Coming dissertations at Uppsala university
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Polymer Dots for Solar Chemicals : Material Design and Photocatalytic Mechanism
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-539849
The urgent need to replace traditional fossil fuels has accelerated the development of sustainable energy technologies, with photocatalysis emerging as one promising approach. Conjugated polymer dots (Pdots) have gained increasing attention recently for various photocatalytic applications such as hydrogen production and CO2 reduction. However, the use of Pdots as photocatalysts for the production of value-added chemicals, such as hydrogen peroxide (H2O2), aldehydes, and organic acids, remains largely unexplored in this field. My research aims to fill the knowledge gap in such applications and thoroughly investigate key factors that govern photocatalytic activity, including charge transfer efficiency, Pdots morphology, surface reaction kinetics, and the spatial distribution of catalysts within Pdots.
The research in this thesis begins with the development and study of an efficient Pdots photocatalyst composed of PFBT as electron donor and PCBM as electron acceptor for H2O2 production coupled with methanol (MeOH) oxidation into formate (paper I) with a high quantum efficiency of up to 14 %. By optimizing the polymer structure, truxene-based polymers (paper II) can produce a comparable H2O2 and formate production efficiency to the PFBT/PCBM system without the use of a PCBM electron acceptor. In order to further expand the applicable condition to neutral pH region, in Paper III, a molecular catalyst for alcohol oxidation, TEMPO, is covalently grafted onto PFBT backbone. Relative Pdots realize H2O2 production and MeOH oxidation under neutral conditions for the first time. From the study, the photocatalytic activity is found to be low, probably restricted by insufficient interactions between the TEMPO catalysts within the Pdots and MeOH molecules in the solution. Paper IV therefore successfully develops a new method to distribute the TEMPO catalyst close to the surface of Pdots while keeping their good interactions with PFBT. At the same time, an electrostatic adsorption method is used to fabricate Pdots films while preserving high catalytic activity.
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A Comprehensive Analysis of Endothelial Cell Subpopulations in Health and Disease Using Single-Cell Transcriptomics
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-539669
The vascular system consists of blood vessels, lymphatic vessels, and hybrid vessels, each with unique functions defined by specialized endothelial cells (ECs). These ECs show remarkable heterogeneity, adapting to organ- and disease-specific conditions. In this work, we used single-cell RNA sequencing (scRNA-seq) to define the transcriptome of normal blood endothelial cells (BEC), lymphatic endothelial cells (LEC) and hybrid vessel ECs from selected mouse and human tissue. Through this detailed analysis we identified a new population of sinusoidal ECs with a unique hybrid vessel identity in the penile vasculature described in paper I. In addition, in paper II we uncovered a previously undescribed subtype of dermal capillary LECs in mouse skin, characterized by their expression of immune regulatory genes.
By utilizing scRNA-seq and genetic mouse models, we explored the molecular and cellular mechanisms underlying oncogenic PI3K-driven lymphatic and venous malformations (LM and VM, respectively) and showed in paper II and paper III that distinct subpopulations of LECs and BECs respond differently to the PI3K gain-of-function mutation Pik3caH1047R. Specifically, LECs respond by expanding the newly identified immune-interacting capillary subpopulation, which promotes the recruitment of pro-lymphangiogenic myeloid cells. In the blood vasculature, venous-like capillaries and post-capillary venules respond to PI3K activation through selective clonal expansion, leading to the formation of VMs. Furthermore, we identified a venous-specific regulatory feedback loop in paper III, involving the inhibition of the transcription factor FOXO1 and the activation of the Angiopoietin-TIE2 signalling pathway. This feedback loop promotes VM growth and represents a promising therapeutic target for developing effective treatments for VM patients.
Overall, the work presented in papers I-III significantly advanced our understanding of EC heterogeneity and function in normal tissues and vascular diseases, potentially paving the way for the development of new pharmacological targets.
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Scaffold Protein-based Theranostics of HER2-overexpressing Ovarian Cancer: Imaging-guided Therapy
Link: http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-539484
This thesis is based on five original articles aiming to develop HER2-targeting affibody-albumin-binding-domain (ABD)-drug conjugates (AffiDCs) for the treatment of ovarian cancer. The research focused on several aspects of molecular design, including the number of HER2-binding domains (ZHER2), the number and position of functional domains targeting HER2 or albumin, the number of conjugated drug molecules, the composition of linkers between domains, and the drug composition. The cytotoxic payloads DM1, MMAE or MMAF were conjugated via a maleimidocaproyl (mc) linker. All affibody-based constructs were radiolabeled with technetium-99m to quantitatively assess their properties in vitro and in vivo. The selected conjugates were evaluated in therapeutic studies using the HER2-overexpressing SKOV3 ovarian cancer xenograft model in BALB/c nu/nu mice.
In Paper I, the influence of HER2-binding valency on targeting properties, internalization, cytotoxicity, and drug delivery was evaluated. The ZHER2-ABD-E3-DM1 conjugate showed highly potent anti-tumor activity in vivo. Imaging using SPECT/CT visualized the HER2 expression during the treatment. In Paper II, the influence of the number and position of functional domains on cancer cell proliferation was investigated. While dimeric anti-HER2 affibody molecules stimulated the proliferation of cancer cells in vitro and promoted tumor growth in vivo, the additional stimulation of proliferation did not improve the therapeutic effect of DM1. ZHER2-ABD was selected as the most optimal format for targeted delivery of DM1. In Paper III, the influence of the number of conjugated drug molecules on biodistribution and tumor-targeted drug delivery was investigated. Increasing the DM1 number from one to three increased the amount of drug delivered to tumors; however, it also raised the risk of normal organ toxicity. In Paper IV, the influence of linker composition between the affibody domain and ABD on biodistribution was evaluated. Introducing additional serine in the inter-domain linker decreased the hepatic uptake. However, the linker length should be optimal to preserve cytotoxicity and high-affinity binding to the target. In Paper V, the impact of the drug composition on binding properties, cytotoxicity, and biodistribution was examined. ZHER2-ABD-MMAF showed higher efficacy than ZHER2-ABD-DM1 for HER2-targeted therapy in vivo.
In conclusion, modification of molecular design impacts functional properties, biodistribution, and tumor targeting of AffiDCs. Careful optimization of molecular design allowed for selecting several candidates with high anti-tumor efficacy and favorable toxicity profiles in mice.