Conjugates of lanthanide chelates and phenylboronates for molecular recognition of tumors

Molecular imaging has become a highly important tool in medicine. Recent technological developments allow visualization of molecular events in vivo on a level that has never been achievable before. The importance of chemistry in medical science is growing due to the demand of specific agents for biological targets. This thesis describes a multidisciplinary search for optimized contrast agents for MRI. The sensitivity of this major high-resolution technique can be enhanced by the application of an imaging reporter in combination with a targeting vector, which includes the optimization of the physicochemical properties of the lanthanide(III)-complexes and their recognition ability towards the overexpressed target on the tumor cells. Understanding of the water coordination behavior of lanthanide complexes is crucial as the efficiency of MRI contrast agents is determined by the number of coordinated water molecules and their exchange rate the bulk water. The first part of this thesis describes the physical methods for determination of these parameters, followed by an 17O NMR study on pyridine based Ln(III)-chelates with extremely fast water exchange. The increase of the specificity of the agents is another approach to optimize the contrast. Therefore, the second part of the thesis deals with the development of a phenylboronic targeting agent for the visualization of tumors based on the molecular recognition of sialic acid overexpressed on the surface of cancerous cells. The recognition mechanism is elucidated by a fundamental multinuclear NMR study, while the feasibility of the targeting is confirmed by the results of a series of incubation experiments with the human glioma cell line and a radioactive 160Tb-complex bearing two phenylboronic targeting groups. Finally, the in vivo delivery and release of the novel targeting agent to the tumor site was realized by use of thermo-sensitive liposomes with a carefully tuned transitional temperature for hyperthermia.Applied Science

The chemical consequences of the gradual decrease of the ionic radius along the Ln-series

In the periodical system, the lanthanides (the 15 elements in the periodic table between barium and hafnium) are unique in the sense that their trivalent cations have their valence electrons hidden behind the 5s and 5p electrons. They show a gradual decrease in ionic radius with increasing atomic number (also known as the lanthanide contraction). The resulting steric effects determine to a large extent the geometries of complexes of these ions. Here, we discuss these effects, particularly upon the properties of the complexes in aqueous solution, for selected families of Ln3+-complexes of oxycarboxylate and aminocarboxylate ligands. The physical properties of the cations are very different, which is very useful for the elucidation of the configuration, conformation and the dynamics of the complexes by X-ray techniques, NMR spectroscopy, and optical techniques. Often the structural analysis is assisted by computational methods.BT/Biocatalysi

Pt/Al2O3 Catalyzed 1,3-Propanediol Formation from Glycerol using Tungsten Additives

Screening of four commercial catalysts (Pt/Al2O3, Pt/SiO2, Pd/Al2O3, and Pd/SiO2) and four acidic additives (hydrochloric, tungstic, phosphotungstic, and silicotungstic acids) shows that the combination of a platinum hydrogenation catalyst with tungsten containing acidic additives yields 1,3-propanediol from aqueous glycerol. The performance of the best catalytic system Pt/Al2O3 with silicotungstic acid as an additive was optimized by experimental design, capturing the influence of reaction time, glycerol concentration, acid concentration, pressure, and temperature on the formation of 1,3-propanediol from glycerol. High 1,3-propanediol yield in an aqueous batch system can be achieved (49?% conversion, 28?% selectivity) with excellent 1,3-propanediol to 1,2-propanediol ratios. A mechanistic interpretation is given for this bifunctional system, supported by the relative stability of 1,3-propanediol in comparison with 1,2-propanediol under the chosen reaction conditions.ChemE/Chemical EngineeringApplied Science

Polysaccharide-Based Theranostic Systems for Combined Imaging and Cancer Therapy: Recent Advances and Challenges

Designing novel systems for efficient cancer treatment and improving the quality of life for patients is a prime requirement in the healthcare sector. In this regard, theranostics have recently emerged as a unique platform, which combines the benefits of both diagnosis and therapeutics delivery. Theranostics have the desired contrast agent and the drugs combined in a single carrier, thus providing the opportunity for real-time imaging to monitor the therapy results. This helps in reducing the hazards related to treatment overdose or underdose and gives the possibility of personalized therapy. Polysaccharides, as natural biomolecules, have been widely explored to develop theranostics, as they act as a matrix for simultaneously loading both contrast agents and drugs for their utility in drug delivery and imaging. Additionally, their remarkable physicochemical attributes (biodegradability, satisfactory safety profile, abundance, and diversity in functionality and charge) can be tuned via postmodification, which offers numerous possibilities to develop theranostics with desired characteristics. Hence, we provide an overview of recent advances in polysaccharide matrix-based theranostics for drug delivery combined with magnetic resonance imaging, computed tomography, positron emission tomography, single photon emission computed tomography, and ultrasound imaging. Herein, we also summarize the toxicity assessment of polysaccharides, associated contrast agents, and nanotoxicity along with the challenges and future research directions. Accepted Author ManuscriptBT/Biocatalysi

