The body has many defence systems against reactive radical species, but none are as crucial in
the protection of lipid membranes as vitamin E. As a result of a selection process mediated by
the α-tocopherol transfer protein (α-TTP), α-tocopherol is the only form of vitamin E retained
in the body. This chaperon protein has been well studied because of its role in vitamin E
transport. Furthermore, malfunctions of α-TTP cause vitamin E deficiency leading to ataxia and
other neurodegenerative disease. Protection of neuronal tissue is critical and is reflected in the
high retention of α-tocopherol in the central nervous system. Neuronal tissues receive α
tocopherol from astrocytes, cells that are linked to hepatic tissue and able to express α-TTP,
however the exact path of delivery between these cells is still unclear.
A technique called fluorescent microscopy allows the tracking of fluorescent molecules in cells
to find their location and interactions with other parts of the cell. The focus of this study is the
synthesis of a fluorescent tocopherol analogue with a long absorption wavelength, high photostability, and that binds selectively to
α-TTP with high affinity.
Most health benefits associated with vitamin E consumption are based on its capability to
inhibit lipid peroxidation in cell membranes by scavenging reactive oxygen species (ROS).
Oxidative damage in membranes puts cells in a “stressful” state, activating signalling events
that trigger apoptosis. Vitamin E down-regulates apoptotic functions like inflammation,
macrophage activation and cell arrest in a stressed state, returning the cell back to normal
functioning. At the same time, vitamin E has a preventive effect for atherosclerosis,
Alzheimer’s and cancer.
With the deeper understanding of cell signalling processes associated with vitamin E the
question arose whether protein interactions or the ROS scavenging is responsible for cell
survival. To test this hypothesis, a non-antioxidant but α-TTP binding tocopherol analogue was
synthesized and administered into oxidatively stressed, α-TTP deficient cells. If the cells were
unable to restore homeostasis and stop apoptosis with the new molecule, this would suggest that
the antioxidant function of α-tocopherol is the reason for survival.
Cancer is regarded as one of the most detrimental diseases with a high mortality rate. One key
aspect in medical research is the increased drug specificity towards targeting cancer.
Chemotherapy applies cytotoxic compounds, which weaken the immune system because both
malignant and healthy cells are destroyed. The specificity of the anti-cancer drugs are enhanced
when encapsulated into liposomes that bear target-directing molecules such as antibodies which
recognize cancer cell specific antigens on the cell membrane. The question remains if the
encapsulated drug reaches the cancer or not.
Magnetic resonance imaging (MRI) and computed tomography (CT) are used to find malignant
tissue in the body. CT imaging uses highly charged X-ray particles to scan the patient, possibly
having damaging cytotoxic effects. Obtaining MRI results require the use of contrast agents to
enhance the quality of images. These agents are based on transition metals, which potentially
have chronic toxicity when retained in the body. Alternatively short-lived radiotracers that emit
a γ-photon upon positron decay are used through a process called positron emission tomography
(PET). Rapid decay times make the use of PET a less toxic alternative, however the decay
products might be toxic to the cell.
For this reason a vitamin E based PET agent was created, which produces naturally safe decay
products based on known metabolites of vitamin E, useful to track liposomal delivery of
chemotherapeutic agents. This work describes the non-radioactive synthetic procedures towards
a variety of vitamin E PET analogues. The cytotoxicity of the most promising vitamin E PET
tracer was evaluated along with its synthetic byproducts
