Development and characterization of lipid nanocapsules loaded with iron oxide nanoparticles for magnetic targeting to the blood–brain barrier

Brain drug delivery is severely hindered by the presence of the blood–brain barrier (BBB). Its functionality relies on the interactions of the brain endothelial cells with additional cellular constituents, including pericytes, astrocytes, neurons, or microglia. To boost brain drug delivery, nanomedicines have been designed to exploit distinct delivery strategies, including magnetically driven nanocarriers as a form of external physical targeting to the BBB. Herein, a lipid-based magnetic nanocarrier prepared by a low-energy method is first described. Magnetic nanocapsules with a hydrodynamic diameter of 256.7 ± 8.5 nm (polydispersity index: 0.089 ± 0.034) and a ξ-potential of -30.4 ± 0.3 mV were obtained.

Transmission electron microscopy-energy dispersive X-ray spectroscopy analysis revealed efficient encapsulation of iron oxide nanoparticles within the oily core of the nanocapsules. Both thermogravimetric analysis and phenanthroline-based colorimetric assay showed that the iron oxide percentage in the final formulation was 12 wt.%, in agreement with vibrating sample magnetometry analysis, as the specific saturation magnetization of the magnetic nanocapsules was 12% that of the bare iron oxide nanoparticles.

Magnetic nanocapsules were non-toxic in the range of 50–300 μg/mL over 72 h against both the human cerebral endothelial hCMEC/D3 and Human Brain Vascular Pericytes cell lines. Interestingly, higher uptake of magnetic nanocapsules in both cell types was evidenced in the presence of an external magnetic field than in the absence of it after 24 h. This increase in nanocapsules uptake was also evidenced in pericytes after only 3 h. Altogether, these results highlight the potential for magnetic targeting to the BBB of our formulation.

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Phase inversion temperature method

Lipid nanocapsules loaded with iron oxide nanoparticles (15% (w/w)) were prepared by the low-energy phase inversion temperature (PIT) method with minor modifications [24]. Briefly, 84.6 mg of polyethylene glycol (15)-hydroxystearate (Kolliphor HS15, Sigma-Aldrich), 7.5 mg of soybean phospholipids with 70% phosphatidylcholine (Lipoid S75, Lipoïd), 102.8 mg of medium-chain triglycerides of caprylic and capric acids (Labrafac lipophile WL1349, Gattefossé), 296.2 mg of MilliQ water (Millipore) were mixed with 154 μL of a chloroform suspension of oleic acid-coated iron oxide nanoparticles (15%wt.). The mixture was gradually heated over the PIT of the system up to 90 °C to melt the lipids. Subsequently, the mixture was progressively cooled down until the PIT (74.8 ºC) was reached. Then, a rapid quench with 500 µL cold MilliQ water was applied to form the suspension of magnetic nanocapsules. Magnetic nanocapsules were maintained at 4 °C for 30 min to stabilize the nanocapsules and then purified by centrifugation (16,000 g, 150 min, 4 °C) and redispersed in Milli-Q water (Millipore) thrice. The final pellet was redispersed in 1 mL of MilliQ water. For biological studies, magnetic nanocapsules were labelled with the fluorescent Vybrant DiO cell-labelling dye (Invitrogen, V-22886) by incorporating in the formulation procedure 10 μL of this dye and then proceeding as previously reported.

Aparicio-Blanco, J., Pucci, C., De Pasquale, D. et al. Development and characterization of lipid nanocapsules loaded with iron oxide nanoparticles for magnetic targeting to the blood–brain barrier. Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01587-w