Precision design of engineered nanomaterials to guide immune systems for disease treatment

Gathering required information in a fast and inexpensive way is essential for assessing the risks of engineered nanomaterials (ENMs). The extension of conventional (quantitative) structure-activity relationships ((Q)SARs) approach to nanotoxicology, i.e., nano-(Q)SARs, is a possible solution. The preliminary attempts of correlating ENMs’ characteristics to the biological effects elicited by ENMs highlighted the potential applicability of (Q)SARs in the nanotoxicity field. This review discusses the current knowledge on the development of nano-(Q)SARs for metallic ENMs, on the aspects of data sources, reported nano-(Q)SARs, and mechanistic interpretation. An outlook is given on the further development of this frontier. As concluded, the used experimental data mainly concern the uptake of ENMs by different cell lines and the toxicity of ENMs to cells lines and Escherichia coli. The widely applied techniques of deriving models are linear and non-linear regressions, support vector machine, artificial neural network, k-nearest neighbors, etc. Concluded from the descriptors, surface properties of ENMs are seen as vital for the cellular uptake of ENMs; the capability of releasing ions and surface redox properties of ENMs are of importance for evaluating nanotoxicity. This review aims to present key advances in relevant nano-modeling studies and stimulate future research efforts in this quickly developing field of research.

Relatively little is known about the fate of industrially relevant engineered nanomaterials (ENMs) in the lungs that can be used to convert administered doses to delivered doses. Inhalation exposure and subsequent translocation of ENMs across the epithelial lining layer of the lung might contribute to clearance, toxic effects or both. To allow precise quantitation of translocation across lung epithelial cells, we developed a method for tracking industrially relevant metal oxide ENMs in vitro using neutron activation. The versatility and sensitivity of the proposed in vitro epithelial translocation (INVET) system was demonstrated using a variety of industry relevant ENMs including CeO2 of various primary particle diameter, ZnO, and SiO2-coated CeO2 and ZnO particles. ENMs were neutron activated, forming gamma emitting isotopes 141Ce and 65Zn, respectively. Calu-3 lung epithelial cells cultured to confluency on transwell inserts were exposed to neutron-activated ENM dispersions at sub-lethal doses to investigate the link between ENM properties and translocation potential. The effects of ENM exposure on monolayer integrity was monitored by various methods. ENM translocation across the cellular monolayer was assessed by gamma spectrometry following 2, 4 and 24 h of exposure. Our results demonstrate that ENMs translocated in small amounts (e.g. <0.01% of the delivered dose at 24 h), predominantly via transcellular pathways without compromising monolayer integrity or disrupting tight junctions. It was also demonstrated that the delivery of particles in suspension to cells in culture is proportional to translocation, emphasizing the importance of accurate dosimetry when comparing ENM–cellular interactions for large panels of materials. The reported INVET system for tracking industrially relevant ENMs while accounting for dosimetry can be a valuable tool for investigating nano–bio interactions in the future.

During the last few decades, nanotechnology has evolved into a success story, apparent from a steadily increasing number of scientific publications as well as a large number of applications based on engineered nanomaterials (ENMs). Its widespread uses suggest a high relevance for consumers, workers and the environment, hence justifying intensive investigations into ENM-related adverse effects as a prerequisite for nano-specific regulations. In particular, the inhalation of airborne ENMs, being assumed to represent the most hazardous type of human exposure to these kinds of particles, needs to be scrutinized. Due to an increased awareness of possible health effects, which have already been seen in the case of ultrafine particles (UFPs), research and regulatory measures have set in to identify and address toxic implications following their almost ubiquitous occurrence. Although ENM properties differ from those of the respective bulk materials, the available assessment protocols are often designed for the latter. Despite the large benefit ensuing from the application of nanotechnology, many issues related to ENM behavior and adverse effects are not fully understood or should be examined anew. The traditional hypothesis that ENMs exhibit different or additional hazards due to their "nano" size has been challenged in recent years and ENM categorization according to their properties and toxicity mechanisms has been proposed instead. This review summarizes the toxicological effects of inhaled ENMs identified to date, elucidating the modes of action which provoke different mechanisms in the respiratory tract and their resulting effects. By linking particular mechanisms and adverse effects to ENM properties, grouping of ENMs based on toxicity-related properties is supposed to facilitate toxicological risk assessment. As intensive studies are still required to identify these "ENM classes", the need for alternatives to animal studies is evident and advances in cell-based test systems for pulmonary research are presented here. We hope to encourage the ongoing discussion about ENM risks and to advocate the further development and practice of suitable testing and grouping methods.

