title: Resveratrol-loaded nanocarriers: formulation, optimization, characterization and in vitro toxicity on cochlear cells.
abstract: The present work aimed to investigate the suitability of polymeric nanoparticles (NPs) loaded with resveratrol (RES) for drug delivery to cochlear cells. RES-loaded NPs were prepared by a solvent-diffusion method without surfactant. The Box-Behnken design was used to study the effect of the formulation variables on the particle mean diameter (PMD), polydispersity index (PDI), zeta-potential (ζ), percent drug encapsulation efficiency (EE%), and ratio between NP size before and after freeze-drying (Sf/Si). The physicochemical stability of the RES-loaded NPs during freeze-drying was investigated using four well-known cryoprotectants (i.e., lactose, mannitol, sucrose, and trehalose) at different concentrations. The RES-loaded NPs were also characterized by powder X-ray diffraction (PXRD) and in vitro drug release studies. Finally, the in vitro toxicity of the synthesized NPs was evaluated on two cochlear cell lines: HEI-OC1 and SVK-1 cells. The optimal formulation (desirability: 0.86) had 135.5±37.3nm as PMD, 0.126±0.080 as PDI, -26.84±3.31mV as ζ, 99.83±17.59% as EE%, and 3.30±0.92 as Sf/Si ratio. The PMD and PDI of the RES-loaded NPs were maintained within the model space only when trehalose was used at concentrations higher than 15% (w/v). Results from the in vitro cytotoxicity studies showed that blank NPs did not alter the viability of both cells lines, except for concentrations higher than 600μg/mL. However, the cell viability was significantly decreased at high concentrations of native RES (>50μM, p<0.05) in both cell lines. Overall, the results suggested that the RES-loaded polymeric NPs could be a suitable template for cochlea antioxidant delivery and otoproctection.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, via G. Colombo, 71, 20133 Milan Italy.
authors.forename: Umberto M
authors.initials: UM
authors.lastname: Musazzi
authors.affiliation: Laboratory of Future Nanomedicines and Theoretical Chronopharmaceutics, Division of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Ibrahima
authors.initials: I
authors.lastname: Youm
authors.affiliation: Department of Geosciences, University of Missouri-Kansas City, 420 Flarsheim Hall, 5110 Rockhill Rd., Kansas City, MO 64110, USA.
authors.forename: James B
authors.initials: JB
authors.lastname: Murowchick
authors.affiliation: Laboratory of Future Nanomedicines and Theoretical Chronopharmaceutics, Division of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Miezan J
authors.initials: MJ
authors.lastname: Ezoulin
authors.affiliation: Laboratory of Future Nanomedicines and Theoretical Chronopharmaceutics, Division of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO 64108, USA. Electronic address: youanb@umkc.edu.
authors.forename: Bi-Botti C
authors.initials: BB
authors.lastname: Youan
mesh_terms: D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003051:Cochlea / Q000187:drug effects / Q000473:pathology; D003451:Cryoprotective Agents / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry / Q000633:toxicity*; D005612:Freeze Drying; D006801:Humans; D007700:Kinetics; D053758:Nanoparticles / Q000737:chemistry*; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D018675:Toxicity Tests; D014961:X-Ray Diffraction
chemical_list: D003451:Cryoprotective Agents; D004337:Drug Carriers; D013267:Stilbenes; D000077185:Resveratrol
keywords: Box–Behnken design; Ototoxicity; Polymeric nanoparticles; Resveratrol; Trehalose