Gold Complexes in Anticancer Therapy: From New Design Principles to Particle‐Based Delivery Systems

The discovery of the medicinal properties of gold complexes has fuelled the design and synthesis of new anticancer metallodrugs, which have received special attention due to their unique modes of action. Current research in the development of gold compounds with therapeutic properties is predominantly focused on the molecular design of drug leads with superior pharmacological activities, e.g., by introducing targeting features. Moreover, intensive research aims at improving the physicochemical properties of gold compounds, such as chemical stability and solubility in the physiological environment. In this regard, the encapsulation of gold compounds in nanocarriers or their chemical grafting onto targeted delivery vectors could lead to new nanomedicines that eventually reach clinical applications. Herein, we provide an overview of the state-of-the-art progress of gold anticancer compounds, andmore importantly we thoroughly revise the development of nanoparticle-based delivery systems for gold chemotherapeutics

A model for gene deregulation detection using expression data

In tumoral cells, gene regulation mechanisms are severely altered, and these modifications in the regulations may be characteristic of different subtypes of cancer. However, these alterations do not necessarily induce differential expressions between the subtypes. To answer this question, we propose a statistical methodology to identify the misregulated genes given a reference network and gene expression data. Our model is based on a regulatory process in which all genes are allowed to be deregulated. We derive an EM algorithm where the hidden variables correspond to the status (under/over/normally expressed) of the genes and where the E-step is solved thanks to a message passing algorithm. Our procedure provides posterior probabilities of deregulation in a given sample for each gene. We assess the performance of our method by numerical experiments on simulations and on a bladder cancer data set

Molecular Probes, Chemosensors, and Nanosensors for Optical Detection of Biorelevant Molecules and Ions in Aqueous Media and Biofluids

Synthetic molecular probes, chemosensors, and nanosensors used in combination with innovative assay protocols hold great potential for the development of robust, low-cost, and fast-responding sensors that are applicable in biofluids (urine, blood, and saliva). Particularly, the development of sensors for metabolites, neurotransmitters, drugs, and inorganic ions is highly desirable due to a lack of suitable biosensors. In addition, the monitoring and analysis of metabolic and signaling networks in cells and organisms by optical probes and chemosensors is becoming increasingly important in molecular biology and medicine. Thus, new perspectives for personalized diagnostics, theranostics, and biochemical/medical research will be unlocked when standing limitations of artificial binders and receptors are overcome. In this review, we survey synthetic sensing systems that have promising (future) application potential for the detection of small molecules, cations, and anions in aqueous media and biofluids. Special attention was given to sensing systems that provide a readily measurable optical signal through dynamic covalent chemistry, supramolecular host–guest interactions, or nanoparticles featuring plasmonic effects. This review shall also enable the reader to evaluate the current performance of molecular probes, chemosensors, and nanosensors in terms of sensitivity and selectivity with respect to practical requirement, and thereby inspiring new ideas for the development of further advanced systems

Electrochemical Detection of Drugs via a Supramolecular Cucurbit[7]uril-Based Indicator Displacement Assay

Electrochemical detection methods are attractive for developing miniaturized, disposable, and portable sensors for molecular diagnostics. In this article, we present a cucurbit[7]uril-based chemosensor with an electrochemical signal readout for the micromolar detection of the muscle relaxant pancuronium bromide in buffer and human urine. This is possible through a competitive binding assay using a chemosensor ensemble consisting of cucurbit[7]uril as the host and an electrochemically active platinum(II) compound as the guest indicator. The electrochemical properties of the indicator are strongly modulated depending on the complexation state, a feature that is exploited to establish a functional chemosensor. Our design avoids cumbersome immobilization approaches on electrode surfaces, which are associated with practical and conceptual drawbacks. Moreover, it can be used with commercially available screen-printed electrodes that require minimal sample volume. The design principle presented here can be applied to other cucurbit[n]uril-based chemosensors, providing an alternative to fluorescence-based assays

