Studies On Smart Cerium Oxide Based Nanoprobes Possessing Tumor Microenvironment Response For Diagnosis And Treatments

Cancer kills about one million people worldwide every year.Although a lot of human and material resources have been invested in the development of new cancer treatment methods,the current clinical treatment methods can only achieve limited results due to the complexity,diversity and heterogeneity of tumors.Therefore,building a new integrated diagnosis and treatment platform to realize the accurate diagnosis and specific treatment of cancer is particularly important.In the past decade,functional nanoparticles have been regarded as an alternative for traditional drugs.In addition,cancer is usually regarded as abnormal tissue with complex biological microstructure and specific microenvironment.With the rapid development of nanoscience and the exploration of tumor cells,the design of tumor microenvironment responsive nanoprobes has attracted extensive attention in the biomedical field.In inorganic nanomaterials,cerium oxide nanoparticles have many advantages,such as good enzyme-like activity,easy mutual transformation of Ce4+and Ce3+and low cell toxicity,which have important research value in the field of nanomedicine.Therefore,focusing on the catalase activity of cerium oxide nanoparticles and fluorescence resonance energy transfer(FRET),this paper is devoted to design tumor microenvironment responsive cerium oxide nanoprobes,and research the application of cerium oxide in tumor diagnosis and treatment.The result show that the cerium oxide nanoprobe can effectively alleviate tumor hypoxia by decomposing hydrogen peroxide,achieve fluorescence imaging of tumor sites through the specific response of tumor microenvironment and high selective and efficient photodynamic therapy.This paper is divided into the following three parts:Chapter 1:The first chapter briefly introduces the advantages of nanomaterials in cancer diagnosis and treatment,the strategies and problems of diagnosis and treatment at this stage,as well as the application of nanoprobes with tumor microenvironment response in cancer diagnosis and treatmentChapter 2:The catalase like activity of cerium oxide nanoparticles has important research value in the field of biotherapy.We design a smart tumor microenvironment stimulus-responsive nanoprobe CeOx-EGPLGVRGK-PPa to achieve highly selective photodynamic therapy by combining the catalase-like properties of cerium oxide with the FRET effect.In the meantime,through the design of polypeptide chain between CeOx nanoparticles and photosensitizer pheophorbide a(PPa),the nanoprobe could keep silent state before reaching the tumor site,and achieve activated state through cutting polypeptide chain by the response of metallomatrix proteinase-2(MMP-2)to recover the fluorescence and generate 1O2.This probe can not only detect tumor endogenous MMP-2 specifically and fluorescence image in situ,but also has a significant photodynamic effect.This result is expected to provide a new idea for the design of the stimulus response nanoprobe for integrated diagnosis and treatmentChapter 3:The therapeutic effects of chemotherapy and photodynamic therapy are limited seriously by tumor hypoxia and low cell uptake capacity.We designed a smart tumor-microenvironment responsive nanoprobe CeOx/Fe2O3-C&D,not only to strengthen cell uptake capacity,increase drug packaging efficiency and modulate tumor hypoxia,but also as an acceptor of FRET to achieve energy quenching of an excited photosensitizer.In normal tissue,the nanoprobe showed weak cytotoxicity,once into the tumor microenvironment,chemotherapy drug doxorubicin(DOX)was released rapidly and CeOx/Fe2O3 showed catalase-like activity to decompose H2O2 and produce O2 persistently to overcome hypoxia.Meanwhile the photosensitizer chlorin e6(Ce6)was transformed from "silent state" to "activated state",generating the fluorescence and 1O2 by weakening the FRET efficiency.Therefore,based on the study of CeOx in biological environment,our designed urchin-like nanoprobe could not only enhance cell uptake,regulate tumor hypoxia,but also achieve highly selective and efficient combination therapy.The intelligent nanoprobe provides guidance information for the preparation of tumor microenvironment-responsive combination therapy nanoprobes.