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

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.

Nanomedicines and nanodiagnostics come of age.

Although the employment of biomedical colloids is not new, modern biomedical colloids, termed nanomedicines and nanodiagnostics, have enhanced functionality, in that the drug compound/diagnostic probe entrapped within the nanoparticle takes on the properties of the encapsulating nanoparticle. The nanoparticle's properties are specifically dictated by its size, shape, and surface chemistry; the net result in the case of medicines is an alteration of the drug's intrinsic pharmacokinetics and eventual drug targeting to the areas of pathology. The first nanomedicines, which really altered the pharmacokinetics of a drug molecule, were licensed in the early-to-mid 1990s. Since this time, these pioneering nanomedicines: liposomal doxorubicin (Doxil) and liposomal amphotericin B (Ambisome), have been followed by medicines such as albumin-stabilised paclitaxel (Abraxane) and biomedical sentinel lymph node nanodiagnostics such as Sienna+. The clinical trials database is heavily populated with nanosystem trials--an indication that these agents are growing in stature and will be utilised in an expanding list of clinical situations. Although the intravenous route is the route of choice for the current nanoparticles, new administration routes such as the pulmonary route are already in clinical testing, and researchers are working on the preclinical development of oral nanomedicines.

Enhanced oral absorption of hydrophobic and hydrophilic drugs using quaternary ammonium palmitoyl glycol chitosan nanoparticles.

As 95% of all prescriptions are for orally administered drugs, the issue of oral absorption is central to the development of pharmaceuticals. Oral absorption is limited by a high molecular weight (>500 Da), a high log P value (>2.0) and low gastrointestinal permeability. We have designed a triple action nanomedicine from a chitosan amphiphile: quaternary ammonium palmitoyl glycol chitosan (GCPQ), which significantly enhances the oral absorption of hydrophobic drugs (e.g., griseofulvin and cyclosporin A) and, to a lesser extent, the absorption of hydrophilic drugs (e.g., ranitidine). The griseofulvin and cyclosporin A C(max) was increased 6- and 5-fold respectively with this new nanomedicine. Hydrophobic drug absorption is facilitated by the nanomedicine: (a) increasing the dissolution rate of hydrophobic molecules, (b) adhering to and penetrating the mucus layer and thus enabling intimate contact between the drug and the gastrointestinal epithelium absorptive cells, and (c) enhancing the transcellular transport of hydrophobic compounds. Although the C(max) of ranitidine was enhanced by 80% with the nanomedicine, there was no appreciable opening of tight junctions by the polymer particles.