β-Cyclodextrin Based Supramolecular Self-Assemblies Via Host-Guest Interaction And Their Enhanced CDT

Cancer has seriously threatened human health for the decades.At present,traditional chemotherapy,surgical treatment and radiotherapy are gradually replaced by new treatment methods due to their shortcomings,such as drug resistance,high treatment cost,large toxic and side effects.Therefore,the continuous development of new cancer treatment methods has become a key goal in the medical field.Chemodynamic therapy（CDT）,has become a potential treatment method due to its unique treatment model,tumor specificity and excellent treatment effect.Its principle is to convert the over-expressed H₂O₂ in tumor tissue into a higher cytotoxic hydroxyl radical（·OH）through Fenton or Fenton-like reaction,thus inducing cell apoptosis.However,the lack of H₂O₂ content in tumor microenvironment and the high concentration of GSH hinder the development of CDT.Therefore,how to build a CDT treatment system through molecular design to improve the efficacy of CDT is a major challenge.Supramolecular polymers have drawn wide concerns due to their specific stimuli-responsive property and the dynamic self-assembly nature.Specially,host-guest interactions based supramolecular polymers have attracted lots of attention in the cancer therapy fields due to their simplified modular construction strategy,responsive self-assembly behaviors and biodegradable property.As one type of macrocyclic molecules,β-cyclodextrins（β-CD）can not only include specific guest molecules with appropriate size and interactions,but also be endowed with good biocompatibility,thus becoming the "best choice" to construct supramolecular nano carriers based on host-guest interaction.In this paper,two kinds of β-cyclodextrin based supramolecular nano-carriers were constructed for the study of amplified CDT.（1）Firstly,we report the host-guest interactions-based supramolecular polymers（HGSAs）which were constructed withβ-cyclodextrin grafted hyaluromic acid（HA-CD）as active targeting host units and hydrophobic ferrocene-（phenylboronic acid pinacol ester）conjugates（Fc-BE）as guest units,and the PA-loaded supramolecular CDT treatment system（HGSAs）was constructed.After CD44 receptor-mediated cellular internalization,After CD44 receptor-mediated cell uptake,due to host-guest interaction,HGSAs@PA will release PA to increase the level of H₂O₂,and further produce more cytotoxic hydroxyl radicals（·OH）through the Fenton reaction induced by Fc.Moreover,Fc-BE can produce quinone methyl compound（QM）and consume antioxidant GSH through the rearrangement reaction of aryl borate ester induced by H₂O₂.The up-regulation of H₂O₂ and the down-regulation of GSH can increase the production of ·OH,prevent its deactivation,amplify the oxidation partial pressure,and thus enhance the CDT effect.In vitro and in vivo experiments demonstrated that the HGSAs@PA could be applied as active targeting amplified CDT agents.（2）Nitric oxide（NO）has benn reported to react with O₂,superoxide anion（·O₂^-）and transition metal to form more toxic reactive nitrogen species（RNS）,such as NO₂^-,N₂O₃,ONOO^-,etc.,thus accelerating tumor cell apoptosis.Therefore,NO based gas therapy can be an effective candidate to enhance CDT.Here,HA-CD is also used as the host macromolecule,and the ferrocene-NO donor（Fc-NAp-NO）is used as the guest to prepare supramolecular self-assemblies with PA as the cargos（SPSAs@PA）.On the one hand,SPSAs@PA will be dissociated and release PA for the improved level of H₂O₂,and more toxic hydroxyl radicals（·OH）will be produced through the Fenton reaction induced by Fc.On the other hand,Fc-NAp-NO could release NO upon light irradiation,while the generated OH will further react with H₂O₂ to generate the by-product superoxide anion（·O₂^-）which could further react with NO to generate higher toxic ONOO-.Finally,the guest molecule Fc-NAp-NO can also generate fluorescence after irradiation to realize real-time NO monitoring in tumor tissue,thus realizing NO-augmented CDT.