Synthetize And Application Of Multifunctional Near-infrared Nanoparticles For Diagnosis And Treatment Of Gastric Cancer

THESIS:Synthetize and application of multifunctional near-infraredSPECIALIZATION:General Surgery POSTGRADUATE:Zhengyang Yang MENTOR:Prof.Wenxian GuanAbstractGastric cancer is one of the most common malignant tumors in the world,while its incidence rate is the fifth highest in the world and mortality rate is the third highest in malignant tumors.Because the symptoms of early gastric cancer are not obvious,most of these gastric cancer cases are diagnosed as advanced gastric cancer,which has a high risk of invasion and lymph node metastasis,and the survival rate is less than20%.However,most of the early-diagnosed patients can be cured by endoscopy or surgery,followed by radiotherapy and chemotherapy,resulting in a five-year survival rate of 90%.Additionally,the current commonly used chemotherapy drugs such as adriamycin and paclitaxel were limited their further clinical application and efficacy due to the lack of tumor targeting,systemic toxicity and other problems.Therefore,it is very important to find a more accurate early diagnosis method and achieve accurate treatment for gastric cancer.Recently,with the development of science and technology,nanomedicine has attracted more and more attention.It can provide many potential benefits for the diagnosis and treatment of gastric cancer,including the following advantages:1)They can target and accumulate in tumor tissue because they can be functionalized by biomolecules;2)They can overcome the distanvages of solubility and stability of common chemotherapy drugs by surface modification,encapsulation or addition of formula;3)They have novel physical properties,such as near infrared fluorescence imaging and photoacoustic imaging,which can be used in biological imaging;4)They are usually composed of thousands of substances with high surface area,so they can carry higher therapeutic load and kill tumor tissue more seriously;5)They can be accumulated in tumor site by passive or active targeting,which can significantly reduce organ nonspecific toxicity.However,due to the different physical and chemical properties of different nanoparticles,they have different distribution characteristics and half-life period.Thus,it has become a challenging scientific issue that how to apply nanoparticles to the diagnosis and treatment of gastric cancer.This paper aims at the scientific problems of difficult early diagnosis,serious side effects of late treatment and poor prognosis of gastric cancer,we using nano medical technology to prepare the multifunctional nanoparticles which can be used in the integration of diagnosis and treatment of gastric cancer are designed and prepared.Such nanoparticles were used through the targeted imaging of gastric cancer,combined with phototherapy,and applied to the heterotopic transplanted tumor model of gastric cancer,can provide a new way to solve the dilemma of diagnosis and treatment of gastric cancer.The specific research contents are as follows:?1?A multifunctional nanocomposite?Mn₃O₄@MSNs@IR780?was prepared to realize the near-infrared diagnosis of gastric cancer and the mitochondrial targeted photodynamic therapy of gastric cancer under oxygen release.Mn₃O₄ acted as the gatekeeper to block the MSNs channel carrying photosensitizer IR780.Such nanoparticles can effectively target gastric cancer through EPR effect.Mn₃O₄,as an effective catalyst,can continuously decompose the highly expressed H₂O₂ in gastric cancer to produce oxygen,and leaded to the opening of MSNs channel.IR780 released in tumor tissue and further targeted at mitochondria.Under 808 nm laser irradiation,ROS generated and damaged mitochondria and gastric cancer tissue.?2?A multifunctional nanoparticle PEG-PCL-IR780-MET?P-P-I-M?was synthesized by using amphiphilic PEG-PCL to coat photosensitizers IR780 and metformin,which can simultaneously realize the near infrared diagnosis of gastric cancer,as well as the endogenous hypoxia inhibition and mitochondrial targeting PDT and PTT against gastric cancer.PEG-PCL,as a nano carrier,has high stability and can transfer nanoparticles to gastric cancer through EPR effect.Metformin can directly inhibit the activity of NADH dehydrogenase in the mitochondrial electron transport chain,thus inhibiting cell respiration and improving the tumor hypoxic microenvironment.IR780 can target mitochondria rapidly,produce ROS and generate heat,further exert the synergistic therapeutic effect of mitochondria targeting PDT and PTT.In addition,based on the photoacoustic and near-infrared dual-mode imaging characteristics of IR780,such nanoparticles can be used to monitor the synergistic effect of PDT and PTT through dual-mode imaging,and find small tumor tissues.?3?A multifunctional nanoparticle(i RGD-W₁₈O₄₉-17AAG)containing carboxyl functionalized W₁₈O₄₉,i RGD and HSP90 inhibitor 17AAG was designed and prepared,which can effectively enhance the targeting and imaging penetration of the nanoparticles to gastric cancer tissues,and improve its application in the diagnosis and treatment of gastric cancer.W₁₈O₄₉ has active carboxyl group,high photothermal performance and high biological safety in vitro and in vivo,which can be used as a carrier of photothermal therapy.Additionally,it can be used as CT contrast agent because it has strong X-ray absorption capacity.Compared with the traditional RGD peptide,i RGD retains the integrin targeting and improves the penetration of tumor cells.17AAG can be combined with W₁₈O₄₉ through esterification further inhibit the heat shock response of gastric cancer cells and improve the efficacy of PDT.Meanwhile,with the use of Cy5.5 to modify such nanoparticles,we can diagnose gastric cancer lesions by CT/NIR fluorescence dual-mode imaging and monitor the biological distribution of nanoparticles in vitro and in vivo.