The Development of Peroxide-Responsive Arylboronic Acids for Antibody-Drug Conjugates and Small-Molecule Prodrugs

Cancer cells exhibit oxidative stress, which results in the over-production of reactive-oxygen species (ROS), such as hydrogen peroxide. Hence, there are elevated levels of hydrogen peroxide in cancer compared to healthy cells, which can be exploited for the targeted delivery of drugs. Section I of this thesis describes the design, synthesis, and evaluation of antibody-drug conjugates (ADCs) comprising arylboronic acid linkers, which give responsive drug release in the presence of the elevated hydrogen peroxide in cancer. ADCs are a continually expanding therapeutic area, and the linker used for the antibody-drug connection is of upmost importance in determining the stability of the conjugate and the specificity of drug release. Arylboronic acids are known to undergo C-B bond oxidation by action of hydrogen peroxide, and when combined with a suitable self-immolative aryl ring, can subsequently undergo spontaneous 1,6-elimination to release a free drug. Hence, initial studies evaluated a panel of model linkers with a fluorescent reporter molecule and confirmed the linker reactivity with peroxide but otherwise high stability. Trastuzumab peroxide-cleavable ADCs were then synthesised and evaluated *in vitro* against a panel of breast cancer cell lines, and preliminary evidence is presented which suggests the ADCs may not require internalisation for payload release. Hence, peroxide-cleavable ADCs comprising anti-PD-L1 antibody durvalumab were also synthesised and evaluated *in vitro*, with preliminary evidence suggesting the generation of an efficacious non-internalising ADC. Section II of this thesis describes the application of peroxide-responsive arylboronic acids towards the generation of small-molecule prodrugs. Non-targeted drugs, such as olaparib and navitoclax, often suffer from poor tolerability and toxicity because they exert their function on healthy cells as well as target cancer cells. Thus, to improve their efficacy and safety profile, inactive prodrugs of olaparib and navitoclax were designed by capping key amines with the arylboronic acid self-immolative motif. This would enable site-specific release of the free drugs upon encounter with the high levels of hydrogen peroxide in cancer. Synthetic efforts and preliminary investigations towards the peroxide-responsive prodrugs is presented.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2023

Author dc:creator

• Ashman, Nicola

Advisor dc:contributor.advisor

• Spring, David

• antibody-drug conjugate
• boronic acid
• chemistry
• oncology
• prodrug

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/365c6e19-b9be-47c3-9a85-50fd27d771df/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.104039

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/360759