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Materials Advances

Nanomaterials: a review of synthesis methods, properties, recent progress, and challenges.

* Corresponding authors

a Center of Research Excellence in Desalination & Water Treatment, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia E-mail: [email protected] , [email protected]

b Center for Environment and Water, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia

c Interdisciplinary Research Center for Membranes and Water Security, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia

d Department of Chemical & Biological Engineering, University of Alabama, Tuscaloosa, Alabama 35487-0203, USA E-mail: [email protected] , [email protected]

e Department of Mechanical Engineering, King Fahd University of Petroleum and Minerals, Dhahran 31261, Saudi Arabia

Nanomaterials have emerged as an amazing class of materials that consists of a broad spectrum of examples with at least one dimension in the range of 1 to 100 nm. Exceptionally high surface areas can be achieved through the rational design of nanomaterials. Nanomaterials can be produced with outstanding magnetic, electrical, optical, mechanical, and catalytic properties that are substantially different from their bulk counterparts. The nanomaterial properties can be tuned as desired via precisely controlling the size, shape, synthesis conditions, and appropriate functionalization. This review discusses a brief history of nanomaterials and their use throughout history to trigger advances in nanotechnology development. In particular, we describe and define various terms relating to nanomaterials. Various nanomaterial synthesis methods, including top-down and bottom-up approaches, are discussed. The unique features of nanomaterials are highlighted throughout the review. This review describes advances in nanomaterials, specifically fullerenes, carbon nanotubes, graphene, carbon quantum dots, nanodiamonds, carbon nanohorns, nanoporous materials, core–shell nanoparticles, silicene, antimonene, MXenes, 2D MOF nanosheets, boron nitride nanosheets, layered double hydroxides, and metal-based nanomaterials. Finally, we conclude by discussing challenges and future perspectives relating to nanomaterials.

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N. Baig, I. Kammakakam and W. Falath, Mater. Adv. , 2021,  2 , 1821 DOI: 10.1039/D0MA00807A

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Nanomaterials

Advances and Applications

• © 2023
• Dheeraj Kumar Singh 0 ,
• Sanjay Singh 1 ,
• Prabhakar Singh 2

Department of Basic Sciences, Institute of Infrastructure Technology Research And Management, Ahmedabad, India

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National Institute of Animal Biotechnology, Hyderabad, India

Department of physics, indian institute of technology bhu, varanasi, india.

• Highlights recent advances of various nanomaterials and their potential use in interdisciplinary areas
• Includes synthesis and characterization of various nanomaterials, and their desired applications
• Discusses the potential drawbacks and the possible ways to overcome the pitfalls of using nanomaterials in certain areas

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Table of contents (12 chapters)

Front matter, an overview of nanomaterials: history, fundamentals, and applications.

• Hardik L. Kagdada, Amit K. Bhojani, Dheeraj K. Singh

Carbon-Based Nanomaterials: Carbon Nanotube, Fullerene, and Carbon Dots

• Nitika Devi, Rajesh Kumar, Yong-Song Chen, Rajesh Kumar Singh

Graphene-Based Materials: Synthesis and Applications

• Pawan Kumar Dubey, Junsung Hong, Kevin Lee, Prabhakar Singh

Metal Nanoparticles: Synthesis, Characterization, and Biomedical Applications

• Sivasankar Putta, Raj Kumar Sharma, Puneet Khandelwal

Metal Oxide Nanoparticles: Synthesis, Properties, Characterization, and Applications

• Nirav Joshi, Deepak K. Pandey, Bhavita G. Mistry, Dheeraj K. Singh

Nanocrystalline High Entropy Alloys and Oxides as Emerging Materials for Functional Applications

• Priyanka Kumari, Amit K. Gupta, Shashi Kant Mohapatra, Rohit R. Shahi

Layered Chalcogenides: Evolution from Bulk to Nano-Dimension for Renewable Energy Perspectives

• Ankita Singh, Jay Deep Gupta, Priyanka Jangra, Ashish Kumar Mishra

Recent Escalations in MXenes: From Fundamental to Applications

• Jeevan Jyoti, Bhanu Pratap Singh, Manjit Sandhu, Surya Kant Tripathi

Nanocomposite Ceramics for Energy Harvesting

• Raghvendra Pandey, Prabhakar Singh

Polymeric Nanocomposites: Synthesis, Characterization, and Recent Applications

• Saurabh Shivalkar, Sneha Ranjan, Amaresh Kumar Sahoo

Nanotechnology for Biomedical Applications

• Shashank Reddy Pasika, Raviteja Bulusu, Balaga Venkata Krishna Rao, Nagavendra Kommineni, Pradeep Kumar Bolla, Shabari Girinath Kala et al.