Towards Enhanced MRI Performance of Tumor-Specific Dimeric Phenylboronic Contrast Agents

It is known that phenylboronic acid (PBA) can target tumor tissues by binding to sialic acid, a substrate overexpressed by cancer cells. This capability has previously been explored in the design of targeting diagnostic probes such as Gd- and 68Ga-DOTA-EN-PBA, two contrast agents for magnetic resonance imaging (MRI) and positron emission tomography (PET), respectively, whose potential has already been demonstrated through in vivo experiments. In addition to its high resolution, the intrinsic low sensitivity of MRI stimulates the search for more effective contrast agents, which, in the case of small-molecular probes, basically narrows down to either increased tumbling time of the entire molecule or elevated local concentration of the paramagnetic ions, both strategies resulting in enhanced relaxivity, and consequently, a higher MRI contrast. The latter strategy can be achieved by the design of multimeric GdIII complexes. Based on the monomeric PBA-containing probes described recently, herein, we report the synthesis and characterization of the dimeric analogues (GdIII-DOTA-EN)2-PBA and (GdIII-DOTA-EN)2F2PBA. The presence of two Gd ions in one molecule clearly contributes to the improved biological performance, as demonstrated by the relaxometric study and cell-binding investigations.BT/Biocatalysi

Synthesis, characterization and performance of bifunctional catalysts for the synthesis of menthol from citronellal

The synthesis of a series of bifunctional catalysts (1 wt% Pt/W-TUD-1 (Technische Universiteit Delft-1) and 1 wt% Pt/WO3/TUD-1) with different tungsten loadings (5-30 wt% WO3) is described. They were characterized using ICP-OES, INAA, N2 physisorption, XRD and TEM. Their catalytic performance (activity and selectivity) was evaluated in the two-step catalytic synthesis of menthol from citronellal using kinetic analysis. Introducing tungsten during the TUD-1 synthesis results in a high WO3 dispersion, essential for the acidity of the catalyst. High tungsten dispersion is also critical for the Pt hydrogenation activity. Therefore, high dispersion combined with optimal tungsten loading resulted in the highest catalytic activity. The best performing catalyst was 1 wt% Pt/W-TUD-1 (silicon to tungsten ratio of 30), with the highest yields of menthol (96%).BT/BiocatalysisChemE/Catalysis Engineerin

From Structure to Function: Understanding Synthetic Conditions in Relation to Magnetic Properties of Hybrid Pd/Fe-Oxide Nanoparticles

Heterostructured magnetic nanoparticles show great potential for numerous applications in biomedicine due to their ability to express multiple functionalities in a single structure. Magnetic properties are generally determined by the morphological characteristics of nanoparticles, such as the size/shape, and composition of the nanocrystals. These in turn are highly dependent on thesynthetic conditions applied. Additionally, incorporation of a non-magnetic heterometal influences the final magnetic behavior. Therefore, construction of multifunctional hybrid nanoparticles with preserved magnetic properties represents a certain nanotechnological challenge. Here, we focus on palladium/iron oxide nanoparticles designed for combined brachytherapy, the internal form of radiotherapy, and MRI-guided hyperthermia of tumors. The choice of palladium forming the nanoparticle core is envisioned for the eventual radiolabeling with 103Pd to enable the combination of hyperthermia with brachytherapy, the latter being beyond the scope of the present study. At thisstage, we investigated the synthetic mechanisms and their effects on the final magnetic properties of the hybrid nanoparticles. Thermal decomposition was applied for the synthesis of Pd/Fe-oxide nanoparticles via both, one-pot and seed-mediated processes. The latter method was found to provide better control over morphology of the nanoparticles and was therefore examined closely by varying reaction conditions. This resulted in several batches of Pd/Fe-oxide nanoparticles, whose magnetic properties were evaluated, revealing the most relevant synthetic parameters leading to promising performance in hyperthermia and MRI.BT/BiocatalysisRST/Medical Physics & TechnologyRST/Applied Radiation & IsotopesRST/Fundamental Aspects of Materials and EnergyInstrumenten groe