NMR Relaxivities of Paramagnetic Lanthanide-Containing Polyoxometalates

The current trend for ultra-high-field magnetic resonance imaging (MRI) technologies opens up new routes in clinical diagnostic imaging as well as in material imaging applications. MRI selectivity is further improved by using contrast agents (CAs), which enhance the image contrast and improve specificity by the paramagnetic relaxation enhancement (PRE) mechanism. Generally, the efficacy of a CA at a given magnetic field is measured by its longitudinal and transverse relaxivities r(1) and r(2), i.e., the longitudinal and transverse relaxation rates T(1)(−1) and T(2)(−1) normalized to CA concentration. However, even though basic NMR sensitivity and resolution become better in stronger fields, r(1) of classic CA generally decreases, which often causes a reduction of the image contrast. In this regard, there is a growing interest in the development of new contrast agents that would be suitable to work at higher magnetic fields. One of the strategies to increase imaging contrast at high magnetic field is to inspect other paramagnetic ions than the commonly used Gd(III)-based CAs. For lanthanides, the magnetic moment can be higher than that of the isotropic Gd(III) ion. In addition, the symmetry of electronic ground state influences the PRE properties of a compound apart from diverse correlation times. In this work, PRE of water (1)H has been investigated over a wide range of magnetic fields for aqueous solutions of the lanthanide containing polyoxometalates [Dy(III)(H(2)O)(4)GeW(11)O(39)](5–) (Dy-W(11)), [Er(III)(H(2)O)(3)GeW(11)O(39)](5–) (Er-W(11)) and [{Er(III)(H(2)O)(CH(3)COO)(P(2)W(17)O(61))}(2)](16−) (Er(2)-W(34)) over a wide range of frequencies from 20 MHz to 1.4 GHz. Their relaxivities r(1) and r(2) increase with increasing applied fields. These results indicate that the three chosen POM systems are potential candidates for contrast agents, especially at high magnetic fields

Responsive Nucleic Acid-Based Organosilica Nanoparticles

The development of smart nanoparticles (NPs) that encode responsive features in the structural framework promises to extend the applications of NP-based drugs, vaccines, and diagnostic tools. New nanocarriers would ideally consist of a minimal number of biocompatible components and exhibit multiresponsive behavior to specific biomolecules, but progress is limited by the difficulty of synthesizing suitable building blocks. Through a nature-inspired approach that combines the programmability of nucleic acid interactions and sol–gel chemistry, we report the incorporation of synthetic nucleic acids and analogs, as constitutive components, into organosilica NPs. We prepared different nanomaterials containing single-stranded nucleic acids that are covalently embedded in the silica network. Through the incorporation of functional nucleic acids into the organosilica framework, the particles respond to various biological, physical, and chemical inputs, resulting in detectable physicochemical changes. The one-step bottom-up approach used to prepare organosilica NPs provides multifunctional systems that combine the tunability of oligonucleotides with the stiffness, low cost, and biocompatibility of silica for different applications ranging from drug delivery to sensing

Patterned immobilization of polyoxometalate-loaded mesoporous silica particles via amine-ene Michael additions on alkene functionalized surfaces

Polyoxometalates (POM) are anionic oxoclusters of early transition metals that are of great interest for a variety of applications, including the development of sensors and catalysts. A crucial step in the use of POM in functional materials is the production of composites that can be further processed into complex materials, e.g. by printing on different substrates. In this work, we present an immobilization approach for POMs that involves two key processes: first, the stable encapsulation of POMs in the pores of mesoporous silica nanoparticles (MSPs) and, second, the formation of microstructured arrays with these POM-loaded nanoparticles. Specifically, we have developed a strategy that leads to water-stable, POM-loaded mesoporous silica that can be covalently linked to alkene-bearing surfaces by amine-Michael addition and patterned into microarrays by scanning probe lithography (SPL). The immobilization strategy presented facilitates the printing of hybrid POM-loaded nanomaterials onto different surfaces and provides a versatile method for the fabrication of POM-based composites. Importantly, POM-loaded MSPs are useful in applications such as microfluidic systems and sensors that require frequent washing. Overall, this method is a promising way to produce surface-printed POM arrays that can be used for a wide range of applications