Nanomaterials in Animal Nutrition and Disease Treatment: Recent Developments and Future Aspects

• Stuti Bhagat, Divya Mehta, Sanjay Singh
• Carbon-based Nanomaterials
• Carbon dots
• Graphene-based Nanomaterials
• Metal nanoparticles
• Nanometal Oxides
• Magnetic nanomaterials
• Chalcogenides
• Semiconductor nanocomposites
• Polymer nanocomposites
• Green synthesis
• Nanosynthesis

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Dheeraj Kumar Singh

Sanjay Singh

Prabhakar Singh

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Book Title : Nanomaterials

Book Subtitle : Advances and Applications

Editors : Dheeraj Kumar Singh, Sanjay Singh, Prabhakar Singh

DOI : https://doi.org/10.1007/978-981-19-7963-7

Publisher : Springer Singapore

eBook Packages : Physics and Astronomy , Physics and Astronomy (R0)

Copyright Information : The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023

Hardcover ISBN : 978-981-19-7962-0 Published: 14 January 2023

Softcover ISBN : 978-981-19-7965-1 Published: 15 January 2024

eBook ISBN : 978-981-19-7963-7 Published: 13 January 2023

Edition Number : 1

Number of Pages : XX, 361

Number of Illustrations : 9 b/w illustrations, 120 illustrations in colour

Topics : Nanoscale Science and Technology , Nanotechnology and Microengineering , Structural Materials , Nanochemistry , Green Chemistry

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Review article, a comprehensive review of magnetic nanomaterials modern day theranostics.

• 1 Department of Chemistry, Kohat University of Science & Technology, Kohat, Pakistan
• 2 Center of Excellence for Advanced Materials Research (CEAMR), King Abdulaziz University, Jeddah, Saudi Arabia
• 3 Gandhara College of Pharmacy, Gandhara University Peshawar, Peshawar, Pakistan

Substances at nanoscale, commonly known as “nanomaterials,” have always grabbed the attention of researchers for hundreds of years. Among these different types of nanomaterials, magnetic nanomaterials have been the focus of considerable attention during the last two decades as evidenced by an unprecedented increase in the number of research papers focusing these materials. Iron oxide magnetic nanoparticles have occupied a vital position in imaging phenomena; as drug vehicles, controlled/sustained release phenomena and hyperthermia; atherosclerosis diagnosis; prostate cancer. In fact, these are wonderful “theranostic” agents with some under clinical trials for human use. In this review, we have attempted to highlight the advances taking place in the field of magnetic nanoparticles as theranostic agents. Extensive progress has been made in the two most important parameters, namely, control over the size and shape which decide the importance of iron oxide magnetic nanoparticles by developing suitable procedures like precipitation, co-precipitation, thermal decomposition, hydrothermal synthesis, microemulsion synthesis and plant mediated synthesis. After using a suitable synthetic route, workers encounter the most daunting task linked with the materials at nanoscale i.e., the protection against corrosion. Only properly protected iron oxide magnetic nanoparticles can be further connected to different functional systems to make building blocks for application in catalysis, biology and medicines. Finally, “theranostics” which is a combined application of imaging and drug delivery has been discussed. With all the potential uses, toxicity of the of iron oxide magnetic nanoparticles has been discussed.

Introduction

Scientists, and materials scientists particularly, have shown remarkable interest in the properties of magnetic materials on the nanometer scale, while life scientists are also benefiting from nanomagnets ( Buzug, 2010 ). Iron oxide magnetic nanoparticles are quite different from other nanomaterials as the fundamental properties of magnets are defined at the nanoscale and measurements can be made in the range of a micrometer to a few nanometers in size ( Riaz et al., 2015 ; Monsalve et al., 2017 ). Iron oxide magnetic nanoparticles are one of the most promising substances in clinical diagnostic and therapeutic applications (theranostics) ( Ho et al., 2011 ; Ahmed et al., 2012 ). Superparamagnetism displayed by iron oxide magnetic nanoparticles makes ferromagnets useful for application in biomedical sciences; briefly, when compared with other nanomaterials, these are usually coated with inorganic materials like silica, organic fatty acids phospholipids, and so on, and these can be directed to active site by controlling with external AC magnetic field making these attractive for biomedical applications ( Figure 1 ) ( Li et al., 2013 ).

