Dr Chris McConville

Faculty of Science and Engineering

Chris completed his PhD in 2008 in the School of Pharmacy at Queens University Belfast. The work involved the development and characterisation of a novel rod insert vaginal ring (RIVR) for the delivery of protein based HIV microbicides. His subsequent postdoctoral position (Oct 2008 to July 2010) was also conducted in the School of Pharmacy at QUB and involved the development and evaluation of novel vaginal ring formulations, polymer blends and solid dosage forms for the delivery of HIV microbicides.

In July 2010 he was appointed as a senior lecturer in pharmaceutics at Curtin University, Perth, Western Australia, where he continued his research on the development of HIV microbicide products, while also focusing on the solubility enhancement of poorly soluble drugs, the development of biodegradable implantable drug delivery devices and the use of microparticles for controlled pulmonary drug delivery.

In June 2012 he was appointed senior lecturer in pharmaceutics at the University of Wolverhampton.  His research is focused on the development of implantable drug delivery devices for the localised treatment of brain tumours, the development of vaginal dosage forms for the treatment of gynaecological cancers and the development of micro and nanoparticles for the sustained delivery of chemotherapeutic drugs.

Development of implantable drug delivery devices for the treatment of brain tumours

There has been a rise in the number of brain cancers over the last thirty years, particularly glioblastoma multiforme (GBM), medulloblastoma, anaplastic astrocytoma, oligodendroglioma and maixed glioma. The conventional treatment method for glioma is surgical debulking of the tumour from the patient’s brain.  However, the amount of tumour that can be removed is dependent on and often limited by its proximity to critical regions required for brain function.  This significantly increases the risk of tumour regrowth, from residual tumour that could not be removed.  Post-surgical chemotherapy and radiotherapy can be used to reduce the risk of cancer remission.  However, these have resulted in limited clinical effectiveness, due to restricted transport of chemotherapy agents across the blood brain barrier (BBB).  The goal of my research is to develop a range of biodegradable controlled release implantable drug delivery devices off varying shapes (discs, rods, rings etc.) and sizes with a range of flexibilities (very flexible to brittle), degradation rates (days to months) and release rates that can be used for the localised delivery of chemotherapeutic drugs for the treatment of brain tumours.  These devices will be capable of releasing either a single or multiple chemotherapeutic drug(s) and can be implanted into the cavity left after surgical debulking or within and around the tumour via stereotactic surgery to reduce its size and stop it spreading before being removed.

Executive Summary

Introduction

Glioblastoma Multiforme (GBM) is the most common primary malignant brain tumour in adults with a very poor prognosis.  Even after surgery, radiotherapy and chemotherapy, the overall survival rate for patients with GBM is 42.4% at 6 months, 17.7% at 12 months and 3.3% at 2 years1.  The current treatment for GBM is surgical resection of accessible tumour, which is often limited if the tumour is located near to critical regions of the brain, followed by radiotherapy and adjuvant chemotherapy. Systemic delivery of chemotherapeutic drugs into the neurons and glial tissues of the brain is challenging due to the presence of the blood-brain barrier (BBB), which consists of tight junctions between the endothelial cells lining the cerebral capillaries2. The BBB is very selective and consequently only low molecular weight, electrically neutral, hydrophobic molecules are able to freely cross this barrier3-5. One option to overcome this issue is the use of implantable devices to deliver the chemotherapeutic drug directly to the tumour, which offers a number of advantages over systemic administration, including increased drug stability as it remains in the delivery device until released, direct delivery to the site of action, lower dose of drug required and reduced side effects due to the avoidance of systemic circulation6.  Furthermore, local drug delivery may be suitable for the treatment of GBM as approximately 80 to 90% return within 2cm of the resection site7.

Aim

The development and characterisation of a range of implantable drug delivery devices for the localised delivery of chemotherapeutic drugs to the brain.              

Objectives

  1. Manufacture the drug delivery devices using a range of techniques
  2. Characterise the crystalline nature of the drug in the delivery device
  3. Characterise the drug delivery devices for their drug homogeneity, stabilty and release profile
  4. Determine the cytotoxicity of the drug released from the delivery device

Methods

The drug delivery devices where manufactured using a range of manufacturing techniques including compression, solvent casting, heat compression moulding, extrusion and injection moulding.  The crystalline nature of the drug was determined using DSC and XRD, while the homogeneity, stability and release profile of the drug was performed using established extraction and drug release methods coupled with HPLC analysis.  The cytotoxicity of the drug was established using the U373 brain cancer cell line and established methods.   

Summary findings

In all 15 different drug delivery devices (9 wafers and 6 rods) where manufactured and characterised.  Solvent casting was found to be an unsuitable method of manufacture due to the solvent causing an interaction between the drug and the polymer, while injection moulding resulted in approximately 35% degradation of the drug due to the high temperatures required for manufacture.  The drug release was both diffusion (in the arly stages of release) and degradation (in the later stages of release) controlled as well as being dependent on the polymer.  The drug extracted from the compressed, heat compressed and extruded devices had a similar toxicity to that of a control drug solution.

References

  1. H. Ohgaki, P. Dessen, B. Jourde, S. Horstmann, T. Nishikawa, P.L. Di Patre, C. Burkhard, D. Schüler, N.M. Probst-Hensch, P.C. Maiorka, N. Baeza, P. Pisani, Y. Yonekawa, M.G. Yasargil, U.M. Lütolf, P. Kleihues, Genetic pathways to glioblastoma: a population-based study, Cancer Res. 64 (2004) 6892–6899.
  2. T.S. Reese, M.J. Karnovsky, Fine structural localization of a blood–brain barrier to exogenous peroxidase, J. Cell Biol (1967) 207–217.
  3. A. Seelig, R. Gottschlich, R.M. Devant, A method to determine the ability of drugs to diffuse through the blood-brain barrier, PNAS. 91 (1994) 68-72.
  4. N.J. Abbott, I.A. Romero, Transporting therapeutics across the blood-brain barrier, Mol. Med. Today. 2 (1996) 106-113.
  5. E.M. Kemper, A.E van Zandbergen, C. Cleypool, H.A. Mos, W. Boogerd, J.H. Beijnen, O. van Tellingen, Increased Penetration of Paclitaxel into the Brain by Inhibition of P-Glycoprotein, Clin. Cancer Res. 9 (2003) 2849-2855.
  6. J.B. Wolinsky, Y.L. Colson, M.W. Grinstaff, Local drug delivery strategies for cancer treatment: Gels, nanoparticles, polymeric films, rods, and wafers, J. Con. Rel. 159 (2012) 14-26.
  7. P.P. Wang, J. Frazier, H. Brem, Local drug delivery to the brain, Adv. Drug Deliv. Rev. 54 (2002) 987-1013.

Post ERAS Success

Following on from the ERAS Project Chris has published the paper 'Development of Disulfiram-Loaded Poly(Lactic-co-Glycolic Acid) Wafers (PDF 1,451K, Downloads file)'.