Development of a Hypoxia-Activated Trehalose Diester for the Treatment of Solid Tumours

Abstract

The potential of bacterial cell wall components in the treatment of various cancers was initially realised in the late 1800s during pioneering work with Coley’s toxins. Since this preliminary work, efforts have been concentrated on the isolation and identification of bacterial components that lead to tumour regression. Trehalose dimycolates (TDMs) are compounds isolated from the M. tuberculosis cell wall and are known to activate macrophages to give a polarised Th1 immune response resulting in reduced tumour burden. Consequently, TDMs have shown great promise in the treatment of solid tumours.

In this thesis, work is presented towards the synthesis of trehalose glycolipid prodrugs that will be specifically activated inside the hypoxic tumour microenvironment, and thereby lead to a more selective form of cancer therapy. These hypoxia-activated trehalose glycolipids incorporate a nitroimidazole trigger that fragments upon enzymatic reduction (in the absence of oxygen) to give the active glycolipid. Throughout the course of this work, it was determined that the nitroimidazole trigger group could not be directly attached to the glycolipid and thus, an alternative carbonate-linker strategy was explored through the use of a reporter fluoroprobe. The validity of this approach was determined in various enzyme and cell-based assays.