Figure 1 . Magnetism in the presence and absence of an external applied magnetic field.

Recently, substantial efforts have been made in the field of iron oxide magnetic nanoparticles to develop and understand their behavior and for improving their applicability ( Bansal et al., 2017 ). Control over the synthetic procedures including surface functionalization is imperative as it leads to their unique properties, such as physicochemical, stability and biological fate. For application in pharmaceutical and biomedical purposes, iron oxide magnetic nanoparticles should possess smaller size (50–160 nm) and high magnetization values ( Mohammed et al., 2017 ). Surface coatings are meant to ensure stability and biocompatibility for specific localization at the target site ( Figure 2 ) ( Kandasamy, 2017 ).

Figure 2 . Stabilization of iron oxide nanoparticles; (A) polymer end bearing functional group (B) polymer-grafted (C) di-block copolymer with grafting groups (D) wrapping conformation of the polymer (E) coatings with opposite charges (F) amphiphilic polymers [adapted and modified from Barrow et al. (2015) and Habibi et al. (2017) ].

Nevertheless, the intrinsic instability is an inevitable problem related with these particles when stored over certain periods of time; as these small particles tend to agglomerate and reduce the energy associated with high surface to volume ratio of the nanoparticles ( Kovár et al., 2017 ). Uncapped magnetic iron oxide nanoparticles are highly reactive and prone to easy oxidation under ambient conditions damaging in magnet behavior and dispersion ( Yu et al., 2014 ). For these reasons, it is critical to devise strategies to achieve stability of the naked magnetic iron oxide nanoparticles and degradation in the course and after the synthetic procedures. One approach is to coat the magnetic nanoparticles with layers of organic or inorganic stabilizing agents; the major advantage of this strategy is that the coating not only gives stability, but these can further be used for functionalization depending on the anticipated application ( Tombácz et al., 2015 ). After surface functionalization, iron oxide magnetic nanoparticles are capable of use as catalysts and biomarkers etc. ( Pang et al., 2016 ). The objective this review is to bring into focus the syntheses and wide-ranging applications of iron oxide magnetic nanoparticles.

Synthesis of Iron Oxide Magnetic Nanoparticles

A huge number of research papers have appeared during the last several decades describing the synthesis of magnetic iron oxide nanoparticles with versatile compositions and phases.

Synthetic routes are selected to control shape, stability and dispersion trends of iron oxide magnetic nanoparticles ( Figure 3 ). Excellent quality iron oxide magnetic nanoparticle can be synthesized by adopting versatile synthetic approaches include thermal decomposition, co-precipitation, micelle formation, hydrothermal and laser pyrolysis techniques. It was difficult for us to compile all this literature and we have attempted to present each synthetic approach by giving a few examples along with the corresponding formation mechanism ( Ali et al., 2016 ; Martínez-Cabanas et al., 2016 ; Elrouby et al., 2017 ; Kandasamy, 2017 ; Lin et al., 2017 ; Liu et al., 2017 ; Rajiv et al., 2017 ; Sathya et al., 2017 ).

Figure 3 . Comparative presentation of the synthesis of iron oxide magnetic nanoparticles by three different routes [adapted and modified from Ali et al. (2016) ].

Solution Precipitation

To date, precipitation from homogeneous solutions is a classical in use for decades for the lab-scale preparation of iron oxide magnetic nanoparticles ( Pang et al., 2016 ). Routinely, during a precipitation reaction, a precipitating agent is added to the aqueous solution of metal precursor generating an insoluble solid product and the major benefit is the higher yields of the products. Another advantage of homogeneous precipitation reaction is the uniformity of the particles, a process that depends largely on the separation, the nucleation and growth of the particles ( Yang et al., 2014 ).

Overall, precipitation methods are simple and allow the preparation of magnetic iron oxide nanoparticles with rigorous size and shape control and these reactions are employed to obtain uniform size of the product. Nucleation must be avoided during the growth process for achieving the monodispersity of the iron oxide magnetic nanoparticles ( Mahmed et al., 2011 ).

