Colloids and Surfaces B: Biointerfaces 155 (2017) 238–247 Contents lists available at ScienceDirect Colloids and Surfaces B: Biointerfaces jo ur nal ho me p ag e: www.elsevier.com/locate/colsurfb Nanoencapsulation strategies for the delivery of novel bifunctional antioxidant/1 selective ligands Claudia Carbone a,∗ , Emanuela Arena a , Veronica Pepe a , Orazio Prezzavento a , Ivana Cacciatore b , Hasan Turkez b,c , Agostino Marrazzo a , Antonio Di Stefano b , Giovanni Puglisi a a Department of Drug Sciences, University of Catania, v.le A. Doria 6, 95100, Catania, Italy b Department of Pharmacy, University G. d’Annunzio Chieti-Pescara, Via dei Vestini 31, 66100, Chieti, Italy c Department of Molecular Biology and Genetics, Erzurum Technical University, Erzurum 25240, Turkey a r t i c l e i n f o Article history: Received 24 November 2016 Received in revised form 7 April 2017 Accepted 10 April 2017 Available online 12 April 2017 Keywords: Nanoparticles NLC NC Turbiscan Nanotoxicity Total antioxidant capacity Total oxidant status Sigma receptors Lipoic acid a b s t r a c t Nowadays sigma-1 receptors are considered as new therapeutic objectives for central nervous system neurodegenerative diseases. Among different molecules, alpha lipoic acid has been identified as a nat- ural potent antioxidant drug, whose therapeutic efficacy is limited by its many drawbacks, such as fast metabolism, poor bioavailability and high physico-chemical instability. Alfa-lipoic acid derivatives have been recently developed demonstrating their neuroprotective activity and effectiveness in different types of oxidative stress. In this work, two derivatives containing an amide or an ester functional group with different lipophilicity, were selected for their important affinity for sigma-1 receptors. Herein, in order to improve the in vitro stability and antioxidant effectiveness of alpha-lipoic acid derivatives, we focused our efforts in the nanoencapsulation strategies. Aqueous-core nanocapsules for the delivery of the hydrophilic compound and nanostructured lipid carrier for the lipophilic derivative, were properly designed and prepared using a direct or inverse eco-friendly organic solvent-free procedure. All nanosystems were characterized in terms of mean size, polydispersity, stability, morphology, encapsulation efficiency and in vitro release profiles. In order to evaluate the nanocarriers biocompatibility and antioxidant effec- tiveness, in vitro biological studies (cell viability, total antioxidant capacity and total oxidative status) were developed on primary human whole blood cell cultures, on both unloaded and derivatives-loaded nanodevices. © 2017 Elsevier B.V. All rights reserved. Abbreviations: ALA, alpha lipoic acid; BS, back scattering; Brij ® 98, polyoxyethy- lene (20) oleyl ether, Oleth-20; Cutina CP, cetyl palmitate; Cryo–TEM, cryogenic transmission electron microscopy; Da, PDI after freeze-thawing; Db, PDI before freeze-thawing; DDAB, dimethyldioctadecylammonium bromide; DDS, drug deliv- ery systems; T, variation of transmission; EE%, percentage of encapsulation efficiency; FDA, food and drug administration; HWBC, human whole-blood culture; HPLC, high performance liquid cromatography; IPS, isopropyl stearate; LDH, lactate dehydrogenase assay; MTT, 3(4,5-dimethyl-thiazol-2-yl)2,5-diphenyl-tetrazolium bromide; NC, aqueous-core nanocapsule; NLC, nanostructured lipid carrier; Pa, par- ticles diameter after freeze-thawing; Pb, particles diameter before freeze-thawing; P1, hydrophilic compound; P2, lipophilic compound; PCS, photon correlation spec- troscopy; PHWB, primary human whole blood; PDI, polidispersity index; PIT, phase inversion temperature; PLA, polylactic acid or polylactide; ROS, reactive oxygen species; S.D., standard deviation; Span ® 80, sorbitan monooleate; 1R, sigma 1 recep- tor; T, transmission; TAC, total antioxidant capacity; TAGS, turbiscan AG Station; TCT, caprylic/capric triglyceride, Tegosoft ® CT; Tegin O, gliceryl monooleate; TOS, total oxidant status; TSI, turbiscan stability index; Tween ® 80, polysorbate 80; Zave, mean particle size; ZP, zeta potential; W/O, water in oil. ∗ Corresponding author at: Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125, Italy. E-mail address: ccarbone@unict.it (C. Carbone). 1. Introduction In the last decade there has been a renewed interest from the research world in natural compounds, with particular attention to their nanoencapsulation into drug delivery systems (DDS), as demonstrated by the increasing number of scientific publications (Supplementary Fig. 1). Natural compounds are considered as a potential reservoir of innovative therapeutic strategy to human health, with the prospect of integrating and sometimes replac- ing conventional drugs with a consequent improvement of the patient’s compliance and reduction of side effects both on human health and the environmental impact [1–3]. Different natural molecules such as melatonin, curcumin, quercetin, idebenone, ferulic acid and lipoic acid, have been successfully investigated for the potential treatment of human neurodegenerative diseases related to high levels of oxidative stress [4–13]. Alpha lipoic acid (ALA) is an amphiphilic potent natural antioxidant with a central role in energy metabolism, important neuroprotection properties and recently showed to have antimutagenic and anticarcinogenic http://dx.doi.org/10.1016/j.colsurfb.2017.04.016 0927-7765/© 2017 Elsevier B.V. All rights reserved.