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Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels – A Strategy for Brain Cancer Treatments
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Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels – A Strategy for Brain Cancer Treatments
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Journal Article
Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels – A Strategy for Brain Cancer Treatments
2016
Overview
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 AUC
0-4h
ratios for MET and ethanolic lomustine = 0.90 and 0.53 respectively and brain/ liver AUC
0-4h
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.
Publisher
Springer US,Springer,Springer Nature B.V
Subject
/ Antineoplastic Agents, Alkylating - administration & dosage
/ Antineoplastic Agents, Alkylating - adverse effects
/ Antineoplastic Agents, Alkylating - pharmacokinetics
/ Antineoplastic Agents, Alkylating - therapeutic use
/ Biomedical and Life Sciences
/ Biomedical Engineering and Bioengineering
/ Brain Neoplasms - drug therapy
/ Brain Neoplasms - metabolism
/ Cancer
/ Ethylenediaminetetraacetic acid
/ Gliomas
/ Humans
/ Lomustine - administration & dosage
/ Lomustine - pharmacokinetics
/ Male
/ Mice
/ Pharmacy
/ Tumors