Conception et préparation de particules organosilice dégradables pour des applications biomédicales

The work presented in this thesis focused on the preparation and characterization of novel stimuli-responsive organosilica particles. In this respect, a series of organoalkoxysilanes have been synthesized and used to prepare organosilicas, which possess either covalently or supramolecularly linked organic bridging-groups within their silica framework. It has been shown that porous and light-degradable and organosilicas can be prepared which are able to quantitatively release hydrophobic molecules upon light-irradiation and that oligonucleotides, such as DNA and PNA can be integrated into the particles framework in order to prepare materials, which can interact with biological molecules such as enzyme or complementary DNAs. Finally, the possibility to prepare redox-responsive cage-like organosilica particles, a novel type of morphology for organosilicas, was shown and their potential use for the development of novel nanomedicines was evaluated and discusse.Les travaux présentés dans cette thèse se sont concentrés sur la préparation et la caractérisation de nouvelles particules d’organosilice sensibles aux stimuli. À cet égard, une série d'organoalkoxysilanes ont été synthétisés et utilisés pour préparer des organosilices possédant des groupes fonctionnels organiques liés de manière covalente ou supramoléculaire dans leur structure de silice. Il a été démontré qu'il est possible de préparer des organosilices poreuses et photodégradables qui sont capables, sous irradiation lumineuse, de libérer quantitativement des molécules hydrophobes. De plus, certains oligonucléotides, tels que l'ADN et l'ANP, peuvent être intégrés dans la structure des particules afin de préparer des matériaux pouvant interagir avec des molécules biologiques telles que des enzymes ou des ADN complémentaires. Enfin, la possibilité de préparer des particules d'organosilice sous forme de cage et sensibles à l'oxydoréduction a été mis en évidence et leur utilisation potentielle pour le développement de nouvelles techniques de nanomédecine a été évaluée et discutée

Conception et préparation de particules organosilice dégradables pour des applications biomédicales

The work presented in this thesis focused on the preparation and characterization of novel stimuli-responsive organosilica particles. In this respect, a series of organoalkoxysilanes have been synthesized and used to prepare organosilicas, which possess either covalently or supramolecularly linked organic bridging-groups within their silica framework. It has been shown that porous and light-degradable and organosilicas can be prepared which are able to quantitatively release hydrophobic molecules upon light-irradiation and that oligonucleotides, such as DNA and PNA can be integrated into the particles framework in order to prepare materials, which can interact with biological molecules such as enzyme or complementary DNAs. Finally, the possibility to prepare redox-responsive cage-like organosilica particles, a novel type of morphology for organosilicas, was shown and their potential use for the development of novel nanomedicines was evaluated and discusse.Les travaux présentés dans cette thèse se sont concentrés sur la préparation et la caractérisation de nouvelles particules d’organosilice sensibles aux stimuli. À cet égard, une série d'organoalkoxysilanes ont été synthétisés et utilisés pour préparer des organosilices possédant des groupes fonctionnels organiques liés de manière covalente ou supramoléculaire dans leur structure de silice. Il a été démontré qu'il est possible de préparer des organosilices poreuses et photodégradables qui sont capables, sous irradiation lumineuse, de libérer quantitativement des molécules hydrophobes. De plus, certains oligonucléotides, tels que l'ADN et l'ANP, peuvent être intégrés dans la structure des particules afin de préparer des matériaux pouvant interagir avec des molécules biologiques telles que des enzymes ou des ADN complémentaires. Enfin, la possibilité de préparer des particules d'organosilice sous forme de cage et sensibles à l'oxydoréduction a été mis en évidence et leur utilisation potentielle pour le développement de nouvelles techniques de nanomédecine a été évaluée et discutée