Abstract
We currently use Convection-Enhanced Delivery (CED) of the platinum-based drug, carboplatin as a novel treatment strategy for high grade glioblastoma in adults and children. Although initial results show promise, carboplatin is not specifically toxic to tumour cells and has been associated with neurotoxicity at high infused concentrations in pre-clinical studies. Our treatment strategy requires intermittent infusions due to rapid clearance of carboplatin from the brain. In this study, carboplatin was encapsulated in lactic acid-glycolic acid copolymer (PLGA) to develop a novel drug delivery system. Neuronal and tumour cytotoxicity were assessed in primary neuronal and glioblastoma cell cultures. Distribution, tissue clearance and toxicity of carboplatin nanoparticles following CED was assessed in rat and porcine models. Carboplatin nanoparticles conferred greater tumour cytotoxicity, reduced neuronal toxicity and prolonged tissue half-life. In conclusion, this drug delivery system has the potential to improve the prognosis for patients with glioblastomas.
Highlights
Glioblastomas are the most common, heterogeneous, highly invasive tumours of the brain, and are associated with poor prognosis
The direct intracranial administration by Convection-Enhanced Delivery (CED) results in drug compartmentalisation within the brain, thereby reducing systemic toxicity. The potential of this treatment strategy to favourably impact the prognosis of patients with malignant brain tumours is likely to be dependent on achieving a consistent therapeutic drug concentration within a brain tumour and the surrounding penumbra [15] [16]
Convection-enhanced delivery has emerged as a promising strategy for bypassing the blood brain barrier (BBB), and allows anatomically targeted delivery of chemotherapeutic agents to a tumour and the surrounding brain tissue [29,30]
Summary
Glioblastomas are the most common, heterogeneous, highly invasive tumours of the brain, and are associated with poor prognosis. Conventional delivery of chemotherapy suffers from inadequate penetration of the blood brain barrier (BBB), resulting in subtherapeutic drug concentrations at the tumour site [3]. Local administration of chemotherapy following tumour resection facilitates bypass of the BBB, and aims to target the peritumoral sites of tumour invasion and recurrence. The most well known are wafers containing carmustine (Gliadel, Arbor Pharmaceuticals, USA), which are tightly packed into the resection cavity [4]. This type of drug delivery relies upon diffusion and so cannot penetrate deep into the surrounding brain tissue [5].
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