Copper-based And PH-responsive Nanocarrier Combined With HDAC Inhibitor To Enhance Chemodynamic Therapy

Reactive oxygen species（ROS）,mainly includes hydrogen peroxide（H₂O₂）,superoxide anion（O₂·^-）,singlet oxygen（¹O₂）and hydroxyl radical（·OH）,have been considered as very important cancer therapeutics agents.If the ROS level of cells exceeded their threshold,it would increase oxidative stress and disrupt the redox homeostasis,which leads to cellular apoptosis or necrosis.Chemodynamic therapy（CDT）is a new treatment strategy for cancer therapy,which can generate hydroxyl radicals（·OH）through Fenton or Fenton-like reactions.Hydroxyl radicals are the most active free radicals in ROS,and can oxidize proteins,lipids and DNA indiscriminately.Briefly,CDT is the materials containing iron element that can release Ferrous ions in the acidic tumor microenvironment（TEM）and catalyzes the highly impressed H₂O₂（concentration range 100μM to 1 m M）in TEM to generate·OH,which can kill tumor cells and inhibit tumor growth,and does not depend on the input of oxygen and external energy during this process.Since Cu²⁺/Cu⁺has a relatively lower（～0.16 V）redox potential than that of Fe³⁺/Fe²⁺（～0.771 V）,Cu⁺could be oxidized into Cu⁺easily.Furthermore,the Fenton-like reaction of copper ions can exhibit activity at a wider pH range,so Cu⁺has a higher Fenton reaction catalytic activity compared to Fe²⁺.Although nanomaterials containing Cu⁺can catalyze Fenton-like reactions to produce·OH more efficiently,Cu⁺based nanomaterials are unstable and can be easily oxidized in vitro or in vivo.To solve this problem,we used the principle of BCA protein concentration detection and choice albumin（HSA）as the template and reducing agent,and synthesized Nanocarriers（CuNPs）,which contained rich Cu⁺inside,and stable copper ion basic carbonate outside.Compared with normal cells,the histone deacetylase（HDAC）of tumor cells was highly expressed,and the higher expression of HDAC will make the chromatin structure more compact.After the chromatin structure becomes dense,the destruction of DNA by radiotherapy and chemotherapy is weakened.Vorinostat is the first FDA-approved histone deacetylase inhibitor（HDACi）that can inhibit the activity of most HDACs,increasing the level of highly acetylated histones Formation,thereby preventing the interaction of histones with DNA.Loosening of chromatin structure helps the·OH produced by CDT to destroy the DNA of tumor cells,so we speculated that vorinostat can effectively synergize the efficacy of copper ion-based CDT.Herein,considering the strong coordination of copper ions and the acid response of basic carbonate,we designed copper carbonate nanoparticles（CuNPs）as nanocarriers,Vorinostat is loaded into copper carbonate nanoparticles by forming coordination bond between Cu²⁺and vorinostat efficiently.the vorinostat-copper carbonate nanoparticles（V-CuNPs）can retain in blood circulation for longer time than free molecules and better accumulated in tumor sites through the enhanced permeation and retention（EPR）effect.V-CuNPs can keep stable in blood stream and normal tissue,but once it enters the TME or lysosome,the acidity amplification is responsible for the decomposition of V-CuNPs and consequently triggers the release of free vorinostat and Cu²⁺for Synergistic anticancer therapy.the in vivo experiments verified that V-CuNPs exhibited the synergistic therapeutic effect between CDT and HDACi mediated chromatin remodelling to effectively suppress colorectal tumors.