The shape of dendrimer amphiphiles has an unexpected effect on their self-assembly. A series of diaminobutane poly(propylenimine) generation 3 dendrimer (DAB-dendr-(NH(2))(16)) amphiphiles has been synthesized, bearing an average of five (PD5), three (PD3) and one (PD1) palmitoyl group(s) per dendrimer molecule. Additionally DAB-dendr-(NH(2))(16) was derivatized with a layer of poly(ethylene glycol) (PEG, degree of polymerization = 12) groups and conjugated to an average of 1 palmitoyl group at the PEG end (PPD1). A final amphiphile resulted from the conjugation of DAB-dendr-(NH(2))(16) with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-succinimidylpropionate (DSPE-PEG(3400)-SPA), i.e.: DPD5 (with 4 DSPE-PEG arms). The critical micellar concentration in aqueous media followed the trend: DPD5 < PD5 = PD3 < PD1 < PPD1 and amphiphiles eventually formed 10-20 nm monomolecular or multimolecular micelles and/or 200 nm spheres or tubules. Aggregation was entropy driven, as expected, for DPD5, PD5 and PD1 and enthalpy driven with the most hydrophilic compound PPD1, but was unexpectedly enthalpy driven for PD3. PD3 aggregates formed low capacity hydrophobic domains with a limited capacity for encapsulation of cyclosporine A; encapsulation levels (mole drug per mole polymer) were 0.099, 0.014, 0.099, and 0.735 for PD1, PD3, PD5, and DPD5 and, respectively. We conclude that star shaped amphiphiles such as PD3 are sterically hindered from self-assembling into high capacity hydrophobic domains in aqueous media. Amphiphile-membrane interactions were promoted by hydrophobic groups, but diminished by PEG moieties. DPD5 is the most suitable amphiphile for biomedical applications.

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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.

Self-assembly is fundamental to the biological function of cells and the fabrication of nanomaterials. However, the origin of the shape of various self-assemblies, such as the shape of cells, is not altogether clear. Polymeric, oligomeric, or low molecular weight amphiphiles are a rich source of nanomaterials, and controlling their self-assembly is the route to tailored nanosystems with specific functionalities. Here, we provide direct evidence that a particular molecular architecture, polymeric branching, leads to a rare form of self-assembly, the planar nanodisc. Cholesterol containing self-assemblies formed from amphiphilic linear or branched cetyl poly(ethylenimine) (Mn approximately 1000 Da) or amphiphilic cetyl poly(propylenimine) dendrimer derivatives (Mn approximately 2000 Da) show that branching, by reducing the hydrophilic headgroup area, alters the shape of the self-assemblies transforming closed 60 nm spherical bilayer vesicles to rare 50 nm x 10 nm planar bilayer discs. Increasing the hydrophilic headgroup area, by the inclusion of methoxy poly(ethylene glycol) moieties into the amphiphilic headgroup, transforms the planar discs to 100 nm spherical bilayer vesicles. This study provides insight into the key role played by molecular shape on molecular self-organization into rare nanodiscs.