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Background/Objectives: Drug repurposing explores new applications for approved medications, such as simvastatin (SV), a lipid-lowering drug that has shown anticancer potential but is limited by solubility and side effects. This study aims to enhance SV delivery and efficacy against lung cancer cells using bioactive lipid nanoparticles formulated with plant-derived monoterpenes as both nanostructuring agents and anticancer molecules. Methods: Lipid nanoparticles were produced by ultrasonication and characterized for morphology, size, zeta potential, and polydispersity index (PDI). Monoterpenes (linalool-LN-, limonene, 1,8-cineole) or Crodamol® were used as liquid lipids. Encapsulation efficiency (EE), release profiles, stability, biocompatibility, protein adsorption, cytotoxicity, and anticancer effects were evaluated. Results: The nanoparticles exhibited high stability, size: 94.2 ± 0.9–144.0 ± 2.6 nm, PDI < 0.3, and zeta potential: −4.5 ± 0.7 to −16.3 ± 0.8 mV. Encapsulation of SV in all formulations enhanced cytotoxicity against A549 lung cancer cells, with NLC/LN/SV showing the highest activity and being chosen for further investigation. Sustained SV release over 72 h and EE > 95% was observed for NLC/LN/SV. SAXS/WAXS analysis revealed that LN altered the crystallographic structure of nanoparticles. NLC/LN/SV demonstrated excellent biocompatibility and developed a thin serum protein corona in vitro. Cellular studies showed efficient uptake by A549 cells, G0/G1 arrest, mitochondrial hyperpolarization, reactive oxygen species production, and enhanced cell death compared to free SV. NLC/LN/SV more effectively inhibited cancer cell migration than free SV. Conclusions: NLC/LN/SV represents a promising nanocarrier for SV repurposing, combining enhanced anticancer activity, biocompatibility, and sustained stability for potential lung cancer therapy.
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; Scioli-Montoto, Sebastian 3
; Moreno, Ailin 4 ; Huck-Iriart, Cristián 5
; Ruiz, María Esperanza 3
; Cisneros, José S 2
; Lamas, Diego G 6
; Tau, Julia 4
; Gehring, Stephan 1
; Islan, Germán A 7
; Rodenak-Kladniew, Boris 4
1 Children’s Hospital, University Medical Center of the Johannes, Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany;
2 Instituto de Investigaciones Fisicoquímicas Teóricas y Aplicadas (INIFTA), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET)-Universidad Nacional de La Plata (UNLP), La Plata 1900, Buenos Aires, Argentina;
3 Laboratorio de Investigación y Desarrollo de Bioactivos (LIDeB), Departamento de Ciencias Biológicas, Facultad de Ciencias Exactas, Universidad Nacional de La Plata, La Plata 1900, Buenos Aires, Argentina;
4 Instituto de Investigaciones Bioquímicas de La Plata (INIBIOLP), Investigaciones Científicas y Tecnológicas (CONICET)-Universidad Nacional de La Plata (UNLP), CCT-La Plata, Facultad de Ciencias Médicas UNLP, La Plata 1900, Buenos Aires, Argentina;
5 Instituto de Tecnologías Emergentes y Ciencias Aplicadas (ITECA), Universidad Nacional de San Martín (UNSAM)--Investigaciones Científicas y Tecnológicas (CONICET), Escuela de Ciencia y Tecnología (ECyT), Laboratorio de Cristalografía Aplicada (LCA), Campus Miguelete, San Martín 1650, Buenos Aires, Argentina;
6 Instituto de Tecnologías Emergentes y Ciencias Aplicadas (ITECA), Universidad Nacional de San Martín (UNSAM)--Investigaciones Científicas y Tecnológicas (CONICET), Escuela de Ciencia y Tecnología (ECyT), Laboratorio de Cristalografía Aplicada (LCA), Campus Miguelete, San Martín 1650, Buenos Aires, Argentina;
7 Children’s Hospital, University Medical Center of the Johannes, Gutenberg University, Langenbeckstr. 1, 55131 Mainz, Germany;