Design, synthesis and evaluation of protease-activated anti-cancer prodrugs

Matrix metalloproteinases (MMPs) are a family of endoproteases that are overexpressed in tumours and play crucial roles in many tumourigenic processes, not least tumour invasion and angiogenesis. The concept behind our technology is that the increased expression and activity of MMPs within the tumour microenvironment, relative to normal tissues, can be exploited to selectively release potent chemotherapeutics from non-toxic peptide conjugates. The result is high levels of the active agent in the tumour and negligible drug levels in ’normal’ tissues.

Conjugation of a peptide to the active drug molecule renders it inactive until such time that it is activated by MMPs in the tumour. The MMP then cleaves the peptide, resulting in release of the active drug selectively in the tumour microenvironment. The ICT has already successfully used this technology to improve the therapeutic index of a colchicine derivative (ICT2588), which is now licensed to University of Bradford spin-out company Incanthera plc and received global press coverage at the British Science Festival 2011. ICT2588 is about to enter Phase I clinical trials. The group additionally has strong links with Stanford University (USA), having commercialised an MMP-activated ‘theranostic’ version of ICT2588, which simultaneously allows MRI imaging and cancer therapy.

The student will join a successful, motivated multidisciplinary team with expertise in medicinal chemistry, pharmacology, drug metabolism and pharmacokinetics. The project will involve the design, synthesis and biological evaluation of the next generation of MMP-activated prodrugs, with the aim of identifying an agent to progress towards advanced preclinical testing and ultimately the clinic.

Specific aims:

1. Synthesis of novel peptide-drug conjugates, utilizing modern automated solid-phase peptide technology and/or
2. Study of the metabolism of synthesized conjugates in tumour and normal tissues in vitro, using LC-MS;
3. In vivo assessment of the most promising compound – pharmacokinetics and efficacy in a mouse model.

How to apply

Formal applications can be submitted via the University of Bradford web site. Applicants should register an account, select 'Full-time PhD in Cancer Therapeutics' as the course, and include the project title on the Research Proposal section.

Informal enquiries are also welcome.

About the University of Bradford

Bradford is a research-active University supporting the highest-quality research. We excel in applying our research to benefit our stakeholders by working with employers and organisations world-wide across the private, public, voluntary and community sectors and actively encourage and support our postgraduate researchers to engage in research and business development activities.

Faculty of Life Sciences

The faculty comprises a mixture of academic divisions, research centres and outreach facilities. We provide high-quality teaching with a professional focus and engage in cutting-edge research – which we seek to apply through our extensive links with industry and business. We also offer a wide range of postgraduate taught and research courses.

Many of our academics are active researchers and international research experts.

Our interdisciplinary research themes are focus on:

• Computational and Data-driven Science
• Interface of Chemistry Biology and Materials
• Health, Society, People and Place
• The Life Course

Our research centres include:

• Centre for Pharmaceutical Engineering Science
• Digital Health Enterprise Zone
• Institute of Cancer Therapeutics
• Wolfson Centre for Applied Research

University investment in research support services, equipment and infrastructure provides an excellent research environment and broad portfolio of developmental opportunities. 

Positive Action Statement

At the University of Bradford our vision is a world of inclusion and equality of opportunity, where people want to, and can, make a difference. We place equality and diversity, inclusion, and a commitment to social mobility at the centre of our mission and ethos. In working to make a difference we are committed to addressing systemic inequality and disadvantages experienced by Black, Asian and Minority Ethnic staff and students.

Under sections 158-159 of the Equality Act 2010, positive action can be taken where protected group members are under-represented. At Bradford, our data show that people from Black, Asian, and Minority Ethnic groups who are UK nationals are significantly under-represented at the postgraduate researcher level. 

These are lawful measures designed to address systemic and structural issues which result in the under-representation of Black, Asian, and Minority Ethnic students in PGR studies.