Synthesis Of Polyoxometalate Supramolecular Complex-based MRI Contrast Agents And Characterization In Vivo

Polyoxometalates (POMs) are a class of inorganic nano-scale (0.5-5nm) clusters withabundant chemical composition and topologies. Due to the versatile functionalities incatalysis, electronics, and magnetics, POMs are considered to be a new type of functionalinorganic building blocks in the field of materials. In addition, POMs are a class ofsupramolecular building blocks with affirmatory nono-structure, uniform size andnegatively charged surfaces. Modification chemical surface of functional nano-objects byutilizing synergies between the organic component and inorganic component not onlyimparts the thermoresponsivities, but also effectively prevents leakage of the nano objects.It is worth noting that the negatively charged surface of Gd-POMs canstrongly adhere tothe positively charged biological molecules,which influences the biocompatibility ofGd-POMs as contrast agents in clinical use.Firstly, in order to build an effective MRI contrast agent and make it applied in vivo,we synthesized a series of cationic dendrons bearing triethylene glycol monomethyl etherterminal groups of different generations and used them to encapsulate paramagneticinorganic polyanionic cluster K13Gd(SiW11O39)2through electrostatic interactions. Theelemental analys and thermogravimetric analysis (TGA) was also used to determine thechemical compositions of the prepared complexes, At the same time, the results of the1HNMR and IR spectra reveal that (GdSiW11) clusters have been successfully enwrapped bythe dendritic cations through electrostatic interactions.Secondly, we detailed studied factors of relaxivity with temperature–responsiveproperties and found that relaxavity reduced when temperature increased, which because elevated temperatures will not only reduce rotational correlation time of the paramagneticcontrast agent, and increase the retention time of the coordinated water in the paramagneticcenter. relaxivity began to increased when increasing temperature below the LCST, wethought volume effect become a major factor affecting the relaxivity, on the basis ofensuring the coordinated water on the surface of aggregates can effectively inducedexchange with bulk water below the LCST. the hydrophobicity induced by the temperatureincrease above the LCST triggers the enhanced aggregation, so both the hydrophobicityand increase in size of the aggregates make the relaxivity decrease. We use the SBMtheory to give more reasonable explanation for the variation of the relaxation at differenttime. Furthermore, we confirmed that the performance of a certain size aggregates becomea major factor affecting relaxivity by variable-temperature relaxation efficiencyexperiments. Futhermore, to understand the main factors of the supramolecular aggregatesrelaxaxivity, we measured the relaxivity of GdSiW11and (D-2)13GdSiW11and found thatthat complexes bearing second-generation dendrons showed a much higher relaxivity(18.96mM–1s–1) than Gd·POM (16.56mM–1s–1). On the basis of ensuring the externalwater molecules to freely penetrate the interior of the assemblies and to exchange with thecoordinated water of GdSiW, we infer that the relaxivity enhancement of D-2/GdSiWassemblies is attributed to the longer rotational correlation time of GdSiW caused by theself-aggregation among complexes, which indirectly prove the rationality of myexperimental datas.Thirdly, the introduction of TEG groups in the periphery of the surfactants canincrease the water-solubility of the complexes and the results of NMR in D2O prove thatthey are stable in water. DLS and TEM shows that the diameter of GdSiW11(D-3)13isabout5-6nm, which means that the class of contrast agents can be excreted through thekidneys and benefits to ensure the clinical safety. Compared with the clinically appliedgadopentetic acid, relaxivity of GdSiW11(D-3)13is higher. In addition, we also evaluatedthe effect of MRI signal enhancement of various organs in vivo and tracked the metabolicprocesses of contrast agent in vivo by using the MRI scanners. The study found thatGdSiW11(D-3)13not only havn’t showed toxicity to the cell, but also showed longerenhancement of rat liver and favorable kidney excretion capability, indicating thatcomplexs are also removed from the blood and eliminated through the kidney, which maybe related to the selective permeability and charges of the glomerular filtration membrane. The gap of layers for filtration membrane only allows the nanoparticles less than15nmparticles get through. Normally, the surface of filtration membrane covers the negativelycharged proteoglycans, thus it limits the the negatively charged molecules to get through.However, the negatively charged surfaces POMs have been widely assembled withcationic organic molecules construct hybrid nanostructures and its size is about6nm,therefore, they can be eliminated through the kidney which is very important for clinicalapplications.In conclution, utilizing the synergic effect between supramolecular structure andmagnetic properties of inorganic clusters, we realized the functionalization ofpolyoxometalate supramolecular complexes as T1MRI contrast agents. More importantly,we can explain the relationship between relaxivity and aggregation states utilizing thethermoresponsivities of the hybrid dendritic complexes, which wil have theoreticalsignificance for developing the new and efficient MRI contrast agent system.