Nanoscale metal–organic frameworks as key players in the context of drug delivery: evolution toward theranostic platforms

This is a post-peer-review, pre-copyedit version of an article published in Analytical and Bioanalytical Chemistry. The final authenticated version is available online at: https://doi.org/10.1007/s00216-019-02217-yMetal–organic frameworks (MOFs) have emerged as one of the most fascinating libraries of porous materials with a huge potential in very diverse application areas. In particular, the bioanalytical and biomedical fields have evolved tremendously due to the emergence of these hybrid inorganic–organic MOF-based materials. This is because these materials possess a series of key properties essential for bioapplications, such as minimal toxicity to living cells, intrinsic biodegradability, and possibility of synthesizing with nanoscale sizes. Additional properties of MOFs such as ultra-large surface-to-volume ratios, tunable pore size, high drug loading capacity, tunable structure and chemical composition, and potential for multiple postsynthetic modification make them ideal candidates for drug delivery. This review highlights recent research progress on MOF-based drug delivery systems (DDS), pointing out the evolution of these systems toward the development of theranostic nanoplatforms. Rather than a comprehensive review, representative recent examples are selected to illustrate such an evolution, and a critical discussion of the advantages and limitations of the different DDS types is given. Finally, the remaining challenges and future opportunities in this field are presented, highlighting that overcoming the current issues will pave the way toward the elusive dream of “personalized medicine.”C.C.C. thanks the financial support from the European Union under the H2020-MSCA-IF-2016 program (MSCA-IF-EF-ST Grant Agreement No. 749667)S

Analytical strategies based on quantum dots for heavy metal ions detection

Heavy metal contamination is one of the major concerns to human health because these substances are toxic and retained by the ecological system. Therefore, in recent years, there has been a pressing need for fast and reliable methods for the analysis of heavy metal ions in environmental and biological samples. Quantum dots (QDs) have facilitated the development of sensitive sensors over the past decade, due to their unique photophysical properties, versatile surface chemistry and ligand binding ability, and the possibility of the encapsulation in different materials or attachment to different functional materials, while retaining their native luminescence property. This paper comments on different sensing strategies with QD for the most toxic heavy metal ions (i.e., cadmium, Cd2+; mercury, Hg2+; and lead, Pb2+). Finally, the challenges and outlook for the QD-based sensors for heavy metals ions are discussedM.V.G. thanks the MICINN for the PhD grant (FPI, BES-2010-032652). C.C.C. acknowledges a postdoctoral fellowship from the Alexander von Humboldt FoundationS

Synthesis and Functionalization of Monodisperse Near-ultraviolet and Visible Excitable Multifunctional Eu3+, Bi3+:REVO4 Nanophosphors for Bioimaging and Biosensing Applications

Near-ultraviolet and visible excitable Eu- and Bi-doped NPs based on rare earth vanadates (REVO4, RE = Y, Gd) have been synthesized by a facile route from appropriate RE precursors, europium and bismuth nitrate, and sodium orthovanadate, by homogeneous precipitation in an ethylene glycol/water mixture at 120 °C. The NPs can be functionalized either by a one-pot synthesis with polyacrylic acid (PAA) or by a Layer-by-Layer approach with poly(allylamine hydrochloride) (PAH) and PAA. In the first case, the particle size can also be tuned by adjusting the amount of PAA. The Eu- Bi-doped REVO4 based nanophosphors show the typical red luminescence of Eu(III), which can be excited through an energy transfer process from the vanadate anions, resulting in a much higher luminescence intensity in comparison to the direct excitation of the europium cations. The incorporation of Bi into the REVO4 structure shifts the original absorption band of the vanadate anions towards longer wavelengths, giving rise to nanophosphors with an excitation maximum at 342 nm, which can also be excited in the visible range. The suitability of such nanophosphors for bioimaging and biosensing applications, as well as their colloidal stability in different buffer media of biological interest, their cytotoxicity, their degradability at low pH, and their uptake by HeLa cells have been evaluated. Their suitability for bioimaging and biosensing applications is also demonstrated.European Union 267226Ministerio de Economía y Competitividad MAT2014-54852-

Surface-Active Fluorinated Quantum Dots for Enhanced Cellular Uptake

Fluorescent nanoparticles, such as quantum dots, hold great potential for biomedical applications, mainly sensing and bioimaging. However, the inefficient cell uptake of some nanoparticles hampers their application in clinical practice. Here, the effect of the modification of the quantum dot surface with fluorinated ligands to increase their surface activity and, thus, enhance their cellular uptake was explored

Rare earth based nanostructured materials: Synthesis, functionalization, properties and bioimaging and biosensing applications

Rare earth based nanostructures constitute a type of functional materials widely used and studied in the recent literature. The purpose of this review is to provide a general and comprehensive overview of the current state of the art, with special focus on the commonly employed synthesis methods and functionalization strategies of rare earth based nanoparticles and on their different bioimaging and biosensing applications. The luminescent (including downconversion, upconversion and permanent luminescence) and magnetic properties of rare earth based nanoparticles, as well as their ability to absorb X-rays, will also be explained and connected with their luminescent, magnetic resonance and X-ray computed tomography bioimaging applications, respectively. This review is not only restricted to nanoparticles, and recent advances reported for in other nanostructures containing rare earths, such as metal organic frameworks and lanthanide complexes conjugated with biological structures, will also be commented on.European Union 267226Ministerio de Economía y Competitividad MAT2014-54852-

In Vitro Cellular Uptake Studies of Self-Assembled Fluorinated Nanoparticles Labelled with Antibodies

