This thesis describes the design, characterization and application of dextran based crosslinked network. Dextran, a neutral and hydrophilic polysaccharide, was functionalized with maleimide or... Show moreThis thesis describes the design, characterization and application of dextran based crosslinked network. Dextran, a neutral and hydrophilic polysaccharide, was functionalized with maleimide or vinyl sulfone groups which are able to form covalent bonds with nucleophilic thiols via a thiol-Michael addition reaction. The functionalized dextran polymers are liable to be crosslinked to generate 3D networks. Novel drug delivery platforms, including dextran-albumin hydrogels and dextran-poly(ethylene glycol)-albumin hydrogels, were established in which human serum albumin acts simultaneously as an affinity-based drug carrier and crosslinker. The obtained drug delivery platforms showed high drug loading efficiency and demonstrated sustained release of drug molecules. This thesis also explores emerging applications of hydrogels. New method to form giant unilamellar vesicles was established by assisting the hydration process of a lipid film with a dextran-poly(ethylene glycol) hydrogel film. Using this approach, polymer and additive-free GUVs can be prepared rapidly in high yield under physiological ionic strength conditions. Show less
O-Nitrobenzyl groepen worden veel gebruikt als moleculaire beschermgroepen die je met licht kunt verwijderen. Deze zogenaamde photocages worden vaak toegepast in zowel de organische chemie als in... Show moreO-Nitrobenzyl groepen worden veel gebruikt als moleculaire beschermgroepen die je met licht kunt verwijderen. Deze zogenaamde photocages worden vaak toegepast in zowel de organische chemie als in de biologie. Photocaging blokkeert de functionaliteit van een molecuul en deze blokkade kan verwijderd worden door middel van licht met een specifieke golflengte. Dit proefschrift laat zien dat licht gebruikt kan worden om precieze controle te verkrijgen over waar en wanneer geneesmiddelenafgifte plaatsvindt. Show less
Proteins play a crucial role in life, taking part in all vital process in the body, and are therefore used as therapeutic agents in a diverse range of biomedical applications. When... Show more Proteins play a crucial role in life, taking part in all vital process in the body, and are therefore used as therapeutic agents in a diverse range of biomedical applications. When administrated into bodily fluids, most native proteins are prone to degradation or inactivation process. The challenges of protein delivery are overcoming poor stability, low permeability toward cell membrane. Among all existing materials for protein delivery, mesoporous silica nanoparticles (MSNs) are one of the most promising intracellular nanocarriers due to its key properties: biocompatible, straightforward synthesis, and surface modification. For various biomedical applications, monodisperse MSNs with a particle size in the 50-200 nm range,3 controllable surface chemistry,4 and a large pore size (> 5 nm) are desired. This thesis presents a new method to synthesize large disc-like pore (10 ± 1 nm) containing MSNs with an elongated cuboidal-like geometry (90 × 43 nm), which effectively encapsulate and release proteins. Show less
This thesis presents another approach for direct cytosolic delivery via membrane fusion. This approach is based on a complementary pair of coiled-coil forming peptides, K (KIAALKE)4 and E (EIAALEK... Show moreThis thesis presents another approach for direct cytosolic delivery via membrane fusion. This approach is based on a complementary pair of coiled-coil forming peptides, K (KIAALKE)4 and E (EIAALEK)4 and is mimicking the action of the SNARE-complex. The SNARE-complex is responsible for fusion between vesicles and membranes of cells in the synapse and is also composed of coiled-coil forming peptides. In our system, the peptides are conjugated to a cholesterol anchor via a polyethylene glycol (PEG) spacer, yielding lipopeptides CP4K4 and CP4E4. Membrane fusion between liposomes and the plasma membrane of the cells is triggered by these two lipopeptides when each embedded within the lipid bilayer of the liposomes or the plasma membrane of the cell. Show less
Ruthenium complexes are promising prodrugs in photoactivated chemotherapy (PACT): to prevent systemic therapeutic side-effects, a non-toxic version of the drug is introduced in the body and is... Show moreRuthenium complexes are promising prodrugs in photoactivated chemotherapy (PACT): to prevent systemic therapeutic side-effects, a non-toxic version of the drug is introduced in the body and is only activated at the place of the tumor by means of visible light irradiation. However, most of these PACT compounds are only sensitive for UV or blue light, while this light does not permeate the body very well, in contrast to red or near-infrared light. To circumvent this problem, the principle of light-upconversion can be used to "upgrade" red light to blue light in a drug carrier such as a nanovesicle: the tumor is irradiated with red light, after which blue light is generated locally and used to activate the prodrug. Among the various methods of light-upconversion, triplet-triplet annihilation upconversion (TTA-UC) was selected as the most promising. In this thesis it is described that green-to-blue and red-to-blue upconverting nanovesicles were prepared. The red-to-blue upconverted light was successfully used to activate a ruthenium polypyridyl complex that was anchored to the same vesicle. Finally, the inherent oxygen-sensitivity of TTA-UC was greatly mitigated by the addition of water-soluble and biocompatible anti-oxidants. We expect that the results of this thesis will lead to exciting applications in PACT. Show less
The aim of this study is to prepare in situ forming hydrogels based on biocompatible polymers for the controlled release of hydrophobic drug and proteins. In order to load hydrophobic drug to the... Show moreThe aim of this study is to prepare in situ forming hydrogels based on biocompatible polymers for the controlled release of hydrophobic drug and proteins. In order to load hydrophobic drug to the hydrophilic hydrogel matrix, beta-cyclodextrin and human serum albumin was introduced to the hydrogel network respectively and acted as the primary accommodation for those hydrophobic molecules within the hydrogel network. Furthermore, supramolecular crosslinked and covalently crosslinked light sensitive hydrogels were prepared whose potential application for light controlled protein release system has been shown. Show less