Structure-activity Relationship Models for Hazard Assessment and Risk Management of Engineered Nanomaterials

The potential applications associated with engineered nanomaterials (ENMs) are seemingly limitless, particularly in the broad disciplines of biomedical therapeutics and diagnostics, or ‘theranostics’ [1]. The National Nanotechnology Initiative has invested a considerable amount of resources, research and infrastructure for material development at dimensions less than 100 nm [2]. Materials manufactured at the nanoscale express unique properties and characteristics that differ from those of their larger counterparts of the same chemical composition. Furthermore, the toxicities and physiochemical properties of these ENMs are distinctly different, and thus are not well understood [3]. Moreover, novel ENMs and ENM properties are generated faster than their toxicities can be determined. Federal resources have been allocated to generate research and development of commercial products and medical technologies within the fields of drug delivery and imaging. To a lesser extent, these resources also support investigations into the toxicokinetics of these novel materials [2,4]. For good reason, most early nanotoxicology research has focused almost exclusively on pulmonary exposures within a young, healthy, male model. Our studies on micro-vascular dysfunction subsequent to ENM inhalation is of no exception. While this approach has yielded important descriptive and mechanistic information, the increased use of ENMs in novel biomedical and consumer products inevitably leads to increased occupational, environmental and domestic exposures to a variety of ENMs that are both intentional and unintentional. Perhaps some of the applications with the greatest potential to improve human health are those that require the intentional introduction of ENMs to the body. Such ENM exposure routes would no longer be limited to the lungs and would include ingestion, transdermal and injections (intravenous or other). Potential applications under development include drug delivery, high-resolution imaging, preventative measures (antioxidants) and implantable devices. The shear breadth of these applications mandates that we considerably widen our exposure models. The fetomaternal relationship during gestation is a unique, dynamic and complex physiological system. The term ‘milieu’, coined by Claude Bernard, or homeostatic environment is often used to describe different compartments, conditions and components associated with a given physiological function. At the outset, maternal health and homeostasis is paramount for a successful gestational outcome; therefore, uterine adaptation to pregnancy (e.g., growth and pressure regulation) or the uterine milieu must be first considered. Incorporated in the gestational uterine milieu is placental development, a transient organ with significant influence over fetal development. In addition to exchange of nutrients and wastes, the placenta serves as an endocrine organ to both the maternal and fetal circulations [5]. Lastly, the intrauterine environment where the fetus develops, or the fetal milieu, must be established and maintained to promote appropriate growth and development. Any dysfunction within the coordinated exchange of hormones, nutrients and wastes during gestation may lead to devastating fetal consequences. Therefore, regulation of maternal homeostasis and the fetal milieu are highly susceptible to a variety of external influences or exposures. Currently, our understanding of ENM exposure in these regards is quite poor. To date, few studies have explored the consequences of maternal ENM exposure during pregnancy [6–8]. Failure to recognize the consequences of ENM exposure during gestation may lead to untoward outcomes for generations. While it would be easy to label nanomaterial theranostics as contraindicated during pregnancy, the potential benefits within the field of obstetric theranostics may be immense. For example, applications of immediate interest to human health may include: fetal imaging, assessment of high-risk pregnancies and early pharmacological interventions. These promising advancements, while exciting and novel, can only reach their full potential if the toxicity of a given ENM, and its terms are first properly understood in all regards.

Chemical basis of interactions between engineered nanoparticles and biological systems.

Effects of engineered nanomaterial exposure on macrophage innate immune function

Novelphysicochemistries of engineered nanomaterials (ENMs) offerconsiderable commercial potential for new products and processes,but also the possibility of unforeseen and negative consequences uponENM release into the environment. Investigations of ENM ecotoxicityhave revealed that the unique properties of ENMs and a lack of appropriatetest methods can lead to results that are inaccurate or not reproducible.The occurrence of spurious results or misinterpretations of resultsfrom ENM toxicity tests that are unique to investigations of ENMs(as opposed to traditional toxicants) have been reported, but havenot yet been systemically reviewed. Our objective in this manuscriptis to highlight artifacts and misinterpretations that can occur ateach step of ecotoxicity testing: procurement or synthesis of theENMs and assessment of potential toxic impurities such as metals orendotoxins, ENM storage, dispersion of the ENMs in the test medium,direct interference with assay reagents and unacknowledged indirecteffects such as nutrient depletion during the assay, and assessmentof the ENM biodistribution in organisms. We recommend thorough characterizationof initial ENMs including measurement of impurities, implementationof steps to minimize changes to the ENMs during storage, inclusionof a set of experimental controls (e.g., to assess impacts of nutrientdepletion, ENM specific effects, impurities in ENM formulation, desorbedsurface coatings, the dispersion process, and direct interferenceof ENM with toxicity assays), and use of orthogonal measurement methodswhen available to assess ENMs fate and distribution in organisms.

