Research paperMesoporous zirconia nanoparticles as drug delivery systems: Drug loading, stability and release
Graphical abstract
Introduction
The most common methods to administer drugs include swallowing and injecting. Between them, traditional drugs available now for oral administrations are not always the optimal formulation. For example, lipophilic oral administered drugs are often considered a challenging task in terms of achieving systemic absorption. In particular, these drugs belong to Biopharmaceutical Classification System (BCS) II, having limited dissolution rate [1]. For pharmaceutical companies, carriers to deliver these API can be a possible solution to overcome the problem of their consequent low bioavailability [2]. These opened the way to drug delivery systems (DDS) and nanotechnologies, whose high surface area and the plethora of possible surface modifications can adsorb and control release conditions for molecules of interest [2,3]. Recent studies are focused on the employment of nanoparticles as DDS and underlined the main advantages of mesoporous carriers based on their structural parameters, such as size, surface area, pore volume and pore distribution. As long as silica nanoparticles are concerned, typical properties are the surface area that often exceed 1000 m2/g and pore volume in the range 0.5–1.0 cm3/g [[4], [5], [6], [7], [8], [9], [10], [11], [12]]. These specific features are fundamental to host molecules of different size, shape and steric hindrance. Other physical-chemical properties, such as surface charge or the presence of specific functional groups, can be properly modified to specifically load molecules with peculiar features. The possibility to functionalize with organic moieties both the inner and outer surface of the nanoparticles (NPs) makes them extremely versatile materials for further investigations [7]. For example, surfaces can be made hydrophobic or hydrophilic, or the presence of organic residues could increase the affinity for a specific molecular target or influence the bioavailability or the biodistribution of the NPs. Moreover, different functionalizations could coexist on the same surface, broadening the field of the possible applications [8,9]. In particular, well-known titanium oxide or silicon dioxide NPs could enable sustained and controlled release of the drugs at the site of interest while preserving the stability of the loaded molecules and enhancing their bio-availability for a prolonged time [[10], [11], [12]]. Further advantages could be an improved solubility and biological membrane permeability, a better temporal stability and enhanced therapeutic performance of the drugs, protecting them from degradation. For some specific applications, bio-inert mesoporous carriers could therefore be an interesting choice [1].
While mesoporous silica NPs as DDS has been a highly investigated field of research thanks to the ease of modification of the properties of these NPs, recently introduced Mesoporous Zirconia Nanoparticles (MZNs) have received much lower attention [[13], [14], [15], [16], [17], [17]a), [17]b), [18], [19], [20]]. Zirconia is a well-known non-toxic biocompatible material exploited for its properties as bulk, in particular in orthopedics and dentistry, just to name two of the most relevant applications [[21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]]. Regarding zirconia NPs, toxicological profile is first of all strongly dependent from their dimensions. For instance, two recent publications investigated ZrO2 NPs of <100 nm diameter observing toxicity on PC12 and N2a Cells and embryonic development of zebrafish, at concentrations of >31 μg/ml[33] and 0,5–1 μg/ml[34], respectively. Similar results were observed by other authors [35,36]. On the other hand, Yang et al. described intravenous administration of hollow ZrO2 nanoparticles whose diameter higher than 150 nm without observing toxicity up to 500 mg/kg in mice [37]. MZNs could show important advantages for in vivo biomedical applications and for drug loading processes [16]. Recently our group reported about the controlled synthesis of new MZNs and demonstrated their biocompatibility and cell permeability and degradability, making them an ideal candidate for theranostic applications [[17], [17]a), [17]b)]. Based on these results, to assess the real potentialities of MZNs as drug carrier, in the present contribution we report about our investigation on both the loading and the release properties as function of the medium and the molecular structure of the API investigated. In particular, a wide range of Active Pharmaceutical Ingredients (API) was considered characterized by a wide range of polarity, molecular weight, and presence of functional groups (ibuprofen, N-acetyl-l-cysteine, vancomycin, gentamycin, nitrofurantoin, and indomethacin; see Chart 1). Moreover, in consideration of the known acidic and hydrolytic activity of zirconia in aqueous media, we analysed by ESI-MS spectroscopy the integrity of the released API and their stability over time once loaded on the MZNs.
Section snippets
Materials
All reagents were ACS grade and were used as received. Deuterium oxide, methanol-d, dimethylformamide (DMF), acetone, ibuprofen (IBU), zirconium butoxide (ZB), 3-(Cyclohexylamino)-1-propanesulfonic acid (CAPS), sodium acetate, 4-(2-Hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES), phosphoric acid and acetonitrile HPLC grade were purchased from Sigma-Aldrich. N-acetyl Cysteine (NAC) was purchased from ABCR. Absolute ethanol (EtOH) was purchased from AnalaR Normapur; NaF, and NaCl from
Synthesis and characterization of MZNs
The synthesis of the MZNs was carried out as recently reported [38] (see experimental section) and repeated for multiple batches of about 250 mg each. SEM and TEM analyses showed well defined and well-separated porous spherical NPs (Fig. 1). High-resolution TEM analysis showed roughness on MZNs, probably due to their porosity and partial crystallinity as described below. Different synthesis batches gave good reproducibility, with an overall average diameter of 300 ± 70 nm38.
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Conclusions
In conclusion, we described the potentialities of MZNs as a drug carrier for a wide series of API, investigating in detail the loading capacity on the basis of different loading models, the release efficiency as a function of the structural properties of the API investigated, characterized by a wide variability of polarity, solubility and functional group. The integrity of the released drug from the DDS is fundamental for its application and local administration, to exploit its therapeutic
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
CRediT authorship contribution statement
Benedetta Leonetti: Conceptualization, Writing - review & editing, Investigation, Formal analysis. Alessandro Perin: Methodology, Data curation, Formal analysis. Emmanuele Kizito Ambrosi: Methodology, Data curation. Gabriele Sponchia: Methodology, Data curation, Formal analysis. Paolo Sgarbossa: Methodology, Data curation, Formal analysis. Andrea Castellin: Conceptualization, Funding acquisition. Pietro Riello: Conceptualization, Funding acquisition. Alessandro Scarso: Conceptualization,
Declaration of competing interest
The authors have no conflict of interest to declare.
Acknowledgements
The authors acknowledge Dr. D. Cristofori for TEM analyses and M. Marchiori for BET analyses. Università Ca’ Foscari, Ministero dell’Università e della Ricerca and Brenta srl are gratefully acknowledged for support.
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