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

Abstract

PurposeThe 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.MethodsMice 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.ResultsThe 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.ConclusionsParticulate drug formulations improved brain tumour therapy without major bone marrow toxicity.

Emerging Cellular Therapies for Glioblastoma Multiforme

“…However, it carries a 30% risk of causing severe hematological toxicity, so it is suggested only as the second-line treatment for recurrent GBM [ 5 ]. It is likely that the first-line agent for GBM, temozolomide, also carries a risk of dose-limiting bone marrow suppression [ 3 ]. Moreover, Houshyari et al concluded that systemic chemotherapy has no significant survival benefit for patients with GBM [ 6 ].…”

“…In order to bypass the detrimental hematotoxic effects of the current systemic chemotherapeutic regimen, many promising technologies have recently emerged, including the direct placing of Gliadel wafers (Arbor Pharmaceuticals, Atlanta, Georgia, US), a set of biological polymer discs containing carmustine, a nitrosourea, within the brain following tumor resection, and Molecular Envelope Technology (MET) nanoparticles [ 3 , 7 - 9 ].…”

“…In recent years, Fisusi et al have demonstrated that MET nanoparticles have significant efficacy in exposing GBM cells to a higher dosage of chemotherapeutic agents while limiting the myelosuppressive side effects in a mouse model [ 3 ]. These authors enveloped the chemotherapeutic agents in an engineered nanoparticle containing various amounts of hydrophilic and hydrophobic components [ 10 ].…”

“…Glioblastoma multiforme (GBM) is the most common type of malignant primary brain cancer in adults [ 1 - 3 ]. It is composed of highly malignant cells that display metastatic and angiogenic characteristics, making it resistant to current first-line chemotherapy with temozolomide, an alkylating agent [ 1 , 3 ]. A subtype of GBM, which is resistant to both temozolomide and radiotherapy, has also been described in the literature [ 1 ].…”

Facile aqueous, room temperature preparation of high transverse relaxivity clustered iron oxide nanoparticles

“…GCPQ consists of a glucosamine sugar backbone where, a fraction of the amine groups have been functionalised with either a long chained hydrophobic pendant group or a quaternary ammonium cation. Functionalisation in this way creates an amphiphilic polymer which self assembles into nanoparticles [35] and which enables drugs to cross biological barriers to produce formulations with a number of differentiating features [36][37][38]. The cationic polymer binds to the anionic surface of the precipitated SPIONs to form stable nano-sized clusters.…”