Glioblastoma is the most common and most biologically aggressive primary brain tumour in adults. In spite of tremendous investment into research which has led to the development and application of novel diagnostic and therapeutic measures in the management of glioblastoma, the prognosis is still dismal with median survival time of about 12 – 15 months. Also, the success of most cytotoxic drugs clinically employed in the treatment of glioblastoma is greatly limited by their dose-limiting toxicity which typically manifests as clinically significant reduction in blood cell counts. The aim of this study is to demonstrate that a high dose nanoparticle formulation of the cytotoxic drug lomustine using a self-assembling chitosan amphiphile, quaternary ammonium palmitoyl glycol chitosan would lead to improved survival outcomes without a commensurate increase in toxic effects. The novel nanoparticle based lomustine formulation employed in this study enabled the administration of a lomustine dose (13 mg kg-1) 10 times higher than the dose (1.2 mg kg-1) achievable with an ethanolic formulation of lomustine. Human glioblastoma tumour bearing mice treated with the high dose formulation had a mean survival time of 33.1 days while the mice treated with the low dose formulation had a mean survival time of 22.5 days after intravenous administration of the drug once daily for 10 consecutive days. The increased (1.5 times longer) survival time resulting from treatment with the nanoparticle based high dose formulation was not accompanied by an increase in gross toxic effects. Thus, the nanoparticle based formulation afforded the administration of lomustine in a continuous high dose schedule which led to beneficial therapeutic outcomes. In addition, three self-assembling peptide amphiphiles were synthesised and characterised for potential application in the transport and delivery of therapeutic molecules to the brain for the treatment of intracranial tumours.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:632103 |
| Date | January 2014 |
| Creators | Fisusi, F. A. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1456357/ |
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