Lomustine Nanoparticles Enable Both Bone Marrow Sparing and High Brain Drug Levels - A Strategy for Brain Cancer Treatments

Pharmaceutical Research
Funmilola A FisusiIjeoma F Uchegbu

Abstract

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. 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. 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 dif...Continue Reading

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Citations

Jan 30, 2018·Nanomedicine·Funmilola A FisusiIjeoma F Uchegbu
Sep 28, 2017·Nanomedicine·Pablo Játiva, Valentín Ceña
Jul 26, 2019·Expert Opinion on Drug Delivery·Yongwhan ChoiKwangmeyung Kim
Feb 6, 2020·Cardiovascular & Hematological Agents in Medicinal Chemistry·Anupriya AnandAbimanyu Sugumaran
Mar 6, 2019·Nanomaterials·Sally Vanden-HehirAlison N Hulme
Jan 28, 2020·Journal of Chemotherapy·Vahid RezaeiFarzaneh Khademi
May 8, 2020·Molecular Pharmaceutics·Ramesh SoundararajanAndreas G Schätzlein

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Methods Mentioned

BETA
surgical resection
transmission electron microscopy
flow cytometry
scraping
confocal microscopy
electron microscopy

Software Mentioned

WinNonlin®
OSIRIX
Zen
SPSS
FL WinLab
Minitab®

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