Synthetic long peptides (SLP) derived from cancer-associated antigens hold great promise as well-defined antigens for cancer immunotherapy. Clinical studies showed that SLP vaccines have... Show more Synthetic long peptides (SLP) derived from cancer-associated antigens hold great promise as well-defined antigens for cancer immunotherapy. Clinical studies showed that SLP vaccines have functional potency when applied to pre-malignant stage patients, but need to be improved for use as a therapeutic intervention against tumours. So far, SLPs have been administered in Montanide ISA-51, a water-in-oil formulation with reported important drawbacks and induced local side effects. Therefore, there is an urgent need for replacement of Montanide by more potent and safe alternatives. In this thesis, the concept of cationic liposome-based formulations was introduced, as the backbone for improved delivery of SLPs for cancer therapeutic vaccination. The developed formulation’s ability to induce efficient immune responses able to control tumour outgrowth in aggressive independent tumour models, makes cationic liposomes a very promising platform for SLP-based cancer immunotherapy. Their flexibility regarding the properties of loaded SLPs, their relative inexpensive production and the possibility to administer them via different delivery routes are all in favour for liposomal SLP-based cancer immunotherapy to become reality soon. Show less
This thesis is part of NanoNextNL, a micro and nanotechnology innovation consortium of the Government of the Netherlands and 130 partners from academia and industry. More information on www... Show moreThis thesis is part of NanoNextNL, a micro and nanotechnology innovation consortium of the Government of the Netherlands and 130 partners from academia and industry. More information on www.nanonextnl.nl. Show less
Synthetic long peptides (SLPs) derived from cancer antigens hold great promise as well-defined antigens for immunotherapy of cancer. However, the formulation of SLPs for in vivo administration... Show moreSynthetic long peptides (SLPs) derived from cancer antigens hold great promise as well-defined antigens for immunotherapy of cancer. However, the formulation of SLPs for in vivo administration still needs to be improved. So far, SLPs have been formulated in Montanide-based water-in-oil emulsions in (pre-)clinical trials. However, the use of Montanide as an adjuvant has some important limitations, such as: non-biodegradability; significant local side effects; poor control of release rate; lack of specific dentritic cell (DC)-activating capacity; and the presence of organic solvents (needed to dissolve the peptides prior to mixing with the adjuvant) in the final formulation. Therefore, alternative formulations containing an effective delivery system for peptide-based cancer vaccines are highly needed. Among the numerous vaccine delivery systems, poly(lactic-co-glycolic acid) (PLGA) biodegradable particulate delivery systems are particularly interesting because they are biocompatible; can protect soluble antigens from degradation and rapid clearance once administered; allow for co-encapsulation of (multiple) antigens and adjuvants; and mimic the size and structure of a pathogen, being more efficiently taken up by DCs than soluble antigen. This thesis describes fundamental studies on the design and applicability in a preclinical setting of PLGA-based particulate formulations for the delivery of SLP-based cancer vaccines. Show less
Our study emphasizes the importance of two toxicity-modifying factors (the composition of the surrounding exposure media and mixture effects) in the assessment of toxic effects of metals and... Show more Our study emphasizes the importance of two toxicity-modifying factors (the composition of the surrounding exposure media and mixture effects) in the assessment of toxic effects of metals and metal-based NPs on higher plants. Based on the affinity of metals for binding sites on the biotic ligand at the water-organism interface, the mechanistic models we developed provide better links with the toxicity of metal mixtures. We also recommend that finding a statistically significant deviation from additivity can be the starting point for further mechanistic research concerning toxicologically relevant interactions between substances, instead of the endpoint of research used so far. As an extension of the research discussed in the third chapter of this thesis, the commonly known model for the toxicity of mixtures was proven to be suitable for preliminarily assessing the effects of metal-based NPs on terrestrial organisms. The experimental design of nested combinations helps establish a more realistic exposure scenario for the environment and makes it possible to identify where and how chemical-chemical interactions occur with metal-based NPs. Consequently, our findings enrich the rapidly evolving field of toxicology regarding metals and metal-based NPs. Show less
Nanoparticles (NPs) exhibit special physicochemical properties compared to bulk particles. The difference in properties could, in principle, produce different effects on organisms. It is therefore... Show moreNanoparticles (NPs) exhibit special physicochemical properties compared to bulk particles. The difference in properties could, in principle, produce different effects on organisms. It is therefore important to determine the relationship between the physicochemical characteristics of NPs and their toxicity profile, by means of experimental testing. Experimental toxicity testing data can also be used to find the best dose metric for the responses induced by NPs, which was the purpose of the research presented in this thesis. Furthermore, this thesis aims to move forward from toxicity testing primarily in animal models to computational dose metric modeling. Show less
Rahimian, S.; Fransen, M.F.; Kleinovink, J.W.; Christensen, J.R.; Amidi, M.; Hennink, W.E.; Ossendorp, F. 2015
Nature__s own building block, peptide/protein derived materials have been of great interest for supramolecular chemists. The amino acids in peptides/proteins are linked via amide bonds, which makes... Show moreNature__s own building block, peptide/protein derived materials have been of great interest for supramolecular chemists. The amino acids in peptides/proteins are linked via amide bonds, which makes them more stable against degradation as compared to other natural materials such as oligonucleotides. Peptides adopt a secondary structure which is determined by their amino acid sequence resulting in a structure with a specific fold like a beta sheet, a helix or a random coil conformation.These secondary structures can govern the supra-molecular structure of the macromolecule to achieve specific function. Peptides can be short, such as dipeptides or as long as a small protein, which are able to selfassemble into a designed nanostructure and thus providing a wide choice of biomaterials for a chemical biologist. In last decade, peptides have been shown to have great versatility and inherent high affinity for their target to carry out various functions which is the scope of this thesis presented here. Show less