Nano GO Consortium—A Team Science Approach to Assess Engineered Nanomaterials: Reliable Assays and Methods

Deposition of engineered nanomaterials (ENMs) in various environmental compartments is projected to continue rising exponentially. Terrestrial environments are expected to be the largest repository for environmentally released ENMs. Because ENMs are enriched in biosolids during wastewater treatment, agriculturally applied biosolids facilitate ENM exposure of key soil micro-organisms, such as plant growth-promoting rhizobacteria (PGPR). The ecological ramifications of increasing levels of ENM exposure of terrestrial micro-organisms are not clearly understood, but a growing body of research has investigated the toxicity of ENMs to various soil bacteria using a myriad of toxicity end-points and experimental procedures. This review explores what is known regarding ENM toxicity to important soil bacteria, with a focus on ENMs which are expected to accumulate in terrestrial ecosystems at the highest concentrations and pose the greatest potential threat to soil micro-organisms having potential indirect detrimental effects on plant growth. Knowledge gaps in the fundamental understanding of nanotoxicity to bacteria are identified, including the role of physicochemical properties of ENMs in toxicity responses, particularly in agriculturally relevant micro-organisms. Strategies for improving the impact of future research through the implementation of in-depth ENM characterization and use of necessary experimental controls are proposed. The future of nanotoxicological research employing microbial ecoreceptors is also explored, highlighting the need for continued research utilizing bacterial isolates while concurrently expanding efforts to study ENM–bacteria interactions in more complex environmentally relevant media, e.g. soil. Additionally, the particular importance of future work to extensively examine nanotoxicity in the context of bacterial ecosystem function, especially of plant growth-promoting agents, is proposed.

Prediction of protein corona on nanomaterials by machine learning using novel descriptors

Lessons learned: Are engineered nanomaterials toxic to terrestrial plants?

Chapter 4 - Fate of engineered nanomaterials in agroenvironments and impacts on agroecosystems

The majority of exposures to engineered nanomaterials (ENM) are unintentional through occupational or domestic use; however ENM biomedical platforms are being developed for use in individualized and/or tissue‐targeted treatments. The placenta has been described as a barrier organ, yet maternal treatments are limited during pregnancy to diminish untoward fetal effects and direct fetal therapies are rare. While negative maternal and fetal effects have been described after ENM exposure during gestation, it is unclear if these are due to direct ENM transfer into the fetal compartment or if the placental barrier protects the fetus from direct particle exposure. Therefore, the purpose of this study was to identify ENM translocation after maternal pulmonary exposure to the fetal compartment.Sprague‐Dawley rats were exposed to 2974 μg (2.4 × 1013 particles; calculated deposition of 952 ug/dose) of Rhodamine‐labeled 20nm polystyrene (NANOCS) in 300μL or saline control via intratracheal instillation every other day from GD 5 to GD 19. An acute group was also included, with a single ENM exposure on GD19. Animals were exposed to many optical imaging techniques (CT, FX‐Pro optical imaging, and ultrasound), in either the whole animal or dissected tissues on GD 20. Litter health was affected as evidenced by significantly higher rates of reabsorption sites in the exposed dams (18‐fold, chronic; 7‐fold, acute) compared to control. Overall, we were able to identify significantly higher optical intensity measurements in many secondary organs of the exposed animals, indicative of particle translocation from the lung. These included significantly increased optical imaging intensities in the chronic group vs the controls in the placenta (142% ± 78), whole fetal pup (144% ± 17), and in situ fetal liver (146% ± 13). Interestingly even those acutely exposed (24h prior) were also significantly different than control. These were identified as the mother's heart (156% ± 8), spleen (158% ± 6), placenta (142% ± 78), fetal heart (177% ± 37), fetal liver (both excised (190% ± 14) and within body (164% ± 10)), and whole pup (157% ± 13). Using novel placental perfusion methodology, where a placental unit is isolated, dissected, cannulated and perfused (80 mmHg maternal artery and 50 mmHg fetal umbilical artery), ENM introduced in the maternal artery can be quantified within 102 ± 13 minutes from the fetal umbilical vein effluent.Using molecular imaging techniques, we were able to conclusively identify ENM translocation from the maternal lungs to the fetal compartment. These findings may be both beneficial and toxicological depending on the purpose of the ENM exposure. ENM transfer to the fetal compartment may allow for direct fetal treatment with the use of ENM‐based biomedical devices; in contrast the placenta may not be considered a barrier to ENM, with direct fetal contact also occurring after unintentional maternal ENM exposures.Support or Funding InformationNIH‐R00‐ES024783 (PAS); P30‐ES005022This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Environmental and health effects of nanomaterials in nanotextiles and façade coatings