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Coming theses from other universities

  • Microgels as drug delivery vehicles : loading and release of amphiphilic drugs Author: Yassir Al-Tikriti Link: Publication date: 2022-05-17 14:36

    Polyelectrolyte microgels are used as delivery vehicles for amphiphilic drugs in, e.g., treatments of liver cancer by a method called trans-arterial chemoembolization. The thesis deals with fundamental properties of such delivery systems related to the self-assembling properties of the drug molecules and their interaction with the charged polymer network of the microgel. The main objective was to establish mechanistic models describing the loading and release of drugs under relevant conditions. For that purpose experimental techniques providing thermodynamic, compositional and microstructural information were used to elucidate how the kinetics depend on the stability of the drug self-assemblies and the volume response of the microgels. Micromanipulator-assisted microscopy studies showed that negatively charged microgels phase separated during loading and release of cationic amphiphilic drugs. At intermediate loading levels the drug aggregates and part of the network formed a collapsed phase coexisting with a swollen, drug-lean phase. In particular, during release in a medium of physiological ionic strength, the drug-lean phase formed a depletion layer (shell) surrounding a drug-rich core. Investigations of a series of drugs with different molecular architectures showed that the drug release rate was determined mainly by the stability of the drug aggregates in the core and the diffusive mass transport of drug molecules through the shell. Detailed studies of polyacrylate microgels interacting with amitriptyline hydrochloride showed that swelling of the shell network greatly influenced the release rate. Furthermore, experiments with a specially constructed microscopy cell was used to establish that the collapsed and swollen phases could coexist in equilibrium, and that the swelling of the network in the swollen phase depended on the proportion between them when present in the same microgel. The latter effect was related to the elastic coupling between the phases. Confocal Raman microscopy was employed to demonstrate, for the first time, the related elastic effect, that the concentration of amitriptyline in the swollen phase decreased with increasing proportion of the collapsed phase. Small-angle X-ray scattering showed that the collapsed phase had a disordered microstructure of drug micelles with ellipsoidal shape. The aggregation number increased with increasing concentration of drug in the microgel, most likely by incorporating the uncharged base form. By providing detailed information about thermodynamic properties and microstructures, the results of the thesis provide a basis for rational design of microgel drug delivery systems.

  • Techniques for the increased utilization of dose response variability in proton therapy Author: Erik Almhagen Link: Publication date: 2022-05-17 12:08

    Particle therapy is a form of radiation therapy in which protons and heavier ions are used, as opposed to photons in conventional radiation therapy. The biological effectiveness of particles compared to photons is often quantified as relative biological effectiveness (RBE). In clinical practice, protons are assumed to be 10% more efficient than photons, despite the fact that RBE is known to vary. On the other hand, variable RBE models can be used to describe the RBE at a given position as a function of a few parameters, such as the linear energy transfer (LET) of the beam. Questions of accuracy and validation have prevented the clinical introduction of variable RBE models. In this thesis, we tried to develop a variable RBE model for protons and carbon ions, and then apply it in a proton planning study.

    We started with developing a beam model for protons. It was based on measured data at the Skandion Clinic in Uppsala, Sweden. It is capable of describing the spatial, angular and energy distributions of a proton beam at a certain position in a treatment room. This, coupled with a particle transport engine, allows for accurate study of the physical properties of a clinical beam.

    Prior to developing our RBE model, we studied a number of publications containing proton in vitro cell survival data. It was found that the particle beams used included heavy secondary particle contamination and thus this need not be accounted for separately in a proton RBE model based on this data. Taking this into account, the subsequent RBE model did not provided increased accuracy compared to the considered proton RBE models. For carbon ions, accuracy was increased. Coupled with a treatment planning system, treatment plans taking into account RBE variability can thus be made with this RBE model.

    Finally, we applied the nanoCluE RBE model in a proton dose painting planning study, where the tumor target is given a heterogeneous dose based on an estimated radio sensitivity map of the tumor such that more resistant areas are given higher doses. Variable RBE was not beneficial in increasing the control probability of the tumor, but it did help in decreasing doses to nearby, healthy tissue.

  • Pharmaceutical Protection of Beta-Cells in Diabetes : Using Tyrosine Kinase Inhibition and NOX4 Inhibitors Author: Andris Elksnis Link: Publication date: 2022-05-13 13:29

    Diabetes mellitus is a complex and heterogenous disease, with loss of beta-cell function and mass being a characteristic of not only type 1 diabetes (T1D), but also type 2 diabetes (T2D). In T1D, inappropriate inflammatory signaling is thought to participate in the autoimmune suppression and destruction of beta-cells. In T2D progressive insulin resistance with resulting glucolipotoxicity, increased inflammation and oxidative stress, drives islet amyloid formation and subsequent beta-cell exhaustion and failure. Even under best managed care, disease progression and eventual complications are unavoidable. New interventions that aim to improve beta-cell survival are highly needed. This thesis investigates two such possible interventions: the tyrosine kinase inhibitor Imatinib, and selective NADPH-oxidase inhibition.

    Imatinib mesylate, used in treatment of chronic myeloid leukemia and other malignancies, was soon after its introduction reported to possess anti-diabetic properties in both T1D and T2D patients undergoing treatment. Imatinib has been shown to prevent and reverse diabetes in NOD mice and improve glucose tolerance in high fat diet treated rats. In paper I, we aimed to characterize the mechanisms by which imatinib protects beta-cells. We found that imatinib inhibits complex I and II of the respiratory chain, leading to improved beta-cell survival through AMPK activation, reduced amyloid formation and protection against TXNIP upregulation.

    Oxidative stress may play a pivotal role in the development of beta-cell dysfunction and failure in T2D. The NADPH-oxidases are a family of 7 enzymes (NOX1-5 and DUOX 1-2), that produce reactive oxygen species that are important in various physiological processes but may, if excessively activated, also be a source for oxidative stress in T2D. In paper II, we evaluate novel selective NOX inhibitors as protective agents against in vitro induced human beta-cell stress. Selective NOX4 inhibition protected beta-cells against both cytokines and high-glucose + palmitate. In paper III we found that NOX4 inhibition increased mitochondrial membrane potential, mitochondrial reactive oxygen species and ATP/ADP ratio in a human beta-cell line, and this was paralleled with protection against human islet cell death when challenged with high-glucose and palmitate. Finally, in paper IV, we attempt to apply these findings in vivo, by transplanting athymic diabetic mice with human islets and treating them with a NOX4 inhibitor over a period of 4 weeks. Treated mice achieved lower blood glucose levels and water consumption throughout the treatment period, and apoptotic rates of insulin-positive human cells, measured as co-localization of insulin and cleaved caspase-3, were greatly reduced.