Development of an docetaxel-loaded implantable device for the localised treatment of prostate cancer

Summary

Background

ChemoSeed®, from CRISM Therapeutics, is an implantable, biodegradable drug delivery technology designed for the sustained release of chemotherapy directly into cancer tissue thereby improving clinical performance. Prostate cancer is one of the most common types of cancer in men.  Docetaxel (DTX) has been chosen for this project as it is the standard of care for prostate cancer and has been injected bi-weekly intratumourally for evaluation in head, neck and squamous cell carcinoma.  A murine study demonstrated that supradoses were achieved at 1,000-fold over the conventional IV dose. The study proved to be efficacious with lower toxicity than the IV dose given the lower systemic exposure. It is proposed that a ChemoSeed implant is formulated and developed for prostate cancer incorporating DTX.

The project brings together the research interests of all the experienced supervisors and is a strategic area of investigation for the Centre for Genomic Medicine at UU.

Aims & objectives

This project will complete the following objectives with the aim of advancing the DTX-loaded ChemoSeed into the clinic.

1. Investigate the cytotoxicity of DTX against a panel of primary prostate cancer cells.  Prostate cancer cells lines  will be cultured and exposed to increasing doses of DTX and the cytotoxicity determined using MTT assay the IC50s calculated. This will help to determine the dose of DTX that needs to be delivered from ChemoSeed.
2. Hot Melt Extrusion (HME) will be used to manufacture the DTX-loaded ChemoSeed.  A pre-formulation screening study, to identify the optimum hot melt extrusion (HME) processing conditions needed to achieve any therapeutic effect will be performed. A series of rheological experiments involving different DTX and poly lactic glycolic acid (PLGA) loadings and temperatures will be performed to understand the melt rheology of each formulation and thus ascertain appropriate processing conditions. Once the processing conditions have been established DTX and PLGA will be roll mixed, extruded into strands with 2 mm diameter and cut into 3mm ChemoSeeds. The ChemoSeeds will be characterised for surface morphology, crystallinity, drug release, content and stability.
3. The cytotoxicity of the DTX-ChemoSeeds will be evaluated using prostate cancer cell lines.  Briefly, primary prostate cancer cells will be cultured in 6 well plates and the ChemoSeed added directly into the wells of the culture plates and the cells evaluated for their survival using MTT assays. Our findings will reveal the most promising ChemoSeeds to move into in vivo preclinical mouse studies.
4. The most promising ChemoSeeds will be evaluated for their toxicity and efficacy in a mouse flank prostate cancer model.  Prostate tumours will be established on the flank of mice and ChemoSeeds implanted into the tumours.  The tumours will be assessed for their size.  At the end of the study the mice will be euthanized and the tissue around the ChemoSeed assessed for toxicity via H&E staining.
5. Cells and samples collected as part of Steps 1-4 will be subject to cell biology analysis, including PCR, Western blot and cell bioassays to identify important genetic and biological pathways involved in the drug response.

The PhD researcher will interact closely with the CRISM Therapeutics team and will be trained in technology transfer, scale-up, GMP manufacturing and regulatory compliance.

‘This CDP studentship offers an annual non-taxable maintenance grant of approx. £19,500 plus an additional stipend top-up of £1,000 per annum, covers three years of tuition fees (worth over £14,000), in addition to  support for research training and project running costs.’

Skills Required of Applicant

• Good Laboratory skills
• Good oral and written presentation skills
• Good critical thinking and analytical skills
• Good IT skills
• Good work ethic and ability to work independently
• Interest in bioinformatic analysis

Essential criteria

Applicants should hold, or expect to obtain, a First or Upper Second Class Honours Degree in a subject relevant to the proposed area of study.

We may also consider applications from those who hold equivalent qualifications, for example, a Lower Second Class Honours Degree plus a Master’s Degree with Distinction.

In exceptional circumstances, the University may consider a portfolio of evidence from applicants who have appropriate professional experience which is equivalent to the learning outcomes of an Honours degree in lieu of academic qualifications.

• Sound understanding of subject area as evidenced by a comprehensive research proposal
• A comprehensive and articulate personal statement

Desirable Criteria

If the University receives a large number of applicants for the project, the following desirable criteria may be applied to shortlist applicants for interview.

• First Class Honours (1st) Degree
• Completion of Masters at a level equivalent to commendation or distinction at Ulster
• Experience using research methods or other approaches relevant to the subject domain
• Publications record appropriate to career stage
• Experience of presentation of research findings

Equal Opportunities

The University is an equal opportunities employer and welcomes applicants from all sections of the community, particularly from those with disabilities.

Appointment will be made on merit.

Funding and eligibility

This project is funded by:

• DfE CDP Award in collaboration with CRISM Therapeutics

This CDP studentship offers an annual non-taxable maintenance grant of approx. £19,500 plus an additional stipend top-up of £1000 per annum and covers three years of tuition fees (worth over £14,000), in addition to support for research training and project running costs.

To be eligible for these scholarships, applicants must meet the following criteria:

• Be a UK National, or

• Have settled status, or

• Have pre-settled status, or

• Have indefinite leave to remain or enter, or

• be an Irish National

Applicants should also meet the residency criteria which requires that they have lived in the EEA, Switzerland, the UK or Gibraltar for at least the three years preceding the start date of the research degree programme.

Applicants who already hold a doctoral degree or who have been registered on a programme of research leading to the award of a doctoral degree on a full-time basis for more than one year (or part-time equivalent) are NOT eligible to apply for an award.

Due consideration should be given to financing your studies.