A Study On The Application Of Gadolinium-based High-sensitivity MRI Probes In The Diagnosis And Treatment Of Major Diseases

Magnetic resonance imaging（MRI）is one of the main diagnostic methods for major diseases such as cardiovascular and cerebrovascular diseases and malignancies.The advantages of high spatial resolution and absence of ionizing radiation allow MRI to display soft tissue structures inside the body noninvasively and clearly.However,contrast-free MR angiography has always suffered from intrinsic problems of blood flow dependence,and clinically available small molecule gadolinium chelate MR contrast agents are unsatisfactory due to their rapid extravasation and poor contrast enhancement.To accurately characterize anatomical vascular structures and identify abnormalities,we report here two highly sensitive gadolinium-based MRI contrast agents,a polymeric contrast agent based on amphoteric ionic metal chelating polymers（PAA-Gd）versus a biocompatible ultrasmall nanoparticle contrast agent（Na Gd F₄@PEG）.The longitudinal molar relaxivity of the PAA-Gd contrast agent is more than 4.6 times that of individual gadolinium chelates,and it has an appropriate blood half-life（73.8 min）and low immunogenicity,thus enabling excellent MR angiography of complex microvessels in rodent and porcine animal models with resolution to the hundred-micron level.The excellent disease diagnostic monitoring capability of PAA-Gd was explored in major animal models of cardiovascular diseases,including right middle cerebral artery occlusion model,atherosclerosis model and carotid thrombosis model,its excellent biosafety was verified in a rat model of chronic renal failure,and the translational potential of PAA-Gd was demonstrated in large animal Parabasic pigs,which is important for advancing the development of cardiovascular disease.It is of great significance to promote the development of clinical diagnosis and treatment of cardiovascular diseases.Biocompatible ultra-small Na Gd F₄nanoparticles as MRI-enhanced contrast agents,which also have the advantages of high contrast,long circulation and no leakage,can be used to visualize the 3D anatomy of arterial occlusion in stroke rats by 3D MR angiography for acute ischemic stroke and reperfusion-related subarachnoid hemorrhage（SAH）.More importantly,due to the long blood half-life of nanoparticles,the observation time window of MRI angiography can cover the whole time period before and after reperfusion by a single administration,thus monitoring possible SAH in real time during and after thrombolytic therapy,again providing a promising strategy for accurate diagnosis of vascular disease.In addition,we also obtained tumor microenvironment-responsive therapeutic all-in-one probes（NPs@PEG-RGD,DOX）by further modification on the surface of ultrasmall Na Gd F₄nanoparticles.The tumor-targeting functional group RGD peptide modified on the particle surface enables the nanoprobe to perform excellent tumor cell uptake.We have demonstrated the potential of the gadolinium-based MRI probe as a therapeutic all-in-one probe by leveraging the excellent MRI imaging capability and effective radiosensitization potential of gadolinium ions to achieve excellent radiotherapy synergy for malignant glioma cells.In summary,we provide a highly sensitive MRI probe based on gadolinium for accurate diagnosis and prognosis of cardiovascular and cerebrovascular diseases,complete imaging of high-resolution vascular structures and lesions,as well as propose a new strategy for the diagnosis and treatment of malignant glioma,which is important for promoting the development of clinical diagnosis and treatment of major diseases,including cardiovascular and cerebrovascular diseases and malignant tumors.