Design And Anticancer Application Of Several Nanocatalysts For Chemodynamic And Chemodynamic-Synergized Combined Therapy

Chemodaynamic therapy（CDT）is triggered by endogenous chemical energy in the tumor microenvironment（TME）without extra exogenous stimulant.CDT agents catalyze over-expressed and less lethal internal hydrogen peroxide（H₂O₂）in TME to the most toxic reactive oxygen species（ROS）hydroxyl radicals（·OH）for tumor inhibition.Compared with other oncotherapy treatments,CDT possesses kind of advantages,for example:TME-sensitive,tumor-specific,slight side effect,and extra energy independence.Nevertheless,the complex TME still challenge the therapeutic efficiency of CDT,such as mild acid pH,deficient H₂O₂ content and high level of antioxidant agents.With the fleet development of nanotechnology in the past decades.extensive exploration of excellent nanomaterials responding precisely to light,ultrasound,magnet and other stimulus has made it possible to combine CDT with other therapies.And obviously,the combination treatments show superior anticancer activity than monotherapy.Hence,it is necessary to discover varieties of CDT-based nanoplatforms and synergistic therapies for motivating the development of enhanced CDT.Here,the paper mainly focuses the following work:（1）H₂O₂ cycling and light responsive ROS-generation nanocascade system is constructed which integrate CDT,photodynamic therapy（PDT）,photothermal therapy（PTT）,and chemotherapy together.By loading the anticancer doxorubicin（DOX）with hollow copper sulfide catalysts（CS NCs）,the near-infrared Ⅱ（NIR Ⅱ）light and TME responsive drug carriers（CSD NCs）are prepared.CS NCs mimicking dual enzymatic activities are able to achieve light responsive PDT/PTT/CDT in H₂O₂ highly expressed TME with the help of NIR Ⅱ light irradiation.At the same time,the DOX released in the acid environment would stimulate the formation of O2·-by nicotinamide adenine dinucleotide phosphate（NADPH）oxidases（NOXs）,and produce H₂O₂ through SODmediated disproportionated reaction,realizing the ROS strengthen strategy.（2）Establish TME and ultrasound（US）responsive ROS sensitization nanosystem to organize combination treatments of CDT,sonodynamic therapy（SDT）and Ca²⁺overload therapy.Intelligent copper assembling calcium carbonate decorated with sonosensitizer Ce6 nanoparticles（Cu/CaCO3@Ce6.CCC NPs）have been established to realize TME-responsive self-supply of O2 and successively Ca²⁺-overloadingstrengthened CDT/SDT.CCC NPs release Ca²⁺,Cu²⁺.and Ce6 in weakly acid and GSH-excessive TME.Released Cu²⁺ can consume GSH and turn into Cu⁺ via a redox reaction,and provide CDT by creating ·OH through Fenton-like reaction.Under the US irradiation,the intracellular oxidant stress is amplified profoundly relying on 1O2 outburst from SDT.Moreover,Ca²⁺influx aggravates the mitochondrial disruption,which further accelerates the oxidation level.The facile and feasible design of the Cu assembling CaCO3-based nanoregulators will be developed as paradigm in ROScontributed cancer therapy.（3）Synthetic intracellular Zn²⁺-overload and H₂O₂ self-supplying nanosystems to trigger CDT and Zn²⁺-interference synergistic anticancer therapy.Employ one-pot method to synthesize the metal peroxide Cu/ZnOx（CZOx）that rich in Cu²⁺and Zn²⁺.In mild acid TME,CZOx rapidly disintegrates and releases Cu²⁺,Zn²⁺,and H₂O₂.The introduction of Cu²⁺reduces GSH content and promotes the Fenton-like reaction which catalyzes H₂O₂ to produce·OH.The extra supplement of H₂O₂ not only alleviates the ROS by consuming antioxidant substances in TME,but also promotes CDT therapy to increase the production of active free radicals.Zn²⁺ overload will inhibit the mitochondrial electron metastatic chain（ETC）in tumor cells and promote O2·production.It has been proven that the construction of CZOx induces a series of ROS intensification activities within tumor cells and eventually leads apoptosis and necrosis of tumor cells.（4）Biodegradable,safe and tumor-specific hollow manganese carbonate（MnCO3）nanocarriers（HMC NPs）are synthesized by hydrothermal method.HMC NPs loaded with sonosensitizer protoporphyrin（PpIX）constitutes HMC-P NPs,which could be activated in the acidic TME.By degrading and releasing Mn²⁺ and sonosensitizer,the overloaded Mn²⁺ in the tumor triggers the Fenton-like reaction under the physiological buffer HCO3-/CO2 environment,which converts the over-expressed endogenous H₂O₂ to highly toxic ·OH.Moreover,under the irradiation of ultrasound,PpIX could convert O2 to 1O2,forming continuous and accumulated oxidative stress.The synergistic treatment of CDT and SDT could produce a large amount of ROS in tumor cells,which breaks the self-regulation ability of malignant tumor cells,and causes oxidative damage to multiple intracellular organelles.In addition,under the adjuvant treatment of anticancer drugs DOX and ultrasound irradiation,the killing efficiency of cancer cell is about 90%.And the experimental group also achieve good tumor inhibition effects in vivo.