Multimodal Magnetic Resonance Imaging Nanoprobes For Precise Detection Of Tumor Microenvironment

Tumor microenvironment（TEM）is the cellular internal and external environment of tumor during tumor growth and metastasis.It includes not only the structure,function and metabolic parameters of the tissues where the tumor exists,but also the various internal environment of the tumor cells.Real-time detection of tumor microenvironment by imaging technology is of great significance for accurate diagnosis and treatment of tumor,which can be early meet the occurrence and development of tumor.Among multitudinous clinical imaging technologies,magnetic resonance imaging（MRI）is the most common and popular imaging technology,which plays an important role in the diagnosis,monitoring and prognosis of tumors.With the advancement of computer science and physics,a series of new MRI sequences have emerged,which provide a new direction for study tumor microenvironment by employing multimodal imaging probes.In this paper,we synthesized two new types of multimodal MR imaging probes through reasonable material design.Accurate multimodal MR imaging modes in tumor microenvironment detection could achieve accurate detection of tumor vessels and tumor cells.The main contents include the following aspects:（1）Perfusion weighted imaging（DCE-PWI）and diffusion weighted imaging（DWI）based on the ultra-small cerium oxide nanoprobe（PEG-CeO₂:Gd）for accurate tumor microenvironment detection:Tumor vascular microenvironment playing an important role in the growth and development of tumors,is an important index for evaluating the invasiveness of tumors.Based on the phenomenon of oxygen vacancy-enhanced MRI performance found in the previous work in our group,this work proposes a new strategy of“MRI enhancement based on oxygen vacancy regulation”,which utilizes the oxygen vacancies in CeO₂:Gd.An ultra-small MRI probe（PEG-CeO₂:Gd）with oxygen vacancy was designed with ultra-high contrast enhancement performance（5 times more than Magnevist）.The imaging probes have higher sensitivity to traditional structural sequences and new functional sequences such as DWI/DCE-PWI,which can significantly improve the anatomical structure resolution and functional information sensitivity of blood vessels in the tumor area.（2）Metal-organic framework compound（MIL-53@MnO₂）nanoparticles for MR T₁ and multi-flip angle T₁-mapping imaging for evaluating tumor drug resistance:it is difficult to detect adaptive drug-resistance and its related tumorsduring cancer treatment.If the non-invasive,real-time and accurate detection of existenceand distribution of drug-resistant cells can be achieved by imaging methods,the drug resistance of tumors will be improved.Overexpression of multidrug resistance（MDR）genes and P-glycoprotein（Pgp）,are the main cause of drug resistance in most malignant tumors after chemotherapy.Overexpression of Pgp can result in down-regulation of reactive oxygen species（ROS）level in drug-resistant tumors.It is expected that a highly sensitive ROS responsive MRI nanoprobe can be designed for non-invasive and accurate evaluation of drug resistance of tumors.In this work,nano metal-organic frameworks（NH₂-MIL-53,MIL-53）were used as the core,and manganese oxide nanosheets were uniformly grown on the outer surface of the MIL-53.The high sensitivity of MnO₂ nanosheets in response to ROS,combined with and T₁（T₁-weighted image,T₁WI）and the more sensitive multi-flip angle T₁-mapping technology for precise detection of ROS level in tumor tissues has the potential to accurately evaluate and guide the clinical treatment of tumor drug resistance.