| Cancer is a serious threat to human life and health.For patients,accurate diagnosis of cancer is essential to improve the survival rate.Magnetic resonance imaging(MRI)plays an indispensable role in the accurate diagnosis of cancer,which can provide high spatial resolution images of tumor anatomical structure and pathological information without being limited by the depth of tissues.However,MRI generates signals based on water molecules,which leads to insufficient imaging contrast in certain tissues,requiring contrast agents to assist imaging.Clinically,contrast agents are mainly gadolinium-based small molecule chelates,which chelate Gd(Ⅲ)in the ligand structure to reduce toxicity,but also hinder the interaction with water molecules,resulting in low relaxation efficiency.In addition,the metabolism of small-molecule chelates in vivo is fast,resulting in a short imaging time window and low imaging efficiency.The development of nanotechnology injects new vitality to the reserach of MRI contrast agents.The preparation of gadolinium nanoparticles can significantly improve the relaxation efficiency.However,there are still some problems such as limited improvement in relaxation efficiency,the use of inorganic materials,complex synthesis methods,and high costs and so on.Therefore,it’s highly desired to further improve the relaxation efficiency of the contrast agents and extend the imaging time window to obtain higher diagnostic efficiency.The assembly of nanomaterials is a common strategy in the design and synthesis of nanomaterials for biomedical applications in recent years.Molecular cooperativity based on non-covalent interactions can lead to self-assembled nanostructures with emergent properties where the whole is bigger than the sum of the parts.Among them,Pickering emulsion is a self-assembled nanostructures formed by solid particles assembling at the oil-water interface.The versatility of colloidal particles endows Pickering emulsion with unique properties,making it a multi-functional platform to realize the personalized preparation of functional materials.In recent years,Pickering emulsion showed great potential in drug delivery,interface catalysis,bioimaging,and functional materials.In addition,the microenvironment of the organism can also be used to trigger the self-assembly of nanomaterials in vivo,improving the accumulation of nanoparticles and long-term retention in tumor sites.Therefore,self-assembly of molecular components can be leveraged to design nanomedicine with improved diagnostic precision and therapeutic efficacy.In this dissertation,the interfacial self-assembly of functional albumin nanoparticles is proposed based on Pickering emulsion,which can realize the controllable assembly of Gd contrast agent and improve the relaxation efficiency by changing the type and quantity of assembled monomers,leading to significantly enhanced contrast of tumor MR imaging.In addition,the weak hydrogen bonding interaction between albumins can realize the in-situ self-assembly of Pickering emulsion,bringing about retention in tumor,which helps to prolong the MRI time window and improve imaging efficiency.Finally,as an assembly template,Pickering emulsion can also be applied for tumor diagnosis and treatment,such as tumor chemotherapy,photothermal therapy,and multimodal imaging.The main results are summarized as follows:Chapter 1:This chapter describes the research progresses of MRI and its contrast agents,as well as the development of self-assembly strategies of nanomaterials for biomedical applications.Chapter 2:Preparation and characterization of Nanoscale Pickering Emulsion(NPE).Under ultrasonication,gadolinium oxide albumin nanoparticles(Gd2O3@HSA)and copper sulfide albumin nanoparticles(CuS@HSA)are used as assembly units to anchor on the interface of perfluorooctyl bromide(PFOB)and water to form NPE.The NPE has a core-shell structure with Gd2O3@HSA and CuS@HSA on the outer layer and PFOB in the core,realizing interfacial self-assembly of Gd2O3@HSA and CuS@HSA.The NPE retains and enhances the biological function of albumin nanoparticles,which can be proved at the cell level.The NPE significantly improves the relaxation efficiency of Gd contrast agents and has r1 value of 51.47 mM-1s-1,which is about 14 times than that of clinically used Gd-DTPA(r1=3.62 mM-1s-1),showing great potential to significantly improve the contrast of MR imaging.Chapter 3:The NPE improves the relaxation efficiency of Gd contrast agents and enhances tumor MR imaging.By changing the composition of the assembled monomers,a series of NPE with different Gd/Cu molar ratios were prepared to study the principle of improving relaxation efficiency.After assembling into NPE,Gd2O3@HSA is anchored on the oil-water interface.Not only it slows down the tumbling of Gd and increases the molecular rotation time τR,but it also limits the diffusion of water molecules around Gd and increases the diffusion correlation time τD.The combined effect can improve the relaxation efficiency of Gd contrast agents,which will helpful for enhancing tumor MR imaging.Chapter 4:The interaction between NPE and albumin extends the tumor MRI time window.Crowded albumin in NPE solution can mediate the in-situ self-assembly of NPE because of the weak hydrogen bonding interactions between albumin and NPE,inducing the retention of NPE in tumor and extending MRI time window.As a result,NPE can achieve continuously 24-hour high-contrast MR imaging of tumor in different tumor models,which is beneficial to improve the efficiency of MR imaging.Chapter 5:NPE can be used for tumor diagnosis and treatment.As an assembly template,NPE can achieve multiple functions such as tumor diagnosis and treatment by changing assembled monomers.Doxorubicin albumin nanoparticles(DOX@HSA)with tumor chemotherapy function can be assembled into DOX NPE for enhanced tumor chemotherapy.Gd2O3@HSA and CuS@HSA can be assembled into Gd/Cu NPE for tumor photothermal therapy and photoacoustic imaging.Perfluoro-n-pentane(PFP)and Perfluorohexane(PFH)can be used as inner phase to fabricate PFP NPE and PFH NPE for tumor ultrasound imaging.In summary,the NPE designed and prepared in this thesis can improve the relaxation efficiency of Gd contrast agents through interfacial assembly for enhanced tumor MR imaging contrast.It can also prolong MRI time window by staying in tumor because of the hydrogen bonding interaction with albumin for improved efficiency of MRI diagnosis.As an assembly template,NPE can realize multiple functions,including tumor diagnosis,such as MR imaging,ultrasound imaging and photoacoustic imaging as well as tumor treatment,such as chemotherapy and photothermal therapy,showing great prospect of applying to personalized therapy. |
