Multifunctional Drug Delivery Nanosystem For Anti-tumor Synergistic Therapy

Chemotherapy is a systemic treatment method that uses natural or synthetic chemical drugs to prevent the proliferation,infiltration,and metastasis of cancer cells,and finally kill cancer cells.Radiation therapy is the use of high-energy radiation to induce apoptosis,in order to achieve the purpose of tumor ablation.However,in clinical practice,the targeting and specificity of these therapeutic methods are relatively low with large side effects,which may cause systemic discomfort,drug resistance and anti-radiation resistance in patients.Therefore,the use of novel nanomaterials for anti-tumor combination therapy has received extensive attention from researchers.These functional nanomaterials are committed to achieving higher targeting,precise drug delivery and release control,then low biological toxicity.As well as the effect of radiotherapy sensitization,it has long-term clinical application significance in the field of anti-tumor.In this paper,four multifunctional novel nano-drug delivery systems for synergistic cancer therapy are outlined in order to enhance the local and precise release of chemical drugs in tumor tissue,respond to and improve the tumor microenvironment and combined with thermochemotherapy to achieve higher radiotherapy sensitization,thus we evaluated their anti-tumor mechanisms,efficacy and biosecurity.The main research contents and ideas are as described below:1.Carbon monoxide（CO）gas therapy is a novel approach for anti-tumor treatment.High doses of CO can induce cancer cell apoptosis by inhibiting cellular mitochondrial respiration.However,how to precisely deliver the CO gas to the tumor site remains a major problem.To overcome the challenge,in the first research topic we designed a novel stable nanotechnology delivery system ZCM,manganese carbonyl（Mn CO）and the anticancer chemotherapeutic drug camptothecin（CPT）were loaded onto a metal organic framework--a zeolite imidazole framework-8（ZIF-8）.Since ZIF-8 has a tumor microenvironment p H response,after intravenous injection,ZCM nanosystem gradually accumulated in tumor tissue,decomposed in the acidic tumor microenvironment,and released CPT and Mn CO.As a chemotherapy drug,CPT destroys tumors and produces large amounts of hydrogen peroxide（H₂O₂）.Mn CO can react with H₂O₂to generate CO,which has a powerful destructive effect on tumors.All experiments demonstrated that ZCM nanosystem properly regulated the release of CO in tumors,improved the efficiency of CO treatment and reduced the risk of CO poisoning.ZCM behaved great potential to improve the clinical treatment of cancer.2.Although the ZCM nanosystem in the first work can achieve the responsive release and accumulation of the tumor microenvironment after intravenous injection.The intravenously injected drugs cannot escape the immune system,and a considerable amount of drugs are removed through the blood,the medication is also out of controland then drugs reach the tumor.To improve this problem,we developed and utilized a safe and non-toxic light-responsive agarose hydrogel as a carrier of nanomaterials,which can be directly used for intratumoral injection.The release rate of the nanoparticles can be controlled by optimizing parameters,such as laser intensity or laser irradiation period to realize multiple treatments with one injection.In this study,a novel injectable hydrogel was developed as an acid-enhanced chemodynamic therapy（CDT）nanosystem（AES）for amelioration of hydroxyl radical（·OH）mediation dependent on the tumor acidic microenvironment（TME）.AES nanosystem containsed iron-gallic acid nanoparticles（Fe GA）andα-cyano-4-hydroxycinnamic acid（α-CHCA）.As a photothermal agent PTA,Fe GA converted near-infrared laser light into heat,resulting in the dissolution of the hydrogel upon heating,which released the monocarboxylic acid transporter inhibitorα-CHCA and Fe GA.Subsequently,α-CHCA can enhance the acidity in the TME,contributing to the increased·OH production in Fe GA-based CDT.Through the experiments,this method showed good antitumor effect,biological safety and stability.3.The AES nanosystem had achieved good efficacy in tumor suppression,but it was loaded with a wide variety of drugs,and only used the feature of local heating of photothermal therapy（PTT）to release the drug,did not enhance synergistic treatments.Therefore,we need to work on more streamlined,less invasive and efficient nanosystems for synergistic tumor therapy.As a non-chemotherapy intervention therapy,photothermal therapy（PTT）can remove tumor tissue by thermal ablation,and effectively improve the microenvironment of hypoxic cells in tumor tissue,improve radiotherapy sensitivity,and achieve synergy combine PTT and RT（thermal-radiation therapy）treatment produces better results.Thus,we developed an injectable light-controlled hydrogel system as a PB reservoir and release controller by encapsulating Prussian Blue（PB）nanoparticles in agarose hydrogels,named PRC nanosystem.As PB nanoparticles act as an excellent PTA and hydrogen peroxide nanozyme（CAT）to drive the decomposition of endogenous H₂O₂in tumor tissue to generate O₂to improve tumor hypoxic microenvironment and achieve better radiosensitization.Both in vitro and in vivo experiments results,PRC showed excellent efficacy and higher biocompatibility of PTT-RT combined-thermotherapy.4.Although the PRC nanosystem achieved the synergistic anti-tumor effect of thermotherapy,the single nanozyme activity of the PB nanoparticles still limited the radiosensitization effect.To address this issue,we found a tin ferrite（SFO）nanozyme,as a radiosensitizer with excellent dual activity of glutathione oxidase（GSH-OXD）and catalase（CAT）,can significantly reduce the GSH in tumor tissue and effectively catalyze the conversion of endogenous H₂O₂in tumor cells into a large amount of O₂,resulting in the destruction of redox homeostasis in tumor cells,thereby improving the problem of hypoxia condition in tumor microenvironment（TME）,decreased the radiotherapy resistance.We developed a TME-modified nanosystem SIS that addressed radiation resistance induce by high-dose radiotherapy（RT）and could achieve better oxygenation only in combination with low-dose radiation,catalytic and radiosensitizing antitumor effect.In vitro cell experiments could be found,in the state of hypoxia,SIS combined with PTT-RT treatment group produced obvious nuclear double-strand DNA breaks（DSBs）.In vivo experiments,SIS and PTT-RT combined experimental group showed significant tumor ablation without any side effects such as inflammation.In conclusion,the SIS nanosystem exhibited the most excellent radiosensitization effects in the direction of synergistic therapy with thermotherapy and radiotherapy,and had great research prospects in the field of anti-tumor in the future.