Design,Synthesis And Biomedical Applications Of ¹⁹F Magnetic Resonance Imaging Probes

With the rapid development of modern biomedicine and technology,the development of various professional fields in clinical practice reflects the common trend of pursuing"precision".The research of molecular imaging technology is also developing from the traditional morphological imaging diagnosis to the early and accurate molecular imaging diagnosis.Magnetic resonance imaging(MRI)is one of the most popular diagnostic techniques because of its noninvasiveness,high spatial resolution,and deep penetration.Conventional 1H MRI can provide high spatial resolution and detailed anatomical images.However,due to the large number of hydrogen protons in the body,there is a large background interference in the application of 1H MRI in molecular imaging.In the latest decade,19F MRI began to attract widely attention because of its unique characteristics.19F is also a kind of magnetic nuclei,and its gyromagnetic ratio is very close to hydrogen proton;its sensitivity is 83%of that of hydrogen proton;the chemical shift distribution of NMR spectrum in a broad range(>300 ppm).In addition,the content of 19F in the organism is very low(10-6m),mainly distributed in the solid phase such as teeth and bones,which makes the T2 value of 19F is very short,resulting in its signal far lower than the detection limit of ordinary MRI.Endogenous 19F nuclei do not produce 19F signal in 19F MR imaging,which makes the 19F MRI probe present the characteristics of "hot spot" signal in vivo imaging.Therefore,19F MRI technology has unique advantages in the research of molecular imaging,cell tracking,and drug monitoring.In this thesis,several new 19F MRI probes with good biocompatibility and high sensitivity are explored for high-performance 19F MR imaging and detection of biological targets.In Chapter 1,we briefly reviewed the basic principles of MRI and the characteristics and developments of 1H MRI and 19F MRI.We also showed the selection basis and research work of this thesis.In Chapter 2,we have designed and synthesized a cascaded responsive 19F MRI probe(1-ICG NPs),which could realize stepwise two stage 19F MR signal activation and amplification during the reducing environment of the tumor microenvironment and photothermal treatement of the tumor.The 1-ICG NPs are formed by the amphiphilic polymer and NIR-absorbing ICG molecule through n-n stacking and hydrophobic interaction.Initially,19F NMR signals of the 1-ICG NPs are negligible because of the restriction of spin-spin relaxations and molecular mobility.When exposed to the reducing environment of the tumor tissue,the breaking of disulfide bond triggers the dissociation of 1-ICG NPs into ultra-small nanoparticles,and weakens the dipole interaction between 19F atoms,resulting in the activation of 19F MRI signal from "off"to "on".Next,under the radiation of near-infrared(NER)laser,ICG molecules absorb near-infrared light and transform into heat,which leads to the increase of environmental temperature,thus accelerating the molecular movement,resulting in the complete selfassembly of ultra-small nanoparticles,realizing the second amplification of 19F MRI signal.This strategy of cascaded activation and amplification of 19F MRI signal can effectively enhance the specificity and accuracy of 19F MRI in tumor diagnosis.In Chapter 3,we have designed and synthesized a multifunctional pH activated nanoconjugate(FGPs)19F MRI probe,which are composed of pH-responsive 19F bearing gadoliniu chelates(FG)and ultra-small palladium nano-sheets.The paramagnetic Gd3+complex can interact with 19F nucleus through electron-nuclear dipole interactions。which decreases T2 value of 19F atoms,resulting negligible 19F MR signals.When exposed to slightly acidic tumor microenvironments,the hydrazone bond in GF molecule would be cleaved,weakened the electron-nuclear dipole interactions,resulting in the elongation of T2 value and transition of 19F MR signals from "OFF" to"ON".In addition,the Gd complex can improve the 1H MR signal intensity of surrounding water molecules by shortening the T1 value.FGPs nanoprobes can be used as a contrast agent for 1H MRI.Grafting the GF onto palladium nanosheets can shorten the rotational correlation time(τR)of the contrast agent and further enhance the contrast performance in 1H MRI.Therefore,the FGPs nanoprobes could accomplish significant contrast enhancement in Ti-weighted 1H MRI and pH activated 19F MRI on a single MRI scanner,aimed to obtained detailed anatomical information and pathology related molecular information with low background the biorelevant molecular information of living bodies,which could realize sensitively and accurately detection of tumorsIn Chapter 4,The 19F signal during the 19F MR imaging comes from foreign the exogenous 19F probes.As for 19F MRI probes,perfluorocarbon(PFC)emulsions are the most commonly used agent.They are both hydrophobic and lipophobic.Phospholipid surfactants are usually utilized to formulate PFCs as oil-in-water nanoemulsions to overcome the solubility obstacle.Meanwhile,PFC emulsions suffer from several shortcomings,including instability,heterogeneity,complicated formulation,multiple 19F resonance frequencies(especially for linear PFCs;multiple 19F resonance frequencies which are prone to chemical shift artifact in imaging process),and most importantly,excessive and long-term retention in main organs(e.g.,liver and spleen).Therefore,it is necessary to develop a type of new 19F MRI probes with high fluorine content,good water solubility,simple synthesis and preparation process,single 19F resonance frequency and rapid clearance in vivo.Therefore,we developed a new type of water-soluble molecular 19F probes by conjugating fluorine-containing moieties with polyhedral oligomeric silsesquioxane(POSS)through a few steps of simple organic coupling.we attached three small aliphatic molecules bearing CF3,CHF2,and CBrF2 terminal groups to eight linkable arms of POSS,and constructed three 19F probes,POSS-CF3,POSS-CHF2,and POSS-CBrF2.They following outstanding features:(1)high 19F content and favorable T1 and T2 value for sensitive 19F MR imaging;(2)single 19F resonance frequency that prevents chemical shift artifacts;(3)linear relationship between 19F MRI signals and concentrations of 19F probe that permits quantitative analysis;(4)rapid renal clearance;and(5)significantly different 19F chemical shifts among three probes(>10 ppm)suitable for crosstalk-free multicolor 19F MRI.We successfully demonstrated multicolor 19F MRI for cell labeling both in vitro and in vivo with these probes,which provides a potential solution for monitoring and evaluating cell-based anticancer therapy.In Chapter 5,we summarized the research work of this paper,and simply discussed the research status and development prospect of 19F MRI in the future.