Study On NGO For Synergetic Chemo-Photothermal Therapy As An Active Targeting Drug Delivery

In recent years,cancer has become a major disease that threatens people's life safety with the increase of incidence and mortality year by year.Therefore,research on cancer treatment is increasingly urgent.The cancer treatments mainly include surgical treatment,chemotherapy,radiation therapy,phototherapy(PTT)and immunotherapy,and chemotherapy is a commonly used treatment in clinical practice.However,in order to achieve therapeutic effects during chemotherapy,multiple repeated administrations are required,and systemic distribution in the body can easily cause severe side effects.Doxorubicin is a commonly used cytotoxic antitumor drug,but severe side effects such as cardiotoxicity limit its further applications.PTT is also receiving more and more attention because of its advantages such as minimally invasive.IR820 is a kind of organic dye material that can be used for PTT studies,but the in vivo non-specific distribution limits its further applications.Therefore,it is important to develop an effective targeted drug delivery system.Graphene oxide(GO)is a novel inorganic nanomaterial and has shown great potential in drug delivery with excellent physicochemical property.However,GO easily aggregates in physiological solutions,which limits its further application as drug carriers,and therefore the functional modification of GO is necessary.However,non-covalent methods do not destroy the internal structure of the GO and therefore the superior properties will be maximally protected.Thus non-covalent methods are more versatile and attractive than the covalent methods.Stimuli-responsive systems could response to specific signals such as redox potential and pH,thus modulate the drug release as expected,which could reduce side effects.Folic acid(FA)and lactobionic acid(LA)are commonly used as targeting moieties.Thus,nanocarriers incorporated with FA and LA could target tumor cells and internalize through receptor-mediated endocytosis and reduce the side effects.Therefore,the reduction-sensitive amphiphilic polymer-drug prodrug PEG-PLGA-SS-DOX was for the first successfully synthesized and used to stabilize the GO,and PEG-FA was used to provide the active targeting for the constructed drug delivery system,GO/PP-SS-DOX/PEG-FA nanohybrids.To reduce the dose of DOX and reduce the side effects,we for the first time synthesized the IR820-LA prodrug.DOX and IR820-LA as stabilizing agent,photothermal agent and targeting agent were absorbed on the GO to get the GO/DOX/IR820-LA.The main contents are as follows:(1)Herein,we for the first time integrate the dispersant,stabilizing agent and active targeting carrier into a novel drug delivery system based on GO/PP-SS-DOX nanohybrids.In this demonstrated system,PP-SS-DOX markedly increases the stability in physiological solutions of GO and guarantees the DOX release in the reductive environment(cancerous cells).And PEG-FA helps to target to cancerous tissues and induces FR-mediated endocytosis.The in vitro drug release exhibited the obvious reductive sensitivity and the release amount was more sufficient.The in vitro cytotoxicity of targeting nanohybrids was significantly cytotoxic than that of non-targeting nanohybrids.The in vivo results displayed that the as-prepared targeting nanohybrids showed efficacious antitumor effect while it had nearly no systemic adverse toxicity on B16 tumor-bearing mice.(2)The IR820-LA prodrug was for the first time synthesized,and used as a stabilizer,photothermal agent and targeting molecule to non-covalently modify GO.The chemotherapeutic drug DOX was also non-covalently adsorbed onto GO surface,and got the GO/DOX/IR820-LA nanohybrids.The TEM and DLS results showed that GO still maintains the lamellar and wrinkle structure,with appropriate nano-scale particle size,and a narrow range of particle size distribution.The in vitro drug release exhibited the obviously sustained release and pH sensitivity.The in vitro photothermal properties exhibited great photothermal effects.In vitro results exhibited the significantly cytotoxic to Hep 1-6 cells and HepG2 cells than other treatments,indicating the efficient chemo-photothermal therapy.The in vivo infrared thermal imaging exhibited preferential tumor accumulation likely due to the EPR effect and LA targeting.The in vivo results displayed that the as-prepared targeting nanohybrids showed efficacious antitumor effect mediated by synergetic chemo-photothermal therapy while it had nearly no systemic adverse toxicity on Hep 1-6 tumor-bearing mice.In summary,the two GO-based active targeting systems prepared in this project both have good anti-tumor effect in vitro and in vivo,and the prepared nanocomposites are promising carriers in cancer therapy.