Application Of Targeted Peptide Functionalized Nanomaterials In Tumor Diagnosis And Treatment

Early diagnosis of cancer is the key to the prevention and treatment of cancer.In order to detect early treatment,biomarkers are used clinically to refine tumor molecular typing to diagnose and prognose patients,so as to better guide individualized treatment.Among them,CD47,Prominin-1,and ER are highly attractive molecular targets.The status of these tumor markers directly affects the risk level of the tumor,and its expression level is closely related to tumor invasion,recurrence and prognosis.Therefore,CD47,Prominin-1 and ER have been internationally recognized as independent diagnostic and prognostic biomarkers for breast cancer and cancer stem cells.Although related antibody drugs are widely used in targeted therapy of tumors,there are still some limitations: such as large antibody size,difficulty in chemical modification and high cost;acquired drug resistance of antibody drugs;post-translational modification of antibodies such as glycosylation can cause severe allergic reactions;long half-life in vivo is not suitable as a molecular probe,which limits its clinical application.Peptide drugs and diagnostic probes have the advantages of small molecular weight,high specificity,low immunogenicity,strong penetrability,easy synthesis and modification,and have strong advantages in targeted drug delivery and early diagnosis.Due to the large number of peptides and diverse structures,specific peptide ligands for tumor marker receptors can be obtained by high-throughput screening.Therefore,CD47,Prominin-1 and other development of highly sensitive and specific new peptide probes,through functional modification and assembly to form nanomaterials,to achieve targeted high-sensitivity tumor imaging,targeted drug delivery and dual target combination therapy specifically kills tumor cells.This is of great significance for the integrated diagnosis and treatment of cancer.The main research contents and results of this thesis are as follows:(1)Synergetic Estrogen Receptor-targeting Liposome Nanocarriers with Anti-Phagocytic Property for Enhanced Tumors Theranostics:In the first research work,we have developed an effective NCs system named SELS(self-peptide and ER ligand)for enhancing the targeting ability towards tumors and effective escaping behaviors towards mononuclear phagocyte system(MPS).SELS is a synergetic-conjugated liposome system.Anti-ER and an anti-phagocytic moiety SP are used for liposome functionalization.After that,we also evaluated the cellular uptake,cytotoxicities,fluorescence imaging and synergistic antitumor efficiency in vivo.As a tumor-homing navigator,SELS could enhance the tumor accumulation,improve drug delivery efficiency to the therapeutic active site and keep in stable manner in normal tissues and blood circulation.(2)Boosting the Theranostic Effect of Liposomal Probe towards Prominin-1 through Optimized ‘Dual-site Targeting':In this work,we construct a synergetic Prominin-1 targeting liposomal-probe system with dual-targeting peptide functionalization to perform the synergetic binding effect.Herein,a new affinity peptide towards Prominin-1 was reported for the first time.Through a precise molecular docking and experimental assay,liposome probes with rational designed peptide-ligand functionalization were achieved.The targeting efficiency can be dramatically enhanced by precise control of the surface density and systematic optimization of surface spatial distance of targeted peptides.Imaging elements and drug encapsulated liposomes can not only image in vivo CSCs tumor but also inhibit tumor growth effectively compared with either the mono-targeting liposomes or the non-targeting ones.(3)Comparison of the Estrogen Receptor Expression Profile of Circulating Tumor Cells and Primary Tumor and Metastases in Metastatic Breast Cancer Patients:In this study,to investigate the ER expression distribution,we established a detection system for ER evaluation in CTCs that have been isolated with Pep@MNPs,which is a highly sensitive method based on Ep CAM(+)enrichment.It has been confirmed that Pep@MNPs assay could be utilized to isolate CTCs from breast cancer patients.Therefore,the objective of this study was to evaluate the ER expression patterns of CTCs and to compare the ER expression profile of CTCs with the primary tumor and metastases in metastatic breast cancer patients participating in the study.We hope to further optimize and develop multivalent nanoprobes,and to achieve functionalized assembly of nanomaterials by modifying peptides with different target sites,and finally develop a class of diagnostic reagents and therapeutic drugs that can specifically target tumors efficiently and specifically for the early diagnosis of tumors.