The development and delivery of novel therapeutics for cancer
File(s)
Author(s)
Rushworth, James Luke
Type
Thesis
Abstract
Tumour-associated macrophages (TAMs) have recently re-emerged as a viable target in cancer therapy. These cells are dependent on several receptors and signalling nodes for their growth and activity; targeting these receptors is an attractive strategy to eliminate or repolarise TAMs to the pro-inflammatory, tumouricidal (M1) phenotype. However, many current macrophage-specific small molecule inhibitors suffer from poor bioavailability or have a certain degree of promiscuity, leading to off-target effects. One feasible way to mitigate these problems is to encapsulate these small molecules into a drug delivery system.
Herein, we have utilised reversible addition-fragmentation chain transfer (RAFT) polymerisation and high-throughput methodology to access a range of macrophage-targeting cross-linked amphiphilic drug delivery systems that can self-assemble into micelles and higher-order structures such as polymersomes. These quasi-block copolymers were designed and synthesised with the aim of increasing selectivity to macrophages. Effective delivery of the tyrosine kinase inhibitor, dasatinib, was achieved and preferential uptake in macrophages was observed. As an extension to this work, we have designed a novel bioreductive pro-fluorescent pro-drug and have incorporated it into a series of hydrophilic copolymers. These materials selectively release their cargo under hypoxic conditions.
The second project described is the synthesis of [5]-helistatin, the first potential helicene-based drug. The parent compound, combretastatin [A-4], is a stilbene and the Z isomer is a highly potent tubulin inhibitor, whereas the E isomer is inactive. There has been a drive, therefore, to develop ‘Z-locked’ derivatives. The conformation afforded by the [5]-helicene provides this rigidity. Furthermore, the synthesis of unsymmetrical [5]-helicenes is extremely challenging and we are developing an efficient way of accessing these scaffolds with cheap, robust chemistry.
Herein, we have utilised reversible addition-fragmentation chain transfer (RAFT) polymerisation and high-throughput methodology to access a range of macrophage-targeting cross-linked amphiphilic drug delivery systems that can self-assemble into micelles and higher-order structures such as polymersomes. These quasi-block copolymers were designed and synthesised with the aim of increasing selectivity to macrophages. Effective delivery of the tyrosine kinase inhibitor, dasatinib, was achieved and preferential uptake in macrophages was observed. As an extension to this work, we have designed a novel bioreductive pro-fluorescent pro-drug and have incorporated it into a series of hydrophilic copolymers. These materials selectively release their cargo under hypoxic conditions.
The second project described is the synthesis of [5]-helistatin, the first potential helicene-based drug. The parent compound, combretastatin [A-4], is a stilbene and the Z isomer is a highly potent tubulin inhibitor, whereas the E isomer is inactive. There has been a drive, therefore, to develop ‘Z-locked’ derivatives. The conformation afforded by the [5]-helicene provides this rigidity. Furthermore, the synthesis of unsymmetrical [5]-helicenes is extremely challenging and we are developing an efficient way of accessing these scaffolds with cheap, robust chemistry.
Version
Open Access
Date Issued
2019-09
Date Awarded
2020-02
Copyright Statement
Creative Commons Attribution NonCommercial Licence
License URL
Advisor
Fuchter, Matthew
Sponsor
Commonwealth Scientific and Industrial Research Organization (Australia)
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)