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Abstract
Recently, the use of mammalian target of rapamycin (mTOR) inhibitors, in particular rapamycin (Rp), has been suggested to improve the treatment of neurodegenerative diseases. However, as Rp is a strong immunosuppressant, specific delivery to the brain has been postulated to avoid systemic exposure. In this work, we fabricated new Rp loaded solid lipid nanoparticles (Rp-SLN) stabilized with polysorbate 80 (PS80), comparing two different methods and lipids. The formulations were characterized by differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), wide angle X-ray scattering (WAXS), cryo-transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS) and particle tracking. In vitro release and short-term stability were assessed. Biological behavior of Rp-SLN was tested in SH-SY5Y neuroblastoma cells. The inhibition of mTOR complex 1 (mTORC1) was evaluated over time by a pulse-chase study compared to free Rp and Rp nanocrystals. Compritol Rp-SLN resulted more stable and possessing proper size and surface properties with respect to cetyl palmitate Rp-SLN. Rapamycin was entrapped in an amorphous form in the solid lipid matrix that showed partial crystallinity with stable Lβ, sub-Lα and Lβ′ arrangements. PS80 was stably anchored on particle surface. No drug release was observed over 24 h and Rp-SLN had a higher cell uptake and a more sustained effect over a week. The mTORC1 inhibition was higher with Rp-SLN. Overall, compritol Rp-SLN show suitable characteristics and stability to be considered for further investigation as Rp brain delivery system.
Highlights
Nanoparticles represent one of the most innovative non-invasive approaches for the delivery and targeting of drugs and pharmacologically active substances
We report for the first time the development of rapamycin (Rp) solid lipid nanoparticles (SLN) formulations for future application in specific Rp brain delivery for the treatment of neurodegenerative disorders
The different SLN batches produced using the Ultrasound-Assisted Emulsion/evaporation (UAEe) and cold High Pressure Homogenization/evaporation methods are displayed in SLN were large and sometimes aggregated, with mean hydrodynamic diameter (MHD) between 120 and 750 nm and polydispersity index (PI) > 0.4. This behavior may be ascribable to the high shear and cavitation produced at 1500 bars during homogenization cycles that can induce the formation of ultrafine droplets prone to aggregation and fusion upon the solvent evaporation step
Summary
Nanoparticles represent one of the most innovative non-invasive approaches for the delivery and targeting of drugs and pharmacologically active substances. Drug delivery across the blood-brain barrier is a major limitation in the treatment of central nervous. Solid lipid nanoparticles (SLN) are promising candidates to treat neurodegenerative disorders to their brain targeting potential [2]. SLN are colloidal systems made of a homogenous solid lipid matrix, commonly stabilized with surfactants. These nanocarriers show high safety, scalability as well as a specific brain uptake mechanism [3]. SLN are known to favor specific adsorption of apolipoproteins on the particle surface when functionalized, in particular with polysorbate 80 (PS80), and this allows binding to the relative receptors on the blood-brain barrier, which triggers transcytosis [4,5]
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