Robust capsules for biomedical applications
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Date
25/06/2020Author
Grantham, William Rufus
Metadata
Abstract
Metallosupramolecular capsules represent a facile route to three-dimensional structures that possess
a central cavity. The synthetic accessibility is provided by self-assembly, which allows carefully
designed components to form complex three-dimensional structures under thermodynamic control.
The cavities allow the non-covalent binding of guests, changing their properties in a quick and
reversible manner, thereby making capsules promising for catalytic, storage, extraction and
biomedical applications.
However, the requirement for thermodynamic control makes capsules susceptible to degradation by
changes in conditions such as heat, dilution, pH, or the presence of nucleophiles, making them
insufficiently robust for biomedical applications. This project constitutes the continuation of a project
which sought to synthesise more robust capsules. This was achieved by exploiting the cobalt II/III
redox couple, assembling the tetrahedra with labile cobalt (II) and then oxidatively “locking” them as
inert cobalt (III). This led to the development of the tetrahedron C19, which proved stable over a range
of temperatures, dilutions and pH values. C19 was shown to bind the common SPECT imaging agent
precursor [99mTc]TcO4
-, suggesting radioimaging as a potential application of the cage.
During this project, C19 was found to be degraded in biological environments by reducing agents such
as glutathione. Therefore, a ligand with electron donating amine groups, L20, was developed to
increase the strength of interaction with metal centres, and overall stability. A two-step assembly
using C19 as a template and substituting L20 into this prearranged tetrahedron was required to
prevent kinetically trapped byproducts. The resulting cage, C20, was found to have increased
resistance to biological conditions relative to C19, and was able to significantly alter the uptake of
[99mTc]TcO4
- in vivo, proving the potential of the system to act as a delivery agent.
Further functionalisation of C20 was explored to allow bioconjugation and targeting. To this end, the
ligand was functionalised with a terminal alkyne to allow versatile Huisgen “click” functionalisation. A
methyl ether was trialled as an alternative to the amines of L20, and the resulting ligand, L38, was
found to confer similar properties onto its assemblies. Incorporation of alkyne Raman labels into a
cage allowed stimulated Raman scattering imaging of its interaction with cells.
Overall, a robust cage system capable of retaining and altering the uptake of a significant diagnostic
agent in vivo was developed. Progress was also made towards improving the properties, targeting and
monitoring of the system.