeutic efficacy of nitrogen mustard drugs.Herein,the H2O2-responsive prodrug,chlorambucil-(phenylboronic acid pinacol ester)conjugates(Cb-BE),was designed and synthesized.Using water-soluble pillar[6]arene(WP[6])as host units,the complex WP[6]@Cb-BE is prepared based on the host-guest interaction,and can further form supramolecular prodrug self-assemblies(SPSAs)with the higher drug-loading efficiency and specific stimuli-responsive property.Notably,under the specific stimuli in tumor microenvironment,the generation of quinone methide(QM)from phenylboronic acid pinacol ester could significantly consume GSH,enhancing the performance of Cb.The in vitro and in vivo experiments demonstrate that SPSAs with GSH-consumption strategy exhibited enhanced therapeutic effect and might provide a promising strategy for Cb-based nano-medicine.(2)Inspired by the detoxification process that glutathione(GSH)can react with Cb,the amplified oxidative stress strategy through the GSH consumption and ROS elevation was utilized in the construction of supramolecular prodrug self-assemblies(SPSAs).Here,water-soluble pillar[6]arene(WP[6])based host-guest interaction was used to construct Cb-based SPSAs with high drug loading efficiency and specific stimuli-responsive property.Notably,the arylboronic acid was introduced in the design of Cb-based prodrug not only to transform into GSH-scaverger quinone methide(QM)for the down-regulation of GSH levels,but also provide an effective way to rapidly bind curcumin(Cur)which could elevate the ROS levels in cancer cells.The amplified intracellular oxidative stress could effectively break the intracelluar redox microenvironment and trigger enhanced Cb-based cancer cell death.In vitro and in vivo experiments demonstrate that the amplified oxidative stress achieves excellent anti-tumor efficacy.(3)In this chapter,water-soluble pillar[6]arene(WP[6])based supramolecular drug-drug self-assemblies(SDSAs)were developed.Based on the host-guest interactions between WP[6]and chlorambucil(Cb),the drug-loading efficiency and specific stimuli-responsive property could be introduced in this system.In addition,oxoplatin(Oxo-Pt)was incorporated with Cb to down-regulate the GSH level,enhancing the ROS-medidated anticancer performance of Cb.After transcytosis into the cancer cells,Cb-Pt in SDSAs can be reduced by GSH to release Cb and cisplatin with the declining GSH level and ascending ROS level.Moreover,in vitro and in vivo experiments demonstrate that the water-soluble pillar[6]arene based supramolecular drug-drug self-assemblies with oxidative stress amplification strategy exhibited excellent synergistic therapeutic effect.