Design And Synthesis Of Smart Responsive Nanoparticle-Based Magnetic Resonance Imaging Contrast Agents For In Vivo Imaging Of Biological Processes

Molecular imaging undoubtedly plays an important role in the accurate diagnosis and treatment monitoring of clinical diseases.Among many molecular imaging technologies,magnetic resonance imaging(MRI)is favored by doctors or patients for its advantages of high spatial resolution,no radiation,tomography and multi-parameter imaging,and has become an important tool for clinical diagnosis.In order to improve the contrast between lesions and normal tissues in MRI,MR contrast agents(CAs)have been widely used.However,due to the low relaxation efficiency and potential biotoxicity of commercial MR CAs,a new generation of substitutes is urgently needed.Therefore,it is of great clinical significance to develop novel high-efficiency and lowtoxicity nanoparticle-based MR CAs combined with the emerging nanotechnology.Based on this rationale,we developed a series of intelligent responsive nanoparticlebased MR CAs,systematically studied the structure-activity relationship principle of relaxation property changes induced by specific stimuli,and further utilized them to achieve efficient magnetic resonance angiography(MRA)and visualization of important biological processes in deep tissues in vivo.The specific research contents are as follows:In Chapter 1,the basic principle of MRI,the structure-activity relationship theory of MR CAs,or the research progress and biomedical applications of nanoparticle-based MR CAs are briefly introduced.The topic selection basis and research content of this doctoral thesis are also summarized.In Chapter 2,we synthesized Gd-doped TiO2 ellipsoidal nanoparticles through a sequential growth method and coated them with sodium citrate to afford hydrophilic Gd-doped TiO2 nanoparticles(denoted as GdTi-SC NPs),which shows a considerable elevation(35%)in T1 relaxivity(ri)upon exposure to ultraviolet light(UV).Therefore,we proposed a photo-induced superhydrophilic assistance paramagnetic relaxation enhancement(PISA-PRE)effect to explain this phenomenon.Experimental evidence showed that the reduced water contact angle and the increased number of hydroxyl groups on the surface of GdTi-SC NPs after UV irradiation substantiate the existence of the PISA effect.Additionally,in vivo contrast-enhanced magnetic resonance angiography(CE-MRA)with SD rats illustrates the promising potentiality of GdTi-SC NPs as a high-performance blood pool CA for sensitive imaging of blood vessels and accurate diagnosis of vascular lesions.Glutathione(GSH)-mediated biotransformation is a well-known crucial physiological process in liver.However,the effective imaging tools to non-invasively deep-tissue visualize the dynamics of this process are lacking.In Chapter 3,we synthesized amorphous FexMnyO nanoparticles(denoted as AFMO-ZDS NPs)as redox-activated probes for in vivo visualization of GSH-mediated biotransformation in the liver with contrast-enhanced MRI(CE-MRI).This imaging technique reveals the periodic variations in liver GSH concentration during the degradation of AFMO-ZDS NPs due to the limited transportation capacity of GSH carriers in the course of GSH efflux from hepatocytes to perisinusoidal space,which provides direct imaging evidence for this important carrier-mediated sinusoidal GSH efflux during GSHmediated biotransformation.Therefore,this method offers a powerful tool for in vivo real-time visualization of GSH-mediated biotransformation dynamics in liver,which is of considerable benefits for in-depth investigations of GSH-related biological processes in liver under assorted conditions.Cerebral manganese deposition is a typical clinical symptom in patients with chronic hepatic encephalopathy,but the underline molecular mechanism remains unclear.Therefore,in Chapter 4,we synthesized Mn-doped SiO2 nanoparticles(denoted as SiMn NPs),which can disintegrate in the presence of high-concentration of GSH to produce Mn2+-GSH chelates and realize the activation of T1 MRI signal.We found that there are significantly enhanced T1 MRI signals in the brain of mice intravenously injected with SiMn NPs in the T1-weighted CE-MRI.This result was further supported by matrix-assisted laser desorption/ionization time-of-flight(MALDI-TOF)of blood,liver and brain tissue homogenates from mice,matrix-assisted laser desorption/ionization imaging mass spectrometry(MALDI-IMS)of liver and brain tissue homogenates from mice,and tissue distribution of Mn content.Therefore,we believe that SiMn NPs could be selectively taken up by liver and degraded in the presence of high-cocentration of GSH,releasing paramagnetic metal ions(Mn2+)which are soon caught by GSH to generate Mn2+-GSH chelates.These Mn2+-GSH chelates substantially shorten the T1 relaxation times of surrounding water protons and enhance local T1 MR signals,enabling T1-weighted CE-MRI.Subsequently,part of the Mn2+-GSH chelates can travel through the blood circulation system to the brain and cross the blood-brain barrier(BBB)via GSH transporter and eventually accumulates Mn in the brain.This new finding indicates that GSH-mediated biotransformation in liver plays a key role in Mn deposition in brain,which could elucidate the possible molecular mechanism of cerebral manganese deposition in hepatic encephalopathy.In Chapter 5,the main work of this doctoral thesis is briefly summarized.Meanwhile,the future development prospects of structure-activity relationship theory,biomedical applications,and clinical transformation of nanoparticle-based MR CAs are discussed and prospected.