Catalysis is the working horse of the chemical industry. In many cases, it is a poorly understood process taking place at the surfaces of nanoparticles under relatively harsh conditions, such as... Show moreCatalysis is the working horse of the chemical industry. In many cases, it is a poorly understood process taking place at the surfaces of nanoparticles under relatively harsh conditions, such as high pressures and high temperatures. This thesis focuses on new approaches to acquire atomic-scale information on catalytic processes on metal nanoparticles in high-pressure, high-temperature conditions. This thesis starts with a comprehensive approach to the development of novel instruments and methods for in-situ experiments on model catalysts under working conditions. We introduce the ReactorAFM, the world’s first high-pressure, high-temperature non-contact Atomic Force Microscope, and two software packages for data analysis. Next, we have applied several in-situ measurement techniques to study catalytic model systems at atmospheric pressures and elevated temperatures. We describe a study of the interaction of gas mixtures of nitric oxide and hydrogen on the Pt(110) surface, using surface X-ray diffraction. In the next chapter, we used similar mixtures but with a Pt nanoparticle model catalyst in a high-pressure reaction cell in a transmission electron microscope. Lastly, we have applied four in-situ techniques, including our new ReactorAFM, to investigate the role of thin oxide shells in spontaneous reaction oscillations on Pd nanoparticles during the catalytic oxidation of carbon monoxide Show less
The best form of protection against influenza is vaccination, in terms of efficacy to protect individuals and reduction of the social impact of epidemics on our human societies. Chapter 1 of this... Show moreThe best form of protection against influenza is vaccination, in terms of efficacy to protect individuals and reduction of the social impact of epidemics on our human societies. Chapter 1 of this thesis details the current influenza vaccines available and their lack of efficacy, and the current need for new adjuvanted influenza formulations. Pathogens are often particles and formulating antigens into nanoparticles (NP) results in systems that resemble the pathogens in terms of size, and notably can promote antigen uptake by dendritic cells (DC). The principal aim of the research in this thesis was to investigate how NP systems can act as an adjuvant for subunit influenza vaccine Show less
Inorganic nanoparticles are attractive materials due to their unique properties and prominent role in the fields of material science, nanotechnology and nanomedicine. Modern therapies aim to... Show moreInorganic nanoparticles are attractive materials due to their unique properties and prominent role in the fields of material science, nanotechnology and nanomedicine. Modern therapies aim to deliver drugs specifically to defective cells and mesoporous silica nanoparticles (MSNs) are considered to be promising candidates for this goal. In this thesis the synthesis, characterization and bio-applications of silica nanoparticles will be discussed. Moreover, the potential application of mesoporous silica nanoparticles as drug delivery systems will be discussed using two animal models: the Xenopus laevis and the Danio rerio. Show less
This project has dealt with the mechanistic study of the electrocatalytic nitrite reduction, the selectivity-determining step of nitrate reduction. Nitrate is a polluting ion targeted by wastewater... Show moreThis project has dealt with the mechanistic study of the electrocatalytic nitrite reduction, the selectivity-determining step of nitrate reduction. Nitrate is a polluting ion targeted by wastewater remediation; electrochemistry strives to achieve selectivity to harmless products (N2). A multi-pronged approach has been followed, aimed at establishing the influence of several variables (electrocatalyst material, surface structure, pH and electrode potential) on the catalytic activity and the product distribution, which has been determined with in situ analytical techniques (mass spectrometry and infrared spectroscopy). The molecular underpinnings of nitrite reduction have thereby been unravelled for transition metals, showing that an optimal catalytic performance is achieved when metals intermediate affinities to reaction intermediates (Sabatier Principle). The all-important concept of structure sensitivity also applies to nitrite reduction at Pt electrodes, although only in alkaline media: a Pt(100) single-crystal is the sole Pt surface able to achieve the desired direct conversion of nitrite into 100% N2. Such selectivity is unparalleled for a simple monometallic surface and is an outstanding finding. Additionally, the nitrite-reducing performance of bio-inspired catalysts, (electroactive metalloporphyrins) was investigated. A further side-project of this PhD thesis has also been the electrochemical characterization of preferentially-oriented cuboid Pt nanoparticles synthesized with the innovative __cathodic corrosion__. Show less
Microneedle-based transcutaneous immunisation is an appealing alternative to the classical manner of injecting vaccines by intramuscular or subcutaneous route. Importantly, as a consequence of the... Show moreMicroneedle-based transcutaneous immunisation is an appealing alternative to the classical manner of injecting vaccines by intramuscular or subcutaneous route. Importantly, as a consequence of the fact that the skin is in direct contact with the environment and should protect the body against pathogens, it contains more antigen presenting cells, such as dendritic cells than the muscles or subcutaneous tissue and thereby offers the possibility to induce a more effective immune response. The combination of microneedles and adjuvanted subunit vaccines may offer effective vaccination whereas ensuring patient safety and vaccine application in a painless manner. The principal aim of this thesis was to design subunit vaccine formulations that can be combined with microneedles for transcutaneous immunisation. The approaches described in this thesis have generated new insights into the main requirements for transcutaneous immunisation. Microneedles definitively have the potential to be an excellent utensil for the delivery of vaccines into the skin. However, the skin is a very elastic organ and the actual conduits formed by microneedle pre-treatment will be considerably smaller than the diameter of the microneedles. Therefore, a small antigen-adjuvant entity is the preferred formulation, as it will be transported efficiently through the microneedle conduits while it retains the co-delivery of antigen and adjuvant. Show less