Co-precipitation Methods

Co-precipitation is perhaps a more suitable method to prepare magnetic iron oxide nanoparticles from aqueous solution containing Fe(II) and Fe(III) by adding a base under anaerobic condition at ambient or high temperatures ( Lodhia et al., 2010 ). However, there are certain factors like the type of iron salts, Fe(II):Fe(III) ratio, temperature of the reaction, pH of the medium, volume and ionic strength of the solution that markedly affect size, shape and composition of the magnetic iron oxide nanoparticles ( Surowiec et al., 2017 ). In the co-precipitation approach, once the synthetic conditions are met, the quality of the magnetic iron oxide nanoparticles is successfully reproducible. At laboratory conditions, nanoscale magnetite tend to decompose easily to maghemite when dissolved in an acidic solution which is a ferrimagnetic material; therefore, magnetite can be deliberately oxidized to maghemite. This can be achieved by dispersing magnetite in acidic medium followed by the addition of Fe(III) nitrate; thus, the product obtained furnished excellent chemical stability to basic as well as acidic conditions. Therefore, altering conditions of the aforesaid process is the key in controlling the dispersion behavior of magnetic iron oxide nanoparticles; the size and shape of the SPIONs can be successfully tailored by adjustment of pH, ionic strength, temperature, nature of the salts used and concentration ratio of Fe II /Fe III . While addition of organic chelating agents or polymers surface complexing agents during the formation of magnetite can help to control the size of the nanoparticles ( Mascolo et al., 2013 ).

Recently, monodispersed magnetic iron oxide nanoparticles of variable sizes have been reported by the use of the stabilizing agent polyvinylalcohols in chainlike clusters signifying the importance of appropriate surfactant for stability ( Freitas et al., 2015 ). Organic stabilizing agents containing carboxylate and hydroxide anions have been the priority choices as they form surface complexes by competing mechanisms ( Lu et al., 2007 ). First is the complex formation of metal ions which prevents nucleation; second is the adsorption of additives on nuclei thereby inhibiting particles' growth ( Boyer et al., 2010 ). All these facts make co-precipitation as the most widely used excellent synthetic route to obtain magnetic iron oxide nanoparticles.

Thermal Decomposition Approach

In this approach, generally organometallics compounds are decomposed; organometallic precursors are decomposed in organic solvents using surfactants as capping agents under anaerobic conditions and it is a very diverse approach for the synthesis of magnetic iron oxide nanoparticles ( Laurent et al., 2008 ). Thermal decomposition helps achieve control of the size and shape and dispersion behaviors of the nanomaterials; however, safety issues are associated at higher temperatures and pressure of organic liquids and vapor phases used during the reactions conducted in the absence of air ( Figure 4 ) ( Dong et al., 2015 ). But one question has always arisen that, If the reaction is carried out in the absence of oxygen, how can metal oxide nanoparticles be formed successfully and reproducibly? The answer to this is example of iron oxide as in the first step ferrous hydroxide is formed, which is then oxidized to iron oxide by the protons of water to different types of iron oxides.

Figure 4 . Thermal decomposition of iron(III) glucuronate to synthesize superparamagnetic Fe 3 O 4 nanoparticles [adapted and modified from Patsula et al. (2016) ].

Reaction conditions, for instance temperature, duration of the reaction and the aging may also be vital for controlling size and morphology ( Patsula et al., 2016 ). Annealing temperature is another factor which allows for the control of size and size distribution, namely the dispersion of the synthesized iron oxide magnetic nanoparticles, their structural motifs and magnetic properties. Monodispersed iron oxide magnetic nanoparticles in the size range of 6–20 nm were reported prepared by the polymer-catalyzed decomposition of reaction of Fe(CO) 5 ( Smith and Wychick, 1980 ; Huber, 2005 ). Literature also reports very precise control of the size of iron oxide magnetic nanoparticles; this was successfully achieved by thermally decomposing larger concentrations of expensive and toxic precursors as well as surfactants in organic medium. Precursors containing zero-valent metal like Fe(CO) 5 , initially lead to metallic nanoparticles followed by oxidation yielded high quality monodisperse iron oxide magnetic nanoparticles ( Effenberger et al., 2017 ). In contrast, iron(III) acetylacetonate when treated under identical conditions decomposed to cationic metal centers ( Hufschmid et al., 2015 ). Another drawback associated with this method is the solubility of magnetic nanoparticles in organic solvents; this restricts their usage in biology and medicine. Even surface modification has no significant impact on the solubility of nanoparticles which are generally only dissolved in non-polar solvents ( Dong et al., 2015 ).

