Abstract 4519: Lomustine nanoparticles are effective brain cancer treatments

Abstract The therapy of brain cancers such as Glioblastoma multiforme (GBM) is often hampered by the blood-brain-barrier, which limits the access of drugs to the brain. High blood concentrations of a drug can increase transport into the brain but in the case of cytotoxic drugs often lead to dose-limiting peripheral toxicity, typically myelosuppression. In the current study we explore the potential of Nanomerics’ Molecular Envelope Technology (MET) nanoparticles to enhance transport of the cytotoxic drug lomustine to the brain while avoiding dose-limiting peripheral bone marrow toxicity. We have previously shown that these particles increase the brain activity of drugs such as the intravenous anaesthetic propofol by a factor of ten. MET nanoparticles were prepared from a self-assembling amphiphilic chitosan based polymer - quaternary ammonium palmitoyl glycol chitosan. Lomustine, a poorly water soluble alkylating nitrosourea (CCNU), was encapsulated within these particles at a concentration of 2mg mL−1, 20x higher than what is achievable with conventional ethanolic- polysorbate 80 formulations. In order to determine the therapeutic efficacy of the formulations, orthotopic intracranial human glioblastomas (U87- MG cells) were studied in female CD-1 nude mice. Established tumours were treated at the maximal achievable lomustine concentrations using MET lomustine (13 mg kg−1/day) and the conventional formulation (1.2 mg kg−1/day) for 10 days. The mean survival time for animals that received the MET formulation was significantly (p Animal white blood cell and femoral cell counts were not affected by any of the lomustine formulations, however both treated groups of animals showed a transient drop in the platelet count on Day 7 with recovery by day 22. The MET lomustine particulate formulation thus enabled the administration of a more than ten times higher dose of lomustine which dramatically improved therapeutic outcome with little evidence of any additional toxicity or dose limiting toxic effects. The results of this study suggest that MET nanoparticles may provide a safe means to improve therapeutic outcomes in brain cancer using current cytotoxic drugs. Citation Format: Funmilola A. Fisusi, Ahmed Alzharani, Ian Summers, Julian Morger, Omotunde Okubanjo, Kar wai Chooi, Andreas G. Schätzlein, Ijeoma F. Uchegbu. Lomustine nanoparticles are effective brain cancer treatments. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4519. doi:10.1158/1538-7445.AM2013-4519