Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels – A Strategy for Brain Cancer Treatments
Fisusi, Funmilola A.
Chooi, Kar Wai
Serrano, Dolores R.
Schätzlein, Andreas G.
Uchegbu, Ijeoma F.
American Association of Pharmaceutical Scientists / Springer Verlag
This is the author accepted manuscript. The final version is available from American Association of Pharmaceutical Scientists via the DOI in this record.
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.
Tertiary Education Trust Fund (TETFund, formerly Education Trust Fund), Nigeria
Obafemi Awolowo University, Ile-Ife, Nigeria
This is an open access article. The final publication is available at Springer via http://dx.doi.org/10.1007/s11095-016-1872-x.
First online: 22 February 2016
Academic Staff Training and Development Grant