Astaxanthin-Loaded Stealth Lipid Nanoparticles (AST-SSLN) As Potential Carriers for the Treatment of Alzheimer’S Disease: Formulation Development and Optimization
Total Page：16
File Type：pdf, Size：1020Kb
nanomaterials Article Astaxanthin-Loaded Stealth Lipid Nanoparticles (AST-SSLN) as Potential Carriers for the Treatment of Alzheimer’s Disease: Formulation Development and Optimization Debora Santonocito 1,†, Giuseppina Raciti 1,†, Agata Campisi 1, Giovanni Sposito 1, Annamaria Panico 1, Edy Angela Siciliano 1, Maria Grazia Sarpietro 1 , Elisabetta Damiani 2 and Carmelo Puglia 1,* 1 Department of Drug Science and Health, University of Catania, Viale Andrea Doria 6, 95125 Catania, Italy; [email protected] (D.S.); [email protected] (G.R.); [email protected] (A.C.); [email protected] (G.S.); [email protected] (A.P.); [email protected] (E.A.S.); [email protected] (M.G.S.) 2 Department of Life and Environmental Sciences, Polytechnic University of Marche, 60121 Ancona, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-0957-384-206 † These authors equally contributed to the work. Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder associated with marked oxida- tive stress at the level of the brain. Recent studies indicate that increasing the antioxidant capacity could represent a very promising therapeutic strategy for AD treatment. Astaxanthin (AST), a powerful natural antioxidant, could be a good candidate for AD treatment, although its use in clinical practice is compromised by its high instability. In order to overcome this limit, our attention focused on the development of innovative AST-loaded stealth lipid nanoparticles (AST-SSLNs) able to im- Citation: Santonocito, D.; Raciti, G.; prove AST bioavailability in the brain. AST-SSLNs prepared by solvent-diffusion technique showed Campisi, A.; Sposito, G.; Panico, A.; technological parameters suitable for parenteral administration (<200 nm). Formulated nanosystems Siciliano, E.A.; Sarpietro, M.G.; Damiani, E.; Puglia, C. Astaxanthin- were characterized by calorimetric studies, while their toxicological profile was evaluated by the MTT Loaded Stealth Lipid Nanoparticles assay on the stem cell line OECs (Olfactory Ensheathing Cells). Furthemore, the protective effect of (AST-SSLN) as Potential Carriers for the nanocarriers was assessed by a long-term stability study and a UV stability assay confirming that the Treatment of Alzheimer’s Disease: the lipid shell of the nanocarriers was able to preserve AST concentration in the formulation. SSLNs Formulation Development and were also capable of preserving AST’s antioxidant capacity as demonstrated in the oxygen radical Optimization. Nanomaterials 2021, 11, absorbance capacity (ORAC) assay. In conclusion, these preliminary studies outline that SSLNs could 391. https://doi.org/10.3390/nano be regarded as promising carriers for systemic administration of compounds such as AST aimed at 11020391 AD treatment. Received: 28 December 2020 Keywords: astaxanthin; stealth system; SLN; Alzheimer’s disease; ORAC; parenteral administration Accepted: 29 January 2021 Published: 3 February 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in published maps and institutional affil- Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by cognitive iations. impairments. The classical symptoms of the disease include gradual deterioration of mem- ory and language. This disease is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal tau neurofibrillary tangles in the cerebral cortex [1]. The main cause of the pathogenetic process of AD consists in a marked oxidative stress at the level of the encephalic cells affected by the neurodegenerative process [2]. Nowadays, there Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. is no effective pharmacotherapy for the treatment of AD. Recent research and epidemio- This article is an open access article logical studies indicate that potentiating the central nervous system’s (CNS) antioxidant distributed under the terms and capacity, through the administration of antioxidant compounds, such as astaxanthin, could conditions of the Creative Commons represent a promising strategy for the treatment of neurodegenerative disorders such as Attribution (CC BY) license (https:// AD [3,4]. 0 0 0 creativecommons.org/licenses/by/ Astaxanthin (3,3 -dihydroxy-β, β -carotene-4,4 -dione; AST) is a fat-soluble orange- 4.0/). red colored pigment extracted from Haematococcus pluvialis, a unicellular biflagellate green Nanomaterials 2021, 11, 391. https://doi.org/10.3390/nano11020391 https://www.mdpi.com/journal/nanomaterials Nanomaterials 2021, 11, x FOR PEER REVIEW 2 of 18 astaxanthin, could represent a promising strategy for the treatment of neurodegenerative Nanomaterials 2021disorders, 11, 391 such as AD [3,4]. 