Polyol Method

Polyol method is a liquid-phase synthetic approach for magnetic iron oxide nanoparticles in multivalent alcohols under higher boiling conditions ( Hufschmid et al., 2015 ). Ethylene glycol is the simplest representative of the polyol family and, based on this, polyols comprise of a series of glycols diethylene glycol, triethylene glycol, tetraethylene glycol up to polyethylene glycol ( Figure 5 ) ( Deshmukh and Niederberger, 2017 ). Polyethylene glycol is available in a wide range of molecular weights and the respective product may contain up to 100,000 ethylene groups; other examples of this family are propanediol, butanediol, pentanediol, glycerol, and pentaerythritol and certain carbohydrates. Polyol is a very promising approach to synthesize uniform magnetic iron oxide nanoparticles, having the potential use in magnetic resonance imaging. The reason for the success of the polyol method is that all these polyols are water-comparable and chelation; polyols instantaneously coordinate to the nuclei formed and this allow excellent control of particle size, dispersity and particle distribution. Post synthesis treatment for the removal of polyols can be achieved easily by repeated washing with simple water, coordination exchangers like carboxylates, amines etc. and thermal annealing ( Watt et al., 2017 ). Particle size increases with the increasing precursor's concentration and water; particle size can be limited to minimum depending on the solubility of the product in the polyol. A bigger advantage of the polyol method is the production of highly crystalline oxide nanoparticles based on elevation of the temperature of reaction medium; this rules out any post-sintering treatment of the product ( Yang et al., 2014 ). Apart from conventional heating, other sources like microwaves and ultrasonic waves have been successfully applied ( Hemery et al., 2017 ). The synthesis of metal oxides can be restricted by the reducing action of polyols yielding elemental metals, and it is also possible by adjusting the reaction temperature ( Wee et al., 2017 ).

Figure 5 . Polyol route for the synthesis of nanoparticles [adapted and modified from Dong et al. (2015) ].

Microemulsion Synthesis

When two immiscible solvents are mixed together, a thermodynamically stable isotropic dispersion is formed which is defined as microemulsion with the presence of an interfacial layer of surfactant's molecules ( de Toledo et al., 2018 ). Surfactants molecules generally bearing hydrophilic heads soluble in water and hydrophobic tails soluble in oil phase form a monolayer at the interface of the two immiscible liquids (water-oil) ( Williams et al., 2016 ). Surfactant is an amphiphilic molecule playing a role to lower the water-oil interfacial tension to give a transparent solution. Microemulsion technique has several advantages when compared with other synthetic strategies. For example, with the use of simple equipment, a great variety of nanomaterials can be synthesized with excellent control over size, shape and composition, desired crystalline structure and high specific surface area, simple synthetic conditions at ambient/near ambient temperatures and pressures ( Zhao et al., 2016 ). Microemulsions of water-in-oil are formed when microdroplets (up to 50 nm) of water surrounded by a monolayer of surfactant molecules are dispersed in continuous hydrocarbon phase ( Drozdov et al., 2016 ). If two identical water-in-oil microemulsions containing the desired reagents are mixed, the microdroplets formed will experience continuous collisions, coalesce and break again and again leading to the appearance of precipitate inside the micelles. After completion of the reaction, acetone or ethylalcohol are added for extracting the precipitate via filtration or by centrifugation.

Microemulsions are termed as “nanoreactors” to produce nanoparticles, mixed metal-iron oxide magnetic (MFe 2 O 4 , M: first row transition metals) nanoparticles are one of the most interesting materials used for electronic applications ( Gutiérrez et al., 2015 ). MnFe 2 O 4 nanoparticles in the range 4–15 nm are successfully synthesized through water-toluene inverse micelles with sodium dodecylbenzenesulfonate surfactant, aqueous solutions of Mn(NO 3 ) 2 and Fe(NO 3 ) 3 as starting precursors. The microemulsion method used for the magnetic nanoparticles yielded spheroids with a rectangular cross section or as tube ( Hasany et al., 2013 ). A wide range of magnetic nanomaterials have been synthesized using the microemulsion method with good control and the sizes, as well as shapes, usually varied over a wider range. In the microemulsion technique, large quantities of solvents are used to produce considerable amounts of nanomaterial; based on this, it's categorized as a very efficient procedure and relatively difficult to be applied at large scale ( Figure 6 ) ( Kumar et al., 2013 ; Williams et al., 2016 ).

Figure 6 . Reverse phase microemulsion route for size-controlled synthesis of Cu and CuO nanoparticles [adapted and modified from Kumar et al. (2013) and Williams et al. (2016) ].

