Application Of IRGD-conjugated Targeting Nanoparticles For Diagnosis And Therapy Of Gastric Cancer

Gastric cancer is one of the most threat to human health,with high morbidity and mortality.Although the diagnosis and therapy technology of gastric cancer has made great progress,it still faces many problems.For example,the traditional diagnostic modalities(such as ultrasound,CT,MRI,etc.)have been developed rapidly,but still can’t get the targeted diagnosis of lesions,the diagnostic accuracy and specificity of these modalities are unable to meet the clinical needs,totally.In addition,chemotherapeutic drugs such as cisplatin,which are commonly used in gastric cancer therapy.Yet the lack of intended targets of these drugs cause the extensive systemic toxicity largely restrict the clinical application of conventional chemotherapy.Therefore,novel modalities for targeted diagnosis and therapy of gastric cancer to realize precision medicine are urgently needed.In recent years,nanomedicine has been more and more widely applied in the medical field with the development of nanotechnology.Due to the superior modifiability of nanoparticles,targeted nanoparticles could be easily achieved via surface modified with target ligands.Drug delivery by targeted nanoparticles may achieve tumor precise diagnosis and therapy.The tumor-targeted cell penetrating peptides iRGD(CRCGDK/RGPDC)is a cycle RGD peptide which based on disulifide bond.It not only can specifically bind to the integrin which on the surface of tumor cells,but also mediates tumor cell penetration.Since the overexpressed integrin on the surface of gastric cancer cells,the nanoparticles modified with iRGD are possible to achieve targeted diagnosis and therapy of gastric cancer.Based on these backgrounds,we focus on gastric cancer and evaluate the possibility of targeted nanoparticles used for the diagnosis and therapy of gastric cancer.In this thesis,we firstly construct an iRGD-modified heparin(iHP)drug delivery system which is biocompatible and biodegraded and apply it to targeted delivery of NIR fluorescence agents and chemotherapy drugs to gastric cancer cell and tumor.The results confirmed that iRGD-modified nanoparticles could be used in targeted diagnosis and therapy of gastric cancer.After that,we have developed a multifunctional targeted nanoparticle:iRGD-W18O49-Pt-Iodine(iRGD-W@Pt/I).And examine its capability to realize targeted multimodal diagnosis and therapy of gastric cancer.Details were provided as following:(1)In this work,a biocompatible and biodegraded drug delivery system which named iHP is established through conjugating the tumor-targeted cell penetrating peptides iRGD to succinic anhydride-modified heparin.NIR fluorescence agents delivered by iHP could realize targeted drug delivery to cancer cells or tumor,then make a precise NIR diagnosis of gastric cancer.Additionally,delivery of cisplatin by iHP could achieve targeted antitumor effects while decreasing side effects.Since the iRGD and heparin hold great promise for clinical applications with a low toxicity profile,iRGD-heparin nanocarrier has great future potential of application in gastric cancer therapy.(2)This work is based on tungsten oxide nanoparticles(W18O49)which can be used in CT imaging,PA imaging,photodynamic therapy and photothermal therapy.Firstly,in order to enhance its CT imaging effect,we modified it with iodine.Then,to enhance its therapy effect,we coordinate it with cisplatin.Finally,we conjugate iRGD on its surface to get a targeted multifunctional nanoparticle(iRGD-W18O49-Pt-Iodine,iRGD-W@Pt/I).iRGD-W@Pt/I could realize targeted CT imaging,PA imaging,photodynamic therapy,photothermal therapy and chemotherapy at the same time.Through the construction of the theranostic nanoparticles iRGD-W@Pt/I,the multimodal diagnosis and multimodal therapy is realized by single drug which provided a novel idea for targeted diagnosis and therapy of gastric cancer.