Lomustine nanoparticles enable both bone marrow sparing and high brain drug levels - a strategy for brain cancer treatments

Fisusi, Funmilola A. and Siew, Adeline and Chooi, Kar Wai and Okubanjo, Omotunde and Garrett, Natalie and Lalatsa, Katerina and Serrano, Dolores and Summers, Ian and Moger, Julian and Stapleton, Paul and Satchi-Fainaro, Ronit and Schätzlein, Andreas G. and Uchegbu, Ijeoma F. (2016) Lomustine nanoparticles enable both bone marrow sparing and high brain drug levels - a strategy for brain cancer treatments. Pharmaceutical Research, 33 (5). pp. 1289-1303. ISSN 0724-8741 (https://doi.org/10.1007/s11095-016-1872-x)

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Abstract

Purpose: The blood brain barrier compromises glioblastoma chemotherapy. However high blood concentrations of lipophilic, alkylating drugs result in brain uptake, but cause myelosuppression. We hypothesised that nanoparticles could achieve therapeutic brain concentrations without dose-limiting myelosuppression. Methods: Mice were dosed with either intravenous lomustine Molecular Envelope Technology (MET) nanoparticles (13 mg kg-1) or ethanolic lomustine (6.5 mg kg-1) and tissues analysed. Efficacy was assessed in an orthotopic U-87 MG glioblastoma model, following intravenous MET lomustine (daily 13 mg kg-1) or ethanolic lomustine (daily 1.2 mg kg-1 - the highest repeated dose possible). Myelosuppression and MET particle macrophage uptake were also investigated. Results: The MET formulation resulted in modest brain targeting (brain/ bone AUC0-4h ratios for MET and ethanolic lomustine = 0.90 and 0.53 respectively and brain/ liver AUC0-4h ratios for MET and ethanolic lomustine = 0.24 and 0.15 respectively). The MET formulation significantly increased mice (U-87 MG tumours) survival times; with MET lomustine, ethanolic lomustine and untreated mean survival times of 33.2, 22.5 and 21.3 days respectively and there were no material treatment-related differences in blood and femoral cell counts. Macrophage uptake is slower for MET nanoparticles than for liposomes. Conclusions: Particulate drug formulations improved brain tumour therapy without major bone marrow toxicity.

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