Investigations into New Chemical Toolkits for Drug Delivery, Sensing and Cellular Imaging Applications using the Fluorescence Labelling of Biomolecule
Lead Research Organisation:
University of Bath
Department Name: Chemistry
Abstract
As healthcare and technology advances lead to longer life expectancies, an ever increasing and ageing population
faces a growing risk from non-communicable diseases such as cancer. The development of novel, targeted
personalised sensing and imaging drugs is highly desirable. This research would address cleaner, rapid synthetic
processes with pharmaceutical relevance by the utilisation of inexpensive protocols and drugs currently under
development for clinical trials, e.g. immune-therapeutics. The work would be fully embedded in the strategic research
direction of biosensing and imaging/healthcare technology, which could have real impact in early diagnosis of cancer
and personalised medicine. The PhD thesis will focus on the general area of biosensing, imagining and therapeutic
innovations for cancer diagnosis and therapy.
Outline
The project would largely be based on enhancing the understanding of the fundamental interactions between
luminescent probes and targeting biomolecules such as synthetic peptides upon conjugation, leading to a biological
probe, which could potentially target living cancer cells under controlled microenvironments. A secondary aim would
be to gain an in depth understanding of the synthetic and analytical chemistry underpinning the chemistry implicated
in the antibody labelling or tagging with small fluorescent molecules.
We would design, synthesise, and characterise new metal complexes as "all-in-one" imaging probes, centred on
certain antibodies of interest for clinical trials of cancer, such as Avastin or anti-EGFR. Outputs would lead to
improved sensing and bioimaging probes for early cancer diagnosis, including for hypoxic tumours, which are
currently hard to access for imaging or treatment. This could advance our fundamental understanding of the
associated conjugation chemistry in aqueous environments, including using bioorthogonal and supramolecular
assembly protocols, thus allowing for correlation between antibody behaviour post conju gation and its kinetic
stability, with the metal ions present in the molecular appendages and their speciation in aqueous media.
Project Aims
a) Functionalisation of biomolecules of interest for immune-therapies such as simple synthetic peptides, onto metal
bound imaging probes.
b) Understanding how fluorescent metal complexes can be incorporated in multimodality (PET/optical) probes, which
are then anchored onto antibodies without destroying the fragile biomolecular constructs.
c) Labelling of biomolecules with model species of relevance to PET/SPECT metallic radio isotopes such as 68Ga
and 89Zr. Development and testing protocols for the "cold" chelation of Zn(II), Ga(III) and Zr(IV) ions in water.
Dr Charareh Pourzand (20 %) will assist in this project by providing knowledge and training in tissue and cell culture.
This will allow for the imaging probes designed to be tested within cells.
Professor Andy Burrows (10 %) will act as a mentor and will also support in the more chemical aspects of this project
faces a growing risk from non-communicable diseases such as cancer. The development of novel, targeted
personalised sensing and imaging drugs is highly desirable. This research would address cleaner, rapid synthetic
processes with pharmaceutical relevance by the utilisation of inexpensive protocols and drugs currently under
development for clinical trials, e.g. immune-therapeutics. The work would be fully embedded in the strategic research
direction of biosensing and imaging/healthcare technology, which could have real impact in early diagnosis of cancer
and personalised medicine. The PhD thesis will focus on the general area of biosensing, imagining and therapeutic
innovations for cancer diagnosis and therapy.
Outline
The project would largely be based on enhancing the understanding of the fundamental interactions between
luminescent probes and targeting biomolecules such as synthetic peptides upon conjugation, leading to a biological
probe, which could potentially target living cancer cells under controlled microenvironments. A secondary aim would
be to gain an in depth understanding of the synthetic and analytical chemistry underpinning the chemistry implicated
in the antibody labelling or tagging with small fluorescent molecules.
We would design, synthesise, and characterise new metal complexes as "all-in-one" imaging probes, centred on
certain antibodies of interest for clinical trials of cancer, such as Avastin or anti-EGFR. Outputs would lead to
improved sensing and bioimaging probes for early cancer diagnosis, including for hypoxic tumours, which are
currently hard to access for imaging or treatment. This could advance our fundamental understanding of the
associated conjugation chemistry in aqueous environments, including using bioorthogonal and supramolecular
assembly protocols, thus allowing for correlation between antibody behaviour post conju gation and its kinetic
stability, with the metal ions present in the molecular appendages and their speciation in aqueous media.
Project Aims
a) Functionalisation of biomolecules of interest for immune-therapies such as simple synthetic peptides, onto metal
bound imaging probes.
b) Understanding how fluorescent metal complexes can be incorporated in multimodality (PET/optical) probes, which
are then anchored onto antibodies without destroying the fragile biomolecular constructs.
c) Labelling of biomolecules with model species of relevance to PET/SPECT metallic radio isotopes such as 68Ga
and 89Zr. Development and testing protocols for the "cold" chelation of Zn(II), Ga(III) and Zr(IV) ions in water.
Dr Charareh Pourzand (20 %) will assist in this project by providing knowledge and training in tissue and cell culture.
This will allow for the imaging probes designed to be tested within cells.
Professor Andy Burrows (10 %) will act as a mentor and will also support in the more chemical aspects of this project
Organisations
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/N509589/1 | 01/10/2016 | 30/09/2021 | |||
| 2427593 | Studentship | EP/N509589/1 | 01/10/2020 | 31/03/2024 | Megan GREEN |
| EP/T518013/1 | 01/10/2020 | 30/09/2025 | |||
| 2427593 | Studentship | EP/T518013/1 | 01/10/2020 | 31/03/2024 | Megan GREEN |
| Description | A variety of new cellular imaging probes have begun to be synthesized and their ability to image cancer cells tested. Work has now begun to assess their selectivity towards cancer cell lines, and any potential anti-cancer activity they may possess. During the development of these probes the route to their synthesis has been improved to be easier to follow and result in a greater yield of the probes. In the initial development process the synthetic route was unreliable and difficult to replicate - leading to work that is difficult to publish during the early stages. This difficulty led to asking questions of how the probes could be altered/ improved to provide an easier method of functionalisation. However, by going through this difficultly in the original process I have greatly developed my analytic and synthetic skills and knowledge. Once the simple probe scaffold was synthesised work begun to further functionalise this molecule by trying to incorporate peptides which know cancer cell selectivity to create a peptide drug conjugate (PDC). Characterizing and testing theses PDC's is the aim of this project in the next few months. Work has also begun to create a family of metal complexes with the probes. As Cu(II) is a metal of interest for these complexes this has created a possibility to expand my skill sets and collaboration as it allows for electron paramagnetic resonance spectroscopy (EPR) to be run on the probe. Due to the new developed method of synthesis the project is now moving towards its aims. |
| Exploitation Route | Moving forward the outcomes of this funding could be further developed by future PhD students as the work is still preliminary. The outcomes so far provide an improved method of synthesizing imaging probes and their functionalisation with targeting groups - these preliminary findings would need to be further developed and tested before there would be applications to the wider community (outside of academic). The molecules synthesized for this project could be further developed and potential be used as chemical tool kits for cancer diagnosis further in the future if they are found to have beneficial properties. |
| Sectors | Chemicals,Pharmaceuticals and Medical Biotechnology,Other |