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Medical Engineering Across Length Scales Using Structural and Analytical Biomaterial Nanotechnology


Type

Thesis

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Authors

Baumann, Kevin Nils 

Abstract

Cancer and Alzheimer’s disease (AD) are two of the most urgent challenges for healthcare systems worldwide. For these and other diseases, the prognosis and therapeutic success depend strongly on an early-stage diagnosis. This thesis addresses several biophysical aspects of the origin, detection, and treatment of these diseases. The different scopes are connected by the application of DNA and lipid nanotechnology for structural and analytical purposes. The first objective of this thesis describes the development of a DNA-liposome composite structure inspired by the highly ordered architecture of clathrin self-assemblies. A DNA mesh was formed on the surface of nanometre-sized liposomes by interconnecting a clathrin-mimetic DNA triskelion via membrane-anchored linker strands. The DNA coating was found to enhance the mechanical stiffness of the composite structures which was tunable by modifying the rigidity of the DNA triskelion. Decelerated dye leakage from the inside of liposomes upon DNA coating suggests the potential use as a drug delivery carrier. Additionally, incubation experiments with astrocytes provide evidence of cellular uptake of the DNA-coated composite carriers. In the second objective, the DNA-coated liposomes were equipped with a triggerresponsive DNA building block to render triggered-release hybrid nanocarriers. By the addition of a nucleic acid input, the contraction of a DNA hairpin was induced. Functional studies of the DNA coat mobility indicate, that this induces structural changes in the DNA assembly which increases the membrane permeability for dye molecules. By encapsulating doxorubicin, a cytotoxic effect could be observed upon incubation of the triggered-release carriers with HEK293T cells, superior to non-responsive carrier designs. The third objective aimed to investigate the influence of cellular lipid membrane compositions on the aggregation of the AD-associated Aβ42 peptide. By fabricating liposomes mimicking the membrane compositions of the endoplasmatic reticulum (ER), the Golgi apparatus, late endosomes, and the two leaflets of the plasma membrane, the aggregation kinetics of Aβ42 were studied. The findings suggest that from the plasma membrane towards the inner organelles, represented by Golgi apparatus and ER, the membrane composition was optimised to inhibit the aggregation.

Description

Date

2021-06-11

Advisors

Knowles, Tuomas PJ

Keywords

DNA nanotechnology, lipids, liposomes, Alzheimer's disease, misfolding, drug delivery, nanomedicine, biomedical engineering

Qualification

Awarding Institution

University of Cambridge