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Novel fluorinated ligands for gold nanoparticle labelling have been designed and synthesised. Several types of gold nanoparticles have been prepared in the presence of these fluorinated ligands alone, or in combination with non-fluorinated ligands. Their colloidal stability in water and other solvents was tested and the magnetic resonance propertie...
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... In pursuance of the ligands with fluorine atoms in the same chemical environment, PFTB ligands were set up for the preparation of gold NPs. Out of the prepared NPs (fluorinated/non-fluorinated, attaching PEG/thiolate to its side chain, etc.), long-chain PEGylated compounds were proven to be the best option to obtain colloidally stable NPs in vitro and hence obtain a single chemical shift, narrow 19 F-NMR signal, and high fluorine loading [268]. ...
Simultaneously being a non-radiative and non-invasive technique makes magnetic resonance imaging (MRI) one of the highly sought imaging techniques for the early diagnosis and treatment of diseases. Despite more than four decades of research on finding a suitable imaging agent from fluorine for clinical applications, it still lingers as a challenge to get the regulatory approval compared to its hydrogen counterpart. The pertinent hurdle is the simultaneous intrinsic hydrophobicity and lipophobicity of fluorine and its derivatives that make them insoluble in any liquids, strongly limiting their application in areas such as targeted delivery. A blossoming technique to circumvent the unfavorable physicochemical characteristics of perfluorocarbon compounds (PFCs) and guarantee a high local concentration of fluorine in the desired body part is to encapsulate them in nanosystems. In this review, we will be emphasizing different types of nanocarrier systems studied to encapsulate various PFCs and fluorinated compounds, headway to be applied as a contrast agent (CA) in fluorine-19 MRI (19F MRI). We would also scrutinize, especially from studies over the last decade, the different types of PFCs and their specific applications and limitations concerning the nanoparticle (NP) system used to encapsulate them. A critical evaluation for future opportunities would be speculated.
... In pursuance of the ligands with fluorine atoms in the same chemical environment, PFTB ligands were set up for the preparation of gold NPs. Out of the prepared NPs (fluorinated/non-fluorinated, attaching PEG/thiolate to its side chain, etc.), long-chain PEGylated compounds were proven to be the best option to obtain colloidally stable NPs in vitro and hence obtain a single chemical shift, narrow 19 F-NMR signal, and high fluorine loading [268]. ...
Simultaneously being a non-radiative and non-invasive technique makes magnetic resonance imaging (MRI) one of the highly sought imaging techniques for the early diagnosis and treatment of diseases. Despite more than four decades of research on finding a suitable imaging agent from fluorine for clinical applications, it still lingers as a challenge to get the regulatory approval compared to its hydrogen counterpart. The pertinent hurdle is the simultaneous intrinsic hydrophobicity and lipophobicity of fluorine and its derivatives that make them insoluble in any liquids, strongly limiting their application in areas such as targeted delivery. A blossoming technique to circumvent the unfavorable physicochemical characteristics of perfluorocarbon compounds (PFCs) and guarantee a high local concentration of fluorine in the desired body part is to encapsulate them in nanosystems. In this review, we will be emphasizing different types of nanocarrier systems studied to encapsulate various PFCs and fluorinated compounds, headway to be applied as a contrast agent (CA) in fluorine-19 MRI (19F MRI). We would also scrutinize the different types of PFCs and their specific applications and limitations concerning the nanoparticle (NP) system used to encapsulate them studied over the last decade. A critical evaluation for future opportunities would be speculated.
... 18−20 In this context and in the last years, we and others have overcome the fluorine hydrophobicity challenge and prepared fluorinated inorganic nanoparticles that are totally or partially dispersible in water by different strategies. Such fluorinated NPs have been utilized in other nanomedicine related fields, such as to study protein corona in complex environments, 21,22 as potential contrast agents in 19 F MRI, 18,23,24 or as vehicles for enzyme transport, and delivery through fluorine-based interactions 25−27 ( Figure 1C D). The strategies we used so far to introduce fluorinated moieties on the surface of inorganic NPs were either via the direct synthesis of gold NPs from chloroauric acid in the presence of custom-designed fluorinated-thiolated ligands and sodium borohydride ( Figure 1A), 21−23 or by ligand exchange on presynthesized quantum dots with fluorinated-thiolated ligands to prepare fluorinated quantum dots ( Figure 1B). ...
Fluorinated nanoparticles have increasing applications, but they are still challenging to prepare, especially in the case of water-soluble fluorinated nanoparticles. Herein, a fluorine labeling strategy is presented that is based on the conjugation of custom-made small fluorinated building blocks, obtained by simple synthetic transformations, with carboxylated gold nanoparticles through a convenient phase-transfer process. The synthesis of four fluorinated building blocks with different chemical shifts in ¹⁹F nuclear magnetic resonance and varied functionalities is reported, along with their conjugation onto nanoparticles. Fluorinated nanoparticles of small core size obtained by this conjugation methodology and by direct synthesis presented high transverse relaxation times (T2) ranging from 518 to 1030 ms, and a large number of equivalent fluorine atoms per nanoparticle (340–1260 fluorine atoms), which made them potential candidates for ¹⁹F magnetic resonance related applications. Finally, nontargeted fluorinated nanoparticles were probed by performing in vivo¹⁹F magnetic resonance spectroscopy (¹⁹F MRS) in mice. Nanoparticles were detected at both 1 and 2 h after being injected. ¹⁹F MRI images were also acquired after either intravenous or subcutaneous injection. Their fate was studied by analyzing the gold content in tissues by ICP-MS. Thus, the present work provides a general fluorination strategy for nanoparticles and shows the potential use of small fluorinated nanoparticles in magnetic-resonance-related applications.
