Objective: Ferulic acid (Fer) displays antioxidant/anti-inflammatory properties useful against neurodegenerative diseases. To increase Fer uptake and its central nervous system residence time, a dimeric prodrug, optimizing the Fer loading on nasally administrable solid lipid microparticles (SLMs), was developed. Methods: The prodrug was synthesized as Fer dimeric conjugate methylated on the carboxylic moiety. Prodrug antioxidant/anti-inflammatory properties and ability to release Fer in physiologic environments were evaluated. Tristearin or stearic acid SLMs were obtained by hot emulsion technique. In vivo pharmacokinetics were quantified by HPLC. Results: The prodrug was able to release Fer in physiologic environments (whole blood and brain homogenates) and induce in vitro antioxidant/anti-inflammatory effects. Its half-life in rats was 18.0 ± 1.9 min. Stearic acid SLMs, exhibiting the highest prodrug loading and dissolution rate, were selected for nasal administration to rats (1 mg/kg dose), allowing to obtain high prodrug bioavailability and prolonged residence in the cerebrospinal fluid, showing AUC (Area Under Concentration) values (108.5 ± 3.9 μg∙mL-1∙min) up to 30 times over those of Fer free drug, after its intravenous/nasal administration (3.3 ± 0.3/5.16 ± 0.20 μg∙mL-1∙min, respectively) at the same dose. Chitosan presence further improved the prodrug brain uptake. Conclusions: Nasal administration of prodrug-loaded SLMs can be proposed as a noninvasive approach for neurodegenerative disease therapy.

Dimeric ferulic acid conjugate as a prodrug for brain targeting after nasal administration of loaded solid lipid microparticles

Botti, Giada
Primo
Membro del Collaboration Group
;
Bianchi, Anna
Secondo
Membro del Collaboration Group
;
Dalpiaz, Alessandro
Membro del Collaboration Group
;
Tedeschi, Paola
Membro del Collaboration Group
;
Albanese, Valentina
Membro del Collaboration Group
;
Beggiato, Sarah
Membro del Collaboration Group
;
Pavan, Barbara
Ultimo
Membro del Collaboration Group
2023

Abstract

Objective: Ferulic acid (Fer) displays antioxidant/anti-inflammatory properties useful against neurodegenerative diseases. To increase Fer uptake and its central nervous system residence time, a dimeric prodrug, optimizing the Fer loading on nasally administrable solid lipid microparticles (SLMs), was developed. Methods: The prodrug was synthesized as Fer dimeric conjugate methylated on the carboxylic moiety. Prodrug antioxidant/anti-inflammatory properties and ability to release Fer in physiologic environments were evaluated. Tristearin or stearic acid SLMs were obtained by hot emulsion technique. In vivo pharmacokinetics were quantified by HPLC. Results: The prodrug was able to release Fer in physiologic environments (whole blood and brain homogenates) and induce in vitro antioxidant/anti-inflammatory effects. Its half-life in rats was 18.0 ± 1.9 min. Stearic acid SLMs, exhibiting the highest prodrug loading and dissolution rate, were selected for nasal administration to rats (1 mg/kg dose), allowing to obtain high prodrug bioavailability and prolonged residence in the cerebrospinal fluid, showing AUC (Area Under Concentration) values (108.5 ± 3.9 μg∙mL-1∙min) up to 30 times over those of Fer free drug, after its intravenous/nasal administration (3.3 ± 0.3/5.16 ± 0.20 μg∙mL-1∙min, respectively) at the same dose. Chitosan presence further improved the prodrug brain uptake. Conclusions: Nasal administration of prodrug-loaded SLMs can be proposed as a noninvasive approach for neurodegenerative disease therapy.
2023
Botti, Giada; Bianchi, Anna; Dalpiaz, Alessandro; Tedeschi, Paola; Albanese, Valentina; Sorrenti, Milena; Catenacci, Laura; Bonferoni, Maria Cristina; Beggiato, Sarah; Pavan, Barbara
File in questo prodotto:
File Dimensione Formato  
Dimeric ferulic acid_Exp_Op_Drug_Del_2023.pdf

solo gestori archivio

Descrizione: Articolo Principale
Tipologia: Full text (versione editoriale)
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 5.66 MB
Formato Adobe PDF
5.66 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2530415
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact