Publications
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A lab-on-a-chip system with an embedded porous membrane-based impedance biosensor array for nanoparticle risk assessment on placental Bewo trophoblast cells
Schuller P., Rothbauer M., Kratz S.R.A., Höll G., Taus P., Schinnerl M., Genser J., Bastus N., Moriones O.H., Puntes V., Huppertz B., Siwetz M., Wanzenböck H., Ertl P. Sensors and Actuators, B: Chemical; 312 (127946) 2020. 10.1016/j.snb.2020.127946. IF: 7.100
The human placenta is a unique organ serving as the lung, gut, liver, and kidney of the fetus, mediating the exchange of different endogenous as well as exogenous substances and gases between the mother and fetus during pregnancy. Additionally, the placental barrier protects the fetus from a range of environmental toxins, bacterial and viral infections, since any contaminant bridging the placenta may have unforeseeable effects on embryonal and fetal development. A more recent concern in placenta research, however, involves the ability of engineered nanoparticles to cross the placental barrier and/or affect its barrier function. To advance nanoparticle risk assessment at the human placental barrier, we have developed as proof-of-principle a highly integrated placenta-on-a-chip system containing embedded membrane-bound impedance microsensor arrays capable of non-invasively monitoring placental barrier integrity. Barrier integrity is continuously and label-free evaluated using porous membrane-based interdigitated electrode structures located on top of a porous PET membrane supporting a barrier of trophoblast-derived BeWo cell barrier in the absence and presence of standardized silicon dioxide (SiO2), titanium dioxide (TiO2), and zinc oxide (ZnO) nanomaterials. © 2020 Elsevier B.V.
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Addressing Nanomaterial Immunosafety by Evaluating Innate Immunity across Living Species
Boraschi D., Alijagic A., Auguste M., Barbero F., Ferrari E., Hernadi S., Mayall C., Michelini S., Navarro Pacheco N.I., Prinelli A., Swart E., Swartzwelter B.J., Bastús N.G., Canesi L., Drobne D., Duschl A., Ewart M.-A., Horejs-Hoeck J., Italiani P., Kemmerling B., Kille P., Prochazkova P., Puntes V.F., Spurgeon D.J., Svendsen C., Wilde C.J., Pinsino A. Small; 16 (21, 2000598) 2020. 10.1002/smll.202000598. IF: 11.459
The interaction of a living organism with external foreign agents is a central issue for its survival and adaptation to the environment. Nanosafety should be considered within this perspective, and it should be examined that how different organisms interact with engineered nanomaterials (NM) by either mounting a defensive response or by physiologically adapting to them. Herein, the interaction of NM with one of the major biological systems deputed to recognition of and response to foreign challenges, i.e., the immune system, is specifically addressed. The main focus is innate immunity, the only type of immunity in plants, invertebrates, and lower vertebrates, and that coexists with adaptive immunity in higher vertebrates. Because of their presence in the majority of eukaryotic living organisms, innate immune responses can be viewed in a comparative context. In the majority of cases, the interaction of NM with living organisms results in innate immune reactions that eliminate the possible danger with mechanisms that do not lead to damage. While in some cases such interaction may lead to pathological consequences, in some other cases beneficial effects can be identified. © 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Bespoken Nanoceria: An Effective Treatment in Experimental Hepatocellular Carcinoma
Fernández-Varo G., Perramón M., Carvajal S., Oró D., Casals E., Boix L., Oller L., Macías-Muñoz L., Marfà S., Casals G., Morales-Ruiz M., Casado P., Cutillas P.R., Bruix J., Navasa M., Fuster J., Garcia-Valdecasas J.C., Pavel M.C., Puntes V., Jiménez W. Hepatology; 72 (4): 1267 - 1282. 2020. 10.1002/hep.31139. IF: 14.679
Background and Aims: Despite the availability of new-generation drugs, hepatocellular carcinoma (HCC) is still the third most frequent cause of cancer-related deaths worldwide. Cerium oxide nanoparticles (CeO2NPs) have emerged as an antioxidant agent in experimental liver disease because of their antioxidant, anti-inflammatory, and antisteatotic properties. In the present study, we aimed to elucidate the potential of CeO2NPs as therapeutic agents in HCC. Approach and Results: HCC was induced in 110 Wistar rats by intraperitoneal administration of diethylnitrosamine for 16 weeks. Animals were treated with vehicle or CeO2NPs at weeks 16 and 17. At the eighteenth week, nanoceria biodistribution was assessed by mass spectrometry (MS). The effect of CeO2NPs on tumor progression and animal survival was investigated. Hepatic tissue MS-based phosphoproteomics as well as analysis of principal lipid components were performed. The intracellular uptake of CeO2NPs by human ex vivo perfused livers and human hepatocytes was analyzed. Nanoceria was mainly accumulated in the liver, where it reduced macrophage infiltration and inflammatory gene expression. Nanoceria treatment increased liver apoptotic activity, while proliferation was attenuated. Phosphoproteomic analysis revealed that CeO2NPs affected the phosphorylation of proteins mainly related to cell adhesion and RNA splicing. CeO2NPs decreased phosphatidylcholine-derived arachidonic acid and reverted the HCC-induced increase of linoleic acid in several lipid components. Furthermore, CeO2NPs reduced serum alpha-protein levels and improved the survival of HCC rats. Nanoceria uptake by ex vivo perfused human livers and in vitro human hepatocytes was also demonstrated. Conclusions: These data indicate that CeO2NPs partially revert the cellular mechanisms involved in tumor progression and significantly increase survival in HCC rats, suggesting that they could be effective in patients with HCC. © 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.
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Cerium Oxide Nanoparticles: Advances in Biodistribution, Toxicity, and Preclinical Exploration
Casals E., Zeng M., Parra-Robert M., Fernández-Varo G., Morales-Ruiz M., Jiménez W., Puntes V., Casals G. Small; 16 (20, 1907322) 2020. 10.1002/smll.201907322. IF: 11.459
Antioxidant nanoparticles have recently gained tremendous attention for their enormous potential in biomedicine. However, discrepant reports of either medical benefits or toxicity, and lack of reproducibility of many studies, generate uncertainties delaying their effective implementation. Herein, the case of cerium oxide is considered, a well-known catalyst in the petrochemistry industry and one of the first antioxidant nanoparticles proposed for medicine. Like other nanoparticles, it is now described as a promising therapeutic alternative, now as threatening to health. Sources of these discrepancies and how this analysis helps to overcome contradictions found for other nanoparticles are summarized and discussed. For the context of this analysis, what has been reported in the liver is reviewed, where many diseases are related to oxidative stress. Since well-dispersed nanoparticles passively accumulate in liver, it represents a major testing field for the study of new nanomedicines and their clinical translation. Even more, many contradictory works have reported in liver either cerium-oxide-associated toxicity or protection against oxidative stress and inflammation. Based on this, finally, the intention is to propose solutions to design improved nanoparticles that will work more precisely in medicine and safely in society. © 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Epigenetics in breast cancer therapy—New strategies and future nanomedicine perspectives
Buocikova V., Rios-Mondragon I., Pilalis E., Chatziioannou A., Miklikova S., Mego M., Pajuste K., Rucins M., Yamani N.E., Longhin E.M., Sobolev A., Freixanet M., Puntes V., Plotniece A., Dusinska M., Cimpan M.R., Gabelova A., Smolkova B. Cancers; 12 (12, 3622): 1 - 32. 2020. 10.3390/cancers12123622. IF: 6.126
Epigenetic dysregulation has been recognized as a critical factor contributing to the development of resistance against standard chemotherapy and to breast cancer progression via epithelial-to-mesenchymal transition. Although the efficacy of the first-generation epigenetic drugs (epi-drugs) in solid tumor management has been disappointing, there is an increasing body of evidence showing that epigenome modulation, in synergy with other therapeutic approaches, could play an important role in cancer treatment, reversing acquired therapy resistance. However, the epigenetic therapy of solid malignancies is not straightforward. The emergence of nanotechnologies applied to medicine has brought new opportunities to advance the targeted delivery of epi-drugs while improving their stability and solubility, and minimizing off-target effects. Furthermore, the omics technologies, as powerful molecular epidemiology screening tools, enable new diagnostic and prognostic epigenetic biomarker identification, allowing for patient stratification and tailored management. In combination with new-generation epi-drugs, nanomedicine can help to overcome low therapeutic efficacy in treatment-resistant tumors. This review provides an overview of ongoing clinical trials focusing on combination therapies employing epi-drugs for breast cancer treatment and summarizes the latest nano-based targeted delivery approaches for epi-drugs. Moreover, it highlights the current limitations and obstacles associated with applying these experimental strategies in the clinics. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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Gold Nanoparticles Modulate BCG-Induced Innate Immune Memory in Human Monocytes by Shifting the Memory Response towards Tolerance
Benjamin J. Swartzwelter, Francesco Barbero, Alessandro Verde, Maria Mangini, Marinella Pirozzi, Anna Chiara De Luca, Victor F. Puntes, Luciana C. C. Leite, Paola Italiani, Diana Boraschi Cells; 9 (2, 284) 2020. 10.3390/cells9020284. IF: 4.366
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Hepato(Geno)toxicity assessment of nanoparticles in a hepg2 liver spheroid model
Elje E., Mariussen E., Moriones O.H., Bastús N.G., Puntes V., Kohl Y., Dusinska M., Rundén-Pran E. Nanomaterials; 10 (3, 545) 2020. 10.3390/nano10030545. IF: 4.324
(1) In compliance with the 3Rs policy to reduce, refine and replace animal experiments, the development of advanced in vitro models is needed for nanotoxicity assessment. Cells cultivated in 3D resemble organ structures better than 2D cultures. This study aims to compare cytotoxic and genotoxic responses induced by titanium dioxide (TiO2), silver (Ag) and zinc oxide (ZnO) nanoparticles (NPs) in 2D monolayer and 3D spheroid cultures of HepG2 human liver cells. (2) NPs were characterized by electron microscopy, dynamic light scattering, laser Doppler anemometry, UV-vis spectroscopy and mass spectrometry. Cytotoxicity was investigated by the alamarBlue assay and confocal microscopy in HepG2 monolayer and spheroid cultures after 24 h of NP exposure. DNA damage (strand breaks and oxidized base lesions) was measured by the comet assay. (3) Ag-NPs were aggregated at 24 h, and a substantial part of the ZnO-NPs was dissolved in culture medium. Ag-NPs induced stronger cytotoxicity in 2D cultures (EC50 3.8 µg/cm2) than in 3D cultures (EC50 > 30 µg/cm2), and ZnO-NPs induced cytotoxicity to a similar extent in both models (EC50 10.1–16.2 µg/cm2). Ag-and ZnO-NPs showed a concentration-dependent genotoxic effect, but the effect was not statistically significant. TiO2-NPs showed no toxicity (EC50 > 75 µg/cm2). (4) This study shows that the HepG2 spheroid model is a promising advanced in vitro model for toxicity assessment of NPs. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.
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Impact of Ag2S NPs on soil bacterial community – A terrestrial mesocosm approach
Peixoto S., Khodaparast Z., Cornelis G., Lahive E., Green Etxabe A., Baccaro M., Papadiamantis A.G., Gonçalves S.F., Lynch I., Busquets-Fite M., Puntes V., Loureiro S., Henriques I. Ecotoxicology and Environmental Safety; 206 (111405) 2020. 10.1016/j.ecoenv.2020.111405. IF: 4.872
Soils might be a final sink for Ag2S nanoparticles (NPs). Still, there are limited data on their effects on soil bacterial communities (SBC). To bridge this gap, we investigated the effects of Ag2S NPs (10 mg kg−1 soil) on the structure and function of SBC in a terrestrial indoor mesocosm, using a multi-species design. During 28 days of exposure, the SBC function-related parameters were analysed in terms of enzymatic activity, community level physiological profile, culture of functional bacterial groups [phosphorous-solubilizing bacteria (P-SB) and heterotrophic bacteria (HB)], and SBC structure was analysed by 16S rRNA gene-targeted denaturing gradient gel electrophoresis. The SBC exposed to Ag2S NPs showed a significative decrease of functional parameters, such as β-glucosidase activity and L-arginine consumption, and increase of the acid phosphatase activity. At the structural level, significantly lower richness and diversity were detected, but at later exposure times compared to the AgNO3 treatment, likely because of a low dissolution rate of Ag2S NPs. In fact, stronger effects were observed in soils spiked with AgNO3, in both functional and structural parameters. Changes in SBC structure seem to negatively correlate with parameters related to phosphorous (acid phosphatase activity) and carbon cycling (abundance of HB, P-SB, and β-glucosidase activity). Our results indicate a significant effect of Ag2S NPs on SBC, specifically on parameters related to carbon and phosphorous cycling, at doses as low as 10 mg kg-1 soil. These effects were only observed after 28 days, highlighting the importance of long-term exposure experiments for slowly dissolving NPs. © 2020 Elsevier Inc.
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Increasing complexity of nanocrystals
Bastús N.G., Gonzalez E., Puntes V. Nano Today; 32 (100859) 2020. 10.1016/j.nantod.2020.100859. IF: 16.907
[No abstract available]
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MOF-Beads Containing Inorganic Nanoparticles for the Simultaneous Removal of Multiple Heavy Metals from Water
Boix G., Troyano J., Garzón-Tovar L., Camur C., Bermejo N., Yazdi A., Piella J., Bastus N.G., Puntes V.F., Imaz I., Maspoch D. ACS Applied Materials and Interfaces; 12 (9): 10554 - 10562. 2020. 10.1021/acsami.9b23206. IF: 8.758
Pollution of water with heavy metals is a global environmental problem whose impact is especially severe in developing countries. Among water-purification methods, adsorption of heavy metals has proven to be simple, versatile, and cost-effective. However, there is still a need to develop adsorbents with a capacity to remove multiple metal pollutants from the same water sample. Herein, we report the complementary adsorption capacities of metal-organic frameworks (here, UiO-66 and UiO-66-(SH)2) and inorganic nanoparticles (iNPs; here, cerium-oxide NPs) into composite materials. These adsorbents, which are spherical microbeads generated in one step by continuous-flow spray-drying, efficiently and simultaneously remove multiple heavy metals from water, including As(III and V), Cd(II), Cr(III and VI), Cu(II), Pb(II), and Hg(II). We further show that these microbeads can be used as a packing material in a prototype of a continuous-flow water treatment system, in which they retain their metal-removal capacities upon regeneration with a gentle acidic treatment. As proof-of-concept, we evaluated these adsorbents for purification of laboratory water samples prepared to independently recapitulate each of two strongly polluted rivers: the Bone (Indonesia) and Buringanga (Bangladesh) rivers. In both cases, our microbeads reduced the levels of all the metal contaminants to below the corresponding permissible limits established by the World Health Organization (WHO). Moreover, we demonstrated the capacity of these microbeads to lower levels of Cr(VI) in a water sample collected from the Sarno River (Italy). Finally, to create adsorbents that could be magnetically recovered following their use in water purification, we extended our spray-drying technique to simultaneously incorporate two types of iNPs (CeO2 and Fe3O4) into UiO-66-(SH)2, obtaining CeO2/Fe3O4@UiO-66-(SH)2 microbeads that adsorb heavy metals and are magnetically responsive. Copyright © 2020 American Chemical Society.
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Nanocrystal−molecular hybrids for the photocatalytic oxidation of water
Bastús N.G., Gimbert-Suriñach C., Puntes V., Llobet A., Ventosa M., Oliveras J. ACS Applied Energy Materials; 3 (10): 10008 - 10014. 2020. 10.1021/acsaem.0c01685. IF: 4.473
A modular molecular hybrid colloidal photocatalyst composed of TiO2 nanocrystals (TiO2-NCs) as a light absorber and the molecular complex [Ru(tda)(pypyr)2], Ru-tda, as a water oxidation catalyst precursor both anchored onto single-walled carbon nanotubes (SWCNTs) is described. This colloidal molecular hybrid photocatalyst, labeled as Ru-tda/SWCNT/TiO2-NCs, is a robust material that can be easily prepared and scaled up. At neutral pH, in the presence of 3 sun illumination, the molecular hybrid material Ru-tda/SWCNT/TiO2-NCs is capable of achieving the photocatalytic oxidation of water to dioxygen in the presence of persulfate, giving an unprecedented turnover number of 229. © 2020 American Chemical Society
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Probing the immune responses to nanoparticles across environmental species. A perspective of the EU Horizon 2020 project PANDORA
Pinsino A., Bastús N.G., Busquets-Fité M., Canesi L., Cesaroni P., Drobne D., Duschl A., Ewart M.-A., Gispert I., Horejs-Hoeck J., Italiani P., Kemmerling B., Kille P., Procházková P., Puntes V.F., Spurgeon D.J., Svendsen C., Wilde C.J., Boraschi D. Environmental Science: Nano; 7 (11): 3216 - 3232. 2020. 10.1039/d0en00732c. IF: 7.683
Understanding how engineered nanomaterials affect immune responses of living organisms requires a strong collaborative effort between immunologists, toxicologists, ecologists, physiologists, inorganic chemists, nanomaterial scientists and experts in law and risk management. This perspective aims to provide a new viewpoint on the interaction between engineered nanomaterials and the immune defensive systems across living species, gained within the EU Horizon 2020 project PANDORA. We consider the effects of nanoparticle exposure on immune functions in plants, marine and terrestrial invertebrates and their relation to the current state of knowledge for vertebrates (in particular humans). These studies can shed light on the broader perspective of defensive and homeostatic mechanisms (immunity, inflammation, stress responses, microbiota, stem cell differentiation) suggesting ways to: i) perform a comparative analysis of the nanoparticle impact on immunity across model organisms; ii) inspire best practices in experimental methodologies for nanosafety/nanotoxicity studies; iii) regroup and harmonise fragmented research activities; iv) improve knowledge transfer strategies and nano-security; v) propose innovative tools and realistic solutions, thereby helping in identifying future research needs and tackling their challenges. This journal is © The Royal Society of Chemistry.