... 136 A huge gain in sensitivity is potentially also possible by employing fluorinated compounds as contrast agents. 137 MRI however, has a 1000-fold lower sensitivity than PET and requires millimolar concentrations of fluorinated reporter molecules. 136, 137 Polyfluorinated sugars have been far less explored as contrast agents. ...
... 137 MRI however, has a 1000-fold lower sensitivity than PET and requires millimolar concentrations of fluorinated reporter molecules. 136, 137 Polyfluorinated sugars have been far less explored as contrast agents. Sufficient contrast can be obtained by employing labeled polysaccharides 138 or functionalized nanoparticles 137 as reporter molecules or also employing high concentrations of mono-fluorinated small molecules. ...
... 138 Another strategy to increase fluorine density is the presentation of multiple fluorinated ligands on the surface of nanoparticles. 137 Finally, 3-FDG has been used for in vivo brain imaging. 139 Although 3-FDG is phosphorylated by hexokinase 300 times slower than its isomer 2-FDG, it was found to be a better substrate for the aldose reductase than D-glucose itself. ...
Fluorinated carbohydrates have become indispensable in glycosciences. This contribution provides an overview of how fluorine introduction modifies physical and chemical properties of carbohydrates along with selected examples of its applications.
... The used fluorinated ligand, HS-C 11 -(EG) 4 -O-C(CF 3 ) 3 (EG = ethyleneglycol), was synthesized as previously reported. [14] Human cervical cancer cell line (HeLa) was purchased from ATCC-LGC. Dulbecco's modified Eagle's medium (DMEM), fetal bovine serum (FBS), and L-glutamine were purchased from Gibco. ...
Fluorescent inorganic quantum dots are highly promising for biomedical applications as sensing and imaging agents. However, the low internalization of the quantum dots, as well as for most of the nanoparticles, by living cells is a critical issue which should be solved for success in translational research. In order to increase the internalization rate of inorganic CdSe/ZnS quantum dots, they were functionalized with a fluorinated organic ligand. The fluorinated quantum dots displayed an enhanced surface activity, leading to a significant cell uptake as demonstrated by in vitro experiments with HeLa cells. We combined the experimental and computational results of Langmuir monolayers of the DPPC phospholipid as a model cell membrane with in vitro experiments for analyzing the mechanism of internalization of the fluorinated CdSe/ZnS quantum dots. Surface pressure-molecular area isotherms suggested that the physical state of the DPPC molecules was greatly affected by the quantum dots. UV-vis reflection spectroscopy and Brewster Angle Microscopy as in situ experimental techniques further confirmed the significant surface concentration of quantum dots. The disruption of the ordering of the DPPC molecules was assessed. Computer simulations offered detailed insights in the interaction between the quantum dots and the phospholipid, pointing to a significant modification of the physical state of the hydrophobic region of the phospholipid molecules. This phenomenon appeared as the most relevant step in the internalization mechanism of the fluorinated quantum dots by cells. Thus, this work sheds light on the role of fluorine on the surface of inorganic nanoparticles for enhancing their cellular uptake.
... The protocol uses CdO and selenium as precursors for the CdSe cores and the shell of ZnS is formed using diethyl zinc and hexamethyldisilathiane as zinc and sulphur sources, respectively. The used fluorinated ligand, HS-C 11 -(EG) 4 -O-C(CF 3 ) 3 (EG = ethyleneglycol), forming the organic shell around the inorganic core/shell NPs, was synthetized as previously reported [22]. ...
Understanding the interaction of nanoparticles with proteins and how this interaction modifies the nanoparticles’ surface is crucial before their use for biomedical applications. Since fluorinated materials are emerging as potential imaging probes and delivery vehicles, their interaction with proteins of biological interest must be studied in order to be able to predict their performance in real scenarios. It is known that fluorinated planar surfaces may repel the unspecific adsorption of proteins but little is known regarding the same process on fluorinated nanoparticles due to the scarce examples in the literature. In this context, the aim of this work is to propose a simple and fast methodology to study fluorinated nanoparticle-protein interactions based on interfacial surface tension (IFT) measurements. This technique is particularly interesting for fluorinated nanoparticles due to their increased hydrophobicity. Our study is based on the determination of IFT variations due to the interaction of quantum dots of ca. 5 nm inorganic core/shell diameter coated with fluorinated ligands (QD_F) with several proteins at the oil/water interface. Based on the results, we conclude that the presence of QD_F do not disrupt protein spontaneous film formation at the oil/water interface. Even if at very low concentrations of proteins the film formation in the presence of QD_F shows a slower rate, the final interfacial tension reached is similar to that obtained in the absence of QD_F. The differential behaviour of the studied proteins (bovine serum albumin, fibrinogen and apotransferrin) has been discussed on the basis of the adsorption affinity of each protein towards DCM/water interface and their different sizes. Additionally, it has been clearly demonstrated that the proposed methodology can serve as a complementary technique to other reported direct and indirect methods for the evaluation of nanoparticle-protein interactions at low protein concentrations.
