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Controlled Release and Delivery Systems
Design, fabrication, and in vitro evaluation of nanoceria-loaded nanostructured lipid carriers for the treatment of neurological diseases matteo battaglini, Christos Tapeinos, Ivana Cavaliere, Attilio Marino, Andrea Ancona, Nadia Garino, Valentina Cauda, Francisco Palazon, Doriana Debellis, and Gianni Ciofani ACS Biomater. Sci. Eng., Just Accepted Manuscript • DOI: 10.1021/ acsbiomaterials.8b01033 • Publication Date (Web): 20 Dec 2018 Downloaded from http://pubs.acs.org on December 20, 2018
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ACS Biomaterials Science & Engineering
Design, fabrication, and in vitro evaluation of nanoceria-loaded nanostructured lipid carriers for the treatment of neurological diseases Matteo Battaglinia,b,*, Christos Tapeinosa,*, Ivana Cavalierec, Attilio Marinoa, Andrea Anconad, Nadia Garinod,e, Valentina Caudad,e, Francisco Palazonf, Doriana Debellisg, Gianni Ciofania,c,* aIstituto
Italiano di Tecnologia, Smart Bio-Interfaces, Viale Rinaldo Piaggio 34, 56025 Pontedera
(Pisa), Italy bScuola
Superiore Sant’Anna, The Biorobotics Institute, Viale Rinaldo Piaggio 34, 56025 Pontedera
(Pisa), Italy cPolitecnico
di Torino, Department of Mechanical and Aerospace Engineering, Corso Duca degli
Abruzzi 24, 10129 Torino, Italy dPolitecnico
di Torino, Department of Applied Science and Technology, Corso Duca degli Abruzzi
24, 10129 Torino, Italy eIstituto
Italiano di Tecnologia, Center for Sustainable Future Technologies, Corso Trento 21,
10129 Torino, Italy fIstituto
Italiano di Tecnologia, Nanochemistry, Via Morego 30, 16163 Genova, Italy
gIstituto
Italiano di Tecnologia, Electron Microscopy Facility, Via Morego 30, 16163 Genova, Italy
*Corresponding Authors e-mails:
[email protected];
[email protected];
[email protected] 1 ACS Paragon Plus Environment
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Abstract Neurodegenerative diseases comprise a large group of disorders characterized by a dramatic synaptic connections loss, occurring as a result of neurodegeneration, which is closely related to the overproduction of reactive oxygen and nitrogen species. Up to date, the treatment of neurodegenerative diseases has been limited mostly because of the inability of the synthesized delivery systems to cross the blood-brain barrier, and to successfully deliver their therapeutic cargo to the diseased tissue. Taking into consideration the aforementioned limitations, we designed a lipid-based nanotherapeutic vector comprised of biomimetic lipids and CeO2 nanoparticles (nanoceria, NC). NC have shown to be a promising tool for the treatment of several pathological conditions ranging from cancer to neurological diseases, mainly because of their antioxidant properties, while lipid-based structures have been shown to have an inherent ability to cross the blood-brain barrier. The lipid-based nanotherapeutics were successfully fabricated using a combination of ultrasonication and high-pressure homogenization techniques, and were fully characterized morphologically and physicochemically. Their antioxidant ability was demonstrated using electron paramagnetic resonance spectroscopy and antioxidant assays. These innovative nanotherapeutics demonstrated a higher colloidal stability compared to free NC, preserving at the same time their antioxidant properties. Finally, the ability of the lipid carriers to cross a model of the blood-brain barrier and to be internalized by neurons, acting both as a neuroprotective and proneurogenic agent, was demonstrated using in vitro single- and triple-culture systems.
Key-words: Cerium oxide nanoparticles; antioxidants; blood-brain barrier; nanostructured lipid carriers.
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ACS Biomaterials Science & Engineering
Introduction In recent years, CeO2 nanoparticles (nanoceria, NC) have gained the attention of the research community as a potential therapeutic agent for the treatment of several pathological conditions, including Alzheimer’s disease,1 Parkinson’s disease,2 stroke,3 and different forms of cancer.4,5 This is mainly due to NC unique characteristics that distinguish them from other antioxidant compounds. NC have in fact several advantages over other reactive oxygen species (ROS) scavenging substances, like the possibility to act on a broad spectrum of different ROS including hydroxyl radicals (•OH), hydrogen peroxide (H2O2), and the superoxide anion (O2-).6 In addition, NC are able to self-regenerate thanks to the continuous redox cycle that involves Ce3+ and Ce4+ cations on their surface, granting NC the possibility to act as “virtually endless” antioxidant agent, even after a single administration.6 Despite their advantages, the exploitation of NC in biomedical applications has raised several concerns regarding their true effectiveness and toxicity.7 In fact, while it has been widely shown that NC are not intrinsically toxic or harmful,8 it has also been described how their antioxidant properties could not only be “compromised”, but also be “inverted” (changing NC from antioxidant agents to pro-oxidant compounds) resulting in adverse effects. This inversion can be affected by several factors, including aggregation levels,9 interaction with proteins and other macromolecules,10 and exposure to low pH due to a specific sub-cellular localization.11 In this work, we answered to these limitations by designing an innovative nanovector able to encapsulate NC (