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Simple spectroscopic determination of the hard protein corona composition in AuNPs: Albumin at 75%
Vitali M., Casals E., Canals F., Colomé N., Puntes V. Nanoscale; 12 (29): 15832 - 15844. 2020. 10.1039/d0nr02379e. IF: 6.895
We analyzed the different spectroscopic profiles of nanoparticle hard protein corona formation using two model proteins, albumin and immunoglobulin. When compared to serum, this served for the analysis of the hard protein corona main components. To do that, we employed time-resolved UV-Visible light absorption spectroscopy, dynamic light scattering, and zeta potential measurements during nanoparticle-protein incubation. Under the tested experimental conditions, the expected evolution from a non-stable (soft) to a stable (hard) protein corona was confirmed for serum and albumin. At the same time, immunoglobulin incubation inevitably failed to form a corona and led to nanoparticle aggregation. The formation profiles of the protein corona were similar in the case of albumin and serum, indicating the dominance of albumin coating the nanoparticle surface when exposed to plasma. This was confirmed by mass spectrometry. Chemical digestion of the nanoparticles bearing different protein coronas gave indications of the density of the different protein coatings. Overall, this study of the protein corona by determining the adsorption kinetics finger-print enables the development of precise nanotechnologies avoiding cumbersome processes and delaying proteomics analysis. This journal is © The Royal Society of Chemistry.
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Understanding galvanic replacement reactions: the case of Pt and Ag
Merkoçi F., Patarroyo J., Russo L., Piella J., Genç A., Arbiol J., Bastús N.G., Puntes V. Materials Today Advances; 5 (100037) 2020. 10.1016/j.mtadv.2019.100037. IF: 0.000
Synthesis of nanocrystals (NCs), where material science elements are addressed with organic chemistry precision techniques, is especially challenging and difficult to control. This difficulty arises from the increased complexity of the mineralization processes and the generation of a liquid-solid interface. These aspects, along with a strong susceptibility to reaction kinetics, ultimately translate into serious challenges for reproducibility and morphological control. By systematically varying the different parameters used to control the morphology of NCs, including complexing agents, coreducers, and cooxidants, the general reaction landscape can be mapped and the most stable and reproducible recipes can be identified. We apply this concept to the model transmetallation reaction between immiscible Pt and Ag forming hollow Pt NCs by galvanic replacement reactions. In this work, 648 synthetic recipes were performed and characterized per duplicate, from which a subset of 307 recipes leading to the controlled formation of hollow NCs were further analyzed to correlate reaction conditions with the final obtained structure and stability (reproducibility). As a result, we present robust general synthetic protocols leading to the ad hoc production of Pt-based hollow NCs with independent control of shell thickness, void size, surface roughness, and degree of porosity. © 2019 The Authors
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Writing chemical patterns using electrospun fibers as nanoscale inkpots for directed assembly of colloidal nanocrystals
Kiremitler N.B., Torun I., Altintas Y., Patarroyo J., Demir H.V., Puntes V.F., Mutlugun E., Onses M.S. Nanoscale; 12 (2): 895 - 903. 2020. 10.1039/c9nr08056b. IF: 6.895
Applications that range from electronics to biotechnology will greatly benefit from low-cost, scalable and multiplex fabrication of spatially defined arrays of colloidal inorganic nanocrystals. In this work, we present a novel additive patterning approach based on the use of electrospun nanofibers (NFs) as inkpots for end-functional polymers. The localized grafting of end-functional polymers from spatially defined nanofibers results in covalently bound chemical patterns. The main factors that determine the width of the nanopatterns are the diameter of the NF and the extent of spreading during the thermal annealing process. Lowering the surface energy of the substrates via silanization and a proper choice of the grafting conditions enable the fabrication of nanoscale patterns over centimeter length scales. The fabricated patterns of end-grafted polymers serve as the templates for spatially defined assembly of colloidal metal and metal oxide nanocrystals of varying sizes (15 to 100 nm), shapes (spherical, cube, rod), and compositions (Au, Ag, Pt, TiO2), as well as semiconductor quantum dots, including the assembly of semiconductor nanoplatelets. © 2019 The Royal Society of Chemistry.