... Theselection of this ligand was based on several reasons:a )the perfluoro-tert-butyl group permits the introduction of ah igh amount of fluorine atoms on the outer surface of the QDs;b )ethylene glycol units in the linker enhance the solubility,a nd c) thiol group allows binding on the QD surface,a sw ell as on other types of NPs such as Au NPs. [13] Thec hoice of QDs as ab uilding unit to form the nanoassemblies was based on their optical properties,mainly high photoluminescence intensity and very low photobleaching under intracellular conditions.H owever,i np rinciple many other NP materials could be used, for example, biocompatible materials,a nd in the case of QDs,t heir Cdfree counterparts are preferred. ...
Self-assembly of nanoparticles provides unique opportunities as nanoplatforms for controlled delivery. By exploiting the important role of non-covalent hydrophobic interactions in the engineering of stable assemblies, nanoclusters were formed by self-assembly of fluorinated quantum dots in aqueous medium through fluorine-fluorine interactions. These nanoclusters were able to encapsulate different enzymes (laccase and α-galactosidase) obtaining encapsulation efficiencies ≥ 74 %. Importantly, the encapsulated enzymes maintained their catalytic activity, following a Michaelis-Menten kinetics. Under acidic environment the nanoclusters were slowly disassembled allowing the release of encapsulated enzymes. The effective release of the assayed enzymes demonstrated the feasibility of this nanoplatform to be used in pH-mediated enzyme delivery. In addition, the as-synthesized nanoclusters of ca. 50 nm diameter presented high colloidal stability and fluorescence emission, which make them a promising multifunctional nanoplatform.
... As previously described by us 17 , the following ligands (HSC 11 TEG-GlcF; HSC 11 TEG-F and HSC 11 HEG-OH) and corresponding NPs (NP-GlcF/OH and NP-TEGF) were prepared and characterized. NP-GlcF/OH is water dispersible but NP-TEGF is not, hence the latter was coated with PMA functionalized with Dodecylamine (PMA-DDA), as reported before 17 TEM analysis of NP-GlcF/OH and NP-TEGF afforded r c values of 0.9 ± 0.6 nm and 1.1 ± 0.2 nm, respectively. However, when NP-TEGF was coated with PMA, groups of NPs were coated together, most likely due to F-F non covalent interactions. ...
... For this reason, the major challenge when designing fluorine based probes is to find a balance between high fluorine loading to obtain the highest 19 F MRI signal possible and water solubility of the probe by overcoming fluorine intrinsic hydrophobicity. 57 Fluorine based activatable probes have been barely reviewed, 13 hence we will include references from the last decade and not only from the last two years. As before, we will discuss the probes with respect to the trigger that activates them. ...
Magnetic resonance imaging (MRI) is a non-invasive imaging technique with widespread use in diagnosis. Frequently, contrast in MRI is enhanced with the aid of a contrast agent, among which smart, responsive, OFF/ON or activatable probes are of particular interest. These kinds of probes elicit a response to selective stimuli, evidencing the presence of enzymes or acidic pH, for instance. In this review, we will focus on smart probes that are detectable by both 1H and 19F MRI, frequently based on nanomaterials. We will discuss the triggering factors and the strategies employed thus far to activate each probe.
Although albumin has been extensively used in nanomedicine, it is still challenging to fluorinate albumin into fluorine-19 magnetic resonance imaging (19F MRI)-traceable theranostics because existing strategies lead to severe 19F signal splitting, line broadening, and low 19F MRI sensitivity. To this end, 34-cysteine-selectively fluorinated bovine serum albumins (BSAs) with a sharp singlet 19F peak have been developed as 19F MRI-sensitive and self-assembled frameworks for cancer theranostics. It was found that fluorinated albumin with a non-binding fluorocarbon and a long linker is crucial for avoiding 19F signal splitting and line broadening. With the fluorinated BSAs, paclitaxel (PTX) and IR-780 were self-assembled into stable, monodisperse, and multifunctional nanoparticles in a framework-promoted self-emulsion way. The high tumor accumulation, efficient cancer cell uptake, and laser-triggered PTX sharp release of the BSA nanoparticles enabled 19F MRI-near infrared fluorescence imaging (NIR FLI)-guided synergistic chemotherapy (Chemo), photothermal and photodynamic therapy of xenograft MCF-7 cancer with a high therapeutical index in mice. This study developed a rational synthesis of 19F MRI-sensitive albumin and a framework-promoted self-emulsion of multifunctional BSA nanoparticles, which would promote the development of protein-based high-performance biomaterials for imaging, diagnosis, therapy, and beyond.