2 of 17 Astaxanthin (3,3′-dihydroxy-β, β′-carotene-4,4′-dione; AST) is a fat-soluble orange- red colored pigment extracted from Haematococcus pluvialis, a unicellular biflagellate green microalga. It is amicroalga. carotenoid It belonging is a carotenoid to the belonging family of to the the Xanthophylls family of the andXanthophylls it is responsi-and it is responsible ble for the coloringfor theof some coloring fish, ofincluding some fish, salmon including and shellfish salmon [5]. and AST shellfish exhibits [5]. powerful AST exhibits powerful antioxidant activityantioxidant and possesses activity many and possesses valuable manytherapeutical valuable functions, therapeutical such functions,as anti- such as anti- aging, anticanceraging, [6–8], anticancer and neuroprotective [6–8], and neuroprotective effects [9]. The effectsremarkable [9]. The scavenging remarkable activ- scavenging activity ity of AST is dueof to AST its chemical is due to structure its chemical which structure traps radicals which traps in the radicals polyene in chain the polyene (Figure chain (Figure1) . 1). It is a highly Itlipophilic is a highly molecule, lipophilic but molecule,the presence but of the two presence terminal of hydrophilic two terminal groups hydrophilic groups determines a slightdetermines solubility a slightin water. solubility in water. FigureFigure 1. Chemical 1. Chemical structure structure of astaxanthin of astaxanthin (AST). (AST). This dual natureThis and dualits small nature size and allow its it small to easily size permeate allow it tocell easily membranes. permeate In cellfact, membranes. In it is a carotenoidfact, that it carries is a carotenoid out its antioxidant that carries and out anti-inflammatory its antioxidant andactions anti-inflammatory at the level actions at of the eyes, the thebrain level and ofthe the CNS, eyes, as it the ma brainnages andto cross the CNS,the blood–brain as it manages barrier to and cross the the blood–brain blood–retinal barrier.barrier Many and the studies blood–retinal have indicated barrier. Manythat AST studies is a havepromising indicated biologically that AST is a promising active compoundbiologically for the treatment active compound of AD. Wang for and the treatmentcoworkers ofreported AD. Wang that andAST coworkerspro- reported tected neuroblastomathat AST cells protected against neuroblastomaAβ-induced oxidative cells against cell death Aβ-induced through oxidativeinduction cell of death through the antioxidant inductionenzyme HO-1 of the expression antioxidant [10]. enzyme In particular, HO-1 expression AST is able [10 to]. prevent In particular, amy- AST is able to loid-β (Aβ) accumulationsprevent amyloid- throughβ (Atheβ formation) accumulations of hydrogen through bonds the formationand Van der of Waals hydrogen bonds and β interactions withVan Aβ der [11–15]. Waals Furthermore, interactions with it is Areported[11–15 that]. Furthermore, AST is able itto is reduce reported the that AST is able ischemia-relatedto injury reduce in thebrain ischemia-related tissue, mainly through injury in the brain inhibition tissue, mainlyof oxidative through stress the inhibition of [16]. oxidative stress [16]. Although AST possesses a high pharmacological potential, it has no applications Although AST possesses a high pharmacological potential, it has no applications in in the clinical setting due to poor drug stability. The presence of C=C double bonds in the clinical setting due to poor drug stability. The presence of C=C double bonds in the the chemical structure of carotenoids makes the molecule sensitive to oxidation, to air chemical structure of carotenoids makes the molecule sensitive to oxidation, to air and to and to photo-oxidation. All these factors can cause their conversion into a mixture of photo-oxidation. All these factors can cause their conversion into a mixture of stereoiso- stereoisomers (with trans-cis isomerization). Furthermore, AST is sensitive to thermal mers (with trans-cis isomerization). Furthermore, AST is sensitive to thermal degradation degradation and it is poorly water soluble [17]. Therefore, innovative strategies are required and it is poorly water soluble [17]. Therefore, innovative strategies are required in order in order to overcome the limits of this interesting natural active compound, thus allowing to overcome the limits of this interesting natural active compound, thus allowing its ex- its exploitation in the therapeutic field [18,19]. ploitation in the therapeutic field [18,19]. Recently, nanomedicine, in particular the use of solid lipid nanoparticles (SLNs), is Recently, nanomedicine, in particular the use of solid lipid nanoparticles (SLNs), is attracting considerable attention due to its potential advantages for enhancing pharma- attracting considerable attention