Nanoparticles (NPs) functionalized with antibodies (Abs) on their surface are used in a wide range of bioapplications. Whereas the attachment of antibodies to single NPs to trigger the internalization in cells via receptor-mediated endocytosis has been widely studied, the conjugation of antibodies to larger NP assemblies has been much less explored. Taking into account that NP assemblies may be advantageous for some specific applications, the possibility of incorporating targeting ligands is quite important. Herein, we performed the effective conjugation of antibodies onto a fluorescent NP assembly, which consisted of fluorinated Quantum Dots (QD) self-assembled through fluorine–fluorine hydrophobic interactions. Cellular uptake studies by confocal microscopy and flow cytometry revealed that the NP assembly underwent the same uptake procedure as individual NPs; that is, the antibodies retained their targeting ability once attached to the nanoassembly, and the NP assembly preserved its intrinsic properties (i.e., fluorescence in the case of QD nanoassembly).This research was financially supported by the research core of TMU (Grant No: IG-39707) and the Biotechnology Development Council of the Islamic Republic of Iran (Grant No: 950709). Part of this work was funded by the Cluster of Excellence ‘Advanced Imaging of Matter’ of the Deutsche Forschungsgemeinschaft (DFG)-EXC 2056-project ID 390715994

Detection of gluten immunogenic peptides in the urine of patients with coeliac disease reveals transgressions in the gluten-free diet and incomplete mucosal healing

Objective Gluten-free diet (GFD) is the only management for coeliac disease (CD). Available methods to assess GFD compliance are insufficiently sensitive to detect occasional dietary transgressions that may cause gut mucosal damage. We aimed to develop a method to determine gluten intake and monitor GFD compliance in patients with CD and to evaluate its correlation with mucosal damage. Design Urine samples of 76 healthy subjects and 58 patients with CD subjected to different gluten dietary conditions were collected. A lateral flow test (LFT) with the highly sensitive and specific G12 monoclonal antibody for the most dominant gluten immunogenic peptides (GIP) and a LFT reader were used to quantify GIP in solid-phase extracted urines. Results GIP were detectable in concentrated urines from healthy individuals previously subjected to GFD as early as 4–6 h after single gluten intake, and remained detectable for 1–2 days. The urine assay revealed infringement of the GFD in about 50% of the patients. Analysis of duodenal biopsies revealed that most of patients with CD (89%) with no villous atrophy had no detectable GIP in urine, while all patients with quantifiable GIP in urine showed incomplete intestinal mucosa recovery. Conclusion GIP are detected in urine after gluten consumption, enabling a new and non-invasive method to monitor GFD compliance and transgressions. The method was sensitive, specific and simple enough to be convenient for clinical monitoring of patients with CD as well as for basic and clinical research applications including drug development

Fluorinated CdSe/ZnS quantum dots: Interactions with cell membrane

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

Mechanochemical Synthesis of Nickel-Modified Metal–Organic Frameworks for Reduction Reactions

In this work, we report the incorporation of nickel oxide nanoparticles into a metal–organic framework (MOF) structure by a solvent-free mechanochemical strategy. In particular, the zirconium-based MOF UiO-66 was modified with different Ni loadings and characterized using complementary techniques including X-ray diffraction (XRD), N2 porosimetry and X-ray photoelectron spectroscopy (XPS). The catalytic potential of the as-prepared Ni/UiO-66 materials in the hydrogenation reaction of methyl levulinate using 2-propanol as hydrogen donor solvent has been investigated under flow conditions. Under optimized conditions, the 5%Ni/UiO-66 led to the best catalytic performance (70% yield, 100% selectivity to gamma-valerolactone), which could be attributed to the higher content of the Ni species within the MOF structure. The obtained results are promising and contribute to highlighting the great potential of MOFs in biomass upgrading processes, opening the path to the sustainable development of the chemical industry

Toward Diffusion Measurements of Colloidal Nanoparticles in Biological Environments by Nuclear Magnetic Resonance

Protein corona formation on the surface of nanoparticles (NPs) is observed in situ by measuring diffusion coefficients of the NPs under the presence of proteins with a F-19 nuclear magnetic resonance (NMR) based methodology. Formation of a protein corona reduces the diffusion coefficient of the NPs, based on an increase in their effective hydrodynamic radii. With this methodology it is demonstrated that the apparent dissociation constant of protein-NP complexes may vary over at least nine orders of magnitude for different types of proteins, in line with the Vroman effect. Using this methodology, the interaction between one type of protein and one type of nanoparticle can be studied quantitatively. Due to the NMR-based detection, this methodology has no interference by absorption/scattering effects, by which optical detection schemes are affected. By using the potential of the NMR chemical shift, the detection of multiple F-19 signals simultaneously opens the possibility to study the diffusion of several NPs at the same time. The F-19 labeling of the NPs has negligible effect on their acute toxicity and moderate effect on NPs uptake by cells.This work was supported by the Cluster of Excellence "Advanced Imaging of Matter" of the Deutsche Forschungsgemeinschaft (DFG) EXC 2056 - project ID 390715994, by the Basque Government (project IT1196-19) and by the Fundacion Biofisica Bizkaia and the Basque Excellence Research Centre (BERC) program of the Basque Government. This work was performed under the Maria de Maeztu Units of Excellence Programme-Grant No. MDM-2017-0720 Ministry of Science, Innovation and Universities. The help of Marta Gallego in the surface tension and TEM measurements is acknowledged. Parts of the ICP-MS measurements were done at the ICP-MS facility of CIC biomaGUNE by Javier Calvo