Construct And Study Of Highly Sensitive MRI Contrast Agent Based On Chemical Exchange Saturation Transfer

Magnetic resonance imaging(MRI)has been widely used in the clinic due to its non-radioactive property and excellent soft-tissue contrast.Chemical exchange saturation transfer(CEST)is a relatively new powerful MRI technique that is well suited for molecular imaging.One unique advantage of CEST MRI is that MRI contrast can be produced by a variety of organic diamagnetic compounds containing exchangeable protons,such as glucose,glycogen,glutamate.Critical to the success of CEST imaging is selective irradiation of the labile protons while avoiding perturbation of bulk water signal and protons found in tissue.However,exchangeable protons of most CEST agents fall within 4 ppm from bulk water,which will limit the use of selective saturation pulses and increase the background signal.This work focuses on the development of highly sensitive CEST MRI agents for medical imaging applications.The main contents of this work are as follows:1.Natural vitamin B2 analog has been selected for targeted bimodal MRI/fluorescence imaging.The exchangeable imino proton of flavin adenine dinucleotide(FAD)resonates at6.25 ppm from water,shifted outside the tissue magnetization transfer window(0?4 ppm).The exchange rate of the imino proton with water fulfills the“slow to intermediate regime”condition for generating high CEST MRI contrast.In vivo molecular MRI and subsequent fluorescence imaging finally demonstrate that FAD efficiently accumulates in He La tumors,indicating that FAD is a new diamagnetic CEST(diaCEST)agent for the assessment of vascular metabolism in tumors.2.A new set of diaCEST agents with highly upfield shifited exchangeable proton frequencies has been developed.Based on the Z-spectra,the inner protons of porphyrins and chlorin resonate up to-13.5 ppm from water,far shifted from the majority of endogenous metabolites(0?4 ppm)and nuclear Overhauser enhancements(-1?-3.5 ppm).The exchange rates of the inner protons with water are slow enough relative to the chemical shift difference with water to allow robust detection.These results highlight the capabilities of porphyrins and chlorin as highly upfield diaCEST MRI agents and provide a new diaCEST scaffold that can be integrated into a variety of diagnostic or theranostic agents for biomedical applications.3.A novel mesoporous silica nanoparticle has been constructed for hyperpolarized ¹²⁹Xe CEST imaging.The nanoparticle is composed of a perfluorocarbon core and a stable silica shell.The silica shell of nanoparticle is functionalized with cyclic peptide to recognize?_v?₃integrin.The ¹²⁹Xe in nanoparticle resonates at 106 ppm,well seprated from ¹²⁹Xe dissolved in water.The exchange rate of ¹²⁹Xe is relatively slow,making the nanoparticle well suited for CEST MRI detection.In vitro MRI and fluorescence imaging demonstrate that the nanoparticle can provide sufficient signal to specifically detect?_v?₃ integrin-expressing cancer cells.The nanoparticle shows its potential for accurate cancer diagnosis through hyperpolarized ¹²⁹Xe CEST MRI.