MICA: Convection-enhanced delivery of encapsulated nanospheres for controlled delivery of chemotherapy to the brain

Glioblastoma multiforme (GBM) is the commonest primary malignant brain tumour. Despite advances in chemotherapy, radiotherapy and surgical technology, the prognosis remains poor. Only a minority of patients are suitable for maximal treatment comprising surgical excision, radiotherapy and chemotherapy, and even following maximal treatment, average survival remains at approximately 14 months from diagnosis. There is no cure for GBM and patients inevitably suffer from recurrence and progression of the disease. The majority of tumour recurrences occur within 2cm of the site of the original tumour due to microscopic invasion of tumour cells into surrounding brain tissue which escape surgical excision and radiotherapy.

One of the major obstacles to the effective treatment of brain tumours is the existence of the blood-brain barrier (BBB), which prevents the free passage of drugs from the bloodstream into the brain. It is sometimes possible to increase the amount of drug which enters the brain by using high drug doses, but this often results in severe side-effects which are unacceptable to patients.

Our solution is to bypass the BBB by delivering chemotherapy directly to brain tissue surrounding the tumour following excision, using a neurosurgical technique called convection-enhanced delivery (CED). CED describes a method of direct drug delivery to the brain through ultrafine microcatheters. This technique allows us to target the chemotherapy to recurrent brain tumours with very high safety and accuracy, and to distribute effective drug concentrations throughout relevant areas of the brain. This approach also reduces the risk of side-effects by specifically targetting drugs to the brain. We have previously used this technique to deliver drugs to patients with Parkinson's Disease, and over the last 5 years we have been working with industrial collaborators to develop a CED catheter system which allows us to deliver repeated drug doses to the brain.

In this project we propose to combine CED with recent advances in the field of nanotechnology. By encapsulating chemotherapies in biodegradable nanospheres our aim is to achieve controlled drug release within the brain, to reduce the drug doses required to achieve tumour regression, and to limit the risk of side-effects. We have chosen a nanosphere formulation which is widely used in the medical industry and is proven to be safe and non-toxic. We have approval for a clinical trial of CED of unencapsulated chemotherapy, and this study represents a logical progression. By using CED to deliver chemotherapy nanoparticles to the brain we hope to reduce tumour recurrence and progression and to improve the quality of life of patients with this devastating disease.

Our research team comprises a unique collaboration between neurosurgeons, neuroscientists, chemists and chemical engineers with the knowledge and experience to develop this novel technology for patient benefit.

Our aim is to formulate biodegradable polymer-encapsulated carboplatin nanospheres suitable for convection-enhanced delivery (CED) for the treatment of recurrent/progressive Glioblastoma multiforme. The size and charge of nanospheres will be analysed using electron microscopy, dynamic light scattering and a particle zetasizer. Drug loading, size, charge and drug release profile will be optimised by manipulating such parameters as the polymer composition, synthesis conditions and extent of surface hydrolysis.

The structure and associated drug release of nanospheres will be analysed in artificial cerebrospinal fluid, PBS and saline using atomic absorption spectroscopy (AAS), and nuclear magnetic resonance (NMR) relaxometry and cryoporometry. The cytotoxic efficacy of carboplatin nanospheres will be compared to unencapsulated carboplatin in human glioma and neuronal cultures. This will allow us to select the optimum formulation and vehicle for in vivo testing of CED of nanospheres.

The distribution, half-life and toxicity of nanospheres delivered by CED will be studied in vivo. Catheters will be stereotactically inserted into the brain and distribution analysed using fluorescently-labelled nanospheres. The in vivo clearance, half-life and stability of platinum released from nanospheres will be assessed using AAS and liquid chromatography-mass spectrometry. The toxicity of chemotherapy nanospheres will be compared to unencapsulated carboplatin by analysing the extent of astrocytosis, pre-and post-synaptic proteins and neuronal content.

On the basis of in vitro testing of loading efficiency, charge, size and drug release profile as well as in vivo analysis of distribution, half-life and toxicity in a small animal model we will progress to in vivo testing in a large animal model. We will perform intermittent drug delivery at intervals determined by clearance studies using a chronic in-dwelling CED catheter system in order to complete a dose-escalation study

The outcomes of this research project are likely to have a number of economic and societal implications resulting in a number of non-academic beneficiaries both in the short and long-term.

Short-term beneficiaries:
1. The pharmaceutical industry
One of the major aims of this study is to combine advances in convection-enhanced drug delivery technology with the use of nanoformulations. Such a treatment strategy has applications for a range of neuro-therapeutics. We envisage that a successful outcome in this study will attract R&D investment from the pharmaceutical industry which will facilitate rapid translation to clinical trials. The Functional Neurosurgery Research Group has on-going collaborations with a number of US and European pharmaceutical biotechnology companies who also stand to benefit from success in this study. A second major aim is the development of a biocompatible nanoscale drug delivery platform which facilitates controlled drug release over a prolonged period. Such a system has applications for a range of therapeutic agents.

2. UK medical device and nanotechnology regulators
The Medical and Healthcare Regulatory Agency (MHRA) has been actively involved in aiding our research group to obtain approval for clinical trials of CED for both neuro-oncological and neurodegenerative disorders. The MHRA is also committed to monitoring the progress of nanotechnology in healthcare. Successful outcomes from this study and rapid progression to subsequent clinical trials could provide a model for safe and effective translational research in the rapidly expanding field of nanomedicine.

3. Renishaw Plc. (Industrial Collaborators)
The chronic intermittent catheter systems described in this proposal are manufactured by our industrial collaborators. This study has the potential to validate use of this device for chronic intermittent delivery of nanoparticles. Industrial collaboration is paramount for effective translation of this therapeutic strategy to clinical trials, for large-scale production of catheter systems and for collaboration with the pharmaceutical industry. Success in this study is likely to attract further R&D investment from pharmaceutical collaborators and to promote the sustainability of the business, in particular, Renishaw's Neurological Products Division.

4. The general public
Successful results relating to the safety and toxicity of the nanoformulations used in this study are likely to increase public confidence in emerging nanotechnologies and their application to nanomedicine. We plan to contribute to the debate by providing scientifically rigorous content for websites, the press and public science events.

Longer-term beneficiaries:
5. Patients with recurrent/progressive Glioblastoma Multiforme.
The ultimate aim of this research is to facilitate a phase I clinical trial of convection-enhanced delivery of biodegradable polymer-encapsulated carboplatin nanospheres for recurrent/progressive GBM. By delivering the therapeutic agent to peritumoral tissue our aim is to target invasive tumour cells which escape surgical resection and the field of radiotherapy, and thereby reduce the risk of tumour recurrence/progression. By encapsulating chemotherapy in polymeric nanospheres our aim is to reduce the overall dose required and the frequency of dosing, reduce side-effects and also the development of resistance to chemotherapy.

6. The National Health Service
By encapsulating chemotherapy within nanospheres we aim to achieve prolonged drug release within the brain, and thereby reduce the frequency of drug administration without impairing clinical efficacy. The chronic intermittent drug delivery system is designed to allow patients to receive drug infusions on a day case basis, which we envisage will prevent the need for inpatient admission. The reduced requirement for hospital attendance may reduce NHS in patient costs and will also improve our patients' quality of life.