Peptide-lipid nanoconstructs act site-specifically towards glioblastoma growth impairment

• Published in: European journal of pharmaceutics and biopharmaceutics 2020-10, Vol.155, p.177-189
• Main Authors: Basso, João, Mendes, Maria, Silva, Jessica, Sereno, José, Cova, Tânia, Oliveira, Rui, Fortuna, Ana, Castelo-Branco, Miguel, Falcão, Amílcar, Sousa, João, Pais, Alberto, Vitorino, Carla
• Format: Article
• Language: English
• Subjects: Drug repurposing; Glioblastoma; Hyaluronic acid; Surface modification; Targeting peptides; Ultra-small nanostructured lipid carriers
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2020.08.015

[Display omitted] •Surface-bioconjugated usNLCs prompted pre-clinical glioblastoma growth inhibition.•The hierarchical modification of the usNLCs led to a preferential brain targeting.•HA-cRGDfK-H7k(R2)2:HA-FA -surface modified usNLCs were well tolerated by mice.•Relevant biomarkers were identified as a potential glioblastoma signature. Ultra-small nanostructured lipid carriers (usNLCs) have been hypothesized to promote site-specific glioblastoma (GB) drug delivery. Envisioning a multitarget purpose towards tumor cells and microenvironment, a surface-bioconjugated usNLC prototype is herein presented. The comeback of co-delivery by repurposing atorvastatin and curcumin, as complementary therapy, was unveiled and characterized, considering colloidal properties, stability, and drug release behavior. Specifically, the impact of the surface modification of usNLCs with hyaluronic acid (HA) conjugates bearing the cRGDfK and H7k(R2)2 peptides, and folic acid (FA) on GB cells was sequentially evaluated, in terms of cytotoxicity, internalization, uptake mechanism and hemolytic character. As proof-of-principle, the biodistribution, tolerability, and efficacy of the nanocarriers were assessed, the latter in GB-bearing mice through magnetic resonance imaging and spectroscopy. The hierarchical modification of the usNLCs promotes a preferential targeting behavior to the brain, while simultaneously sparing the elimination by clearance organs. Moreover, usNLCs were found to be well tolerated by mice and able to impair tumor growth in an orthotopic xenograft model, whereas for mice administered with the non-encapsulated therapeutic compounds, tumor growth exceeded 181% in the same period. Relevant biomarkers extracted from metabolic spectroscopy were ultimately identified as a potential tumor signature.