Hydrothermal Route

Hydrothermal or solvothermal route is one of the most successful methods to prepare magnetic nanoparticles and ultrafine powders ( Malo de Molina et al., 2016 ). By using this technique, crystals of different materials have been grown satisfactorily. Generally, hydrothermal synthesis accompanies higher temperatures (125–250°C) at very high pressures (0.3–4 MPa) ( Cai et al., 2013 ; Madadlou et al., 2014 ; Yelenich et al., 2015 ). Powdery iron oxide magnetic nanoparticles with 40 nm diameter have been reported using hydrothermal route (140°C) and a saturation magnetization of 85.8 emu. g −1 , which is far lower than that of the bulk iron oxide.

Precursors' concentration controls the size and size distribution; however, the duration of the reaction had affected the average particle size more significantly; monodisperse particles were obtained at shorter reaction times ( Guo et al., 2013 ). An increase in the precursors' concentration with the rest of the variables kept constant lead to spherical particles (15.6–4 nm) ( Naghibi et al., 2014 ). A major drawback of the hydrothermal route is the slowness of kinetics at any given temperature; but this problem can be addressed using microwaves which can increase the kinetics of crystallization. A reaction mixture containing ethylene glycol, iron(III) chloride, sodium acetate and polyethylene glycol sealed inside a stainless-steel autoclave (Teflon-lined) was and heated at 200°C for 8–72 h, yielded monodisperse spheres in the range of 200–800 nm. The mechanism is not yet clear, and the multicomponent approach seemed to be powerful in directing the formation of the desired materials.

Biological Synthesis

The introduction of Green Chemistry in nanotechnology has grabbed a great deal of attention from workers around the globe ( Maryanti et al., 2014 ). The green chemistry approach includes chemical manipulations with the aim to either decrease or eliminate toxic materials dumped into the environment ( Tadic et al., 2014 ; Nassar et al., 2016 ). Biological synthesis of metallic nanomaterials by plants resources is currently under development and one of the most researched areas under investigation. Plant-mediated syntheses of metallic nanomaterials is the most modern option for researchers, carried out by using various parts of plants including tissue, extracts, exudates and other parts of the living plants. Green methods that are environmentally-friendly, safe and non-toxic for the development of reliable and eco-friendly methods to produce nanomaterials are of great importance in biomedical applications.

Biological resources including microbes, enzymes, fungi and plant extracts have been utilized as eco-friendly alternates for the synthesis of nanoparticles ( Shah et al., 2015 ; Dhal et al., 2017 ). In some papers, plants and/or their parts proved to be beneficial over the other biological processes like microbial or enzymatic resources by elaborating work to maintain microbial culture. Plants are green resources for the biological synthesis of nanoparticles containing reducing agents for instance citric acid, ascorbic acid, flavones, crude enzymes like dehydrogenases, reductases and extracellular electron shuttles, which plays a key role in the biological synthesis of nanoparticles ( Figure 7 ) ( Bai et al., 2009 ; Makarov et al., 2014 ; Baranwal et al., 2016 ).

Figure 7 . Plant-mediated synthesis of metallic nanomaterials showing reduction as well as stabilization by secondary metabolites present in plant extracts for numerous applications in clinical research [adapted and modified from Makarov et al. (2014) and Baranwal et al. (2016) ].

Carob leaf extract has been successfully employed as a rapid, non-toxic, facile and green resource for preparation of iron oxide magnetic nanoparticles in a single step reaction using Fe(III): Fe(II) and sodium hydroxide solutions ( Baxter-Plant et al., 2003 ). The reaction occurred at a relatively low temperature range in a single-vessel reaction with an average diameter of the monodispersed nanoparticles (4–8 nm) coated with carboxylic groups of respective amide-I and II chain of the proteins present in the extract ( Rai et al., 2015 ).

As the biological synthesis of nanoparticles is a comparatively newer approach and is developing, these are certain disadvantages associated with it, for example, plants produce low quantities of secreted proteins which lead to a decreased rate of synthesis, creating the following implications: culturing microorganisms which takes more time; the prime objective of the synthesis of nanoparticles regarding control over size, shape and crystallinity is only achieved with difficultly; and most importantly is the dispersity of the nanoparticles, which are preferably monodispersed. Another disadvantage is that all the plants are not capable of being put to use for the synthesis of nanoparticles. The researchers are still working on the mechanisms of metal ion uptake and biological reduction by green approach.

Drug Delivery

About 40 years ago, the concept of “magnetic drug delivery” was introduced as a very promising application of magnetic nanomaterials ( Iravani, 2011 ). The concept of magnetic targeting starts with attaching drug molecules to magnetic nanomaterials followed by the injection and guidance of these particles to a site of action under the influence of localized magnetic field-gradients and holding there at site till the completion of therapy and final removal ( Awwad et al., 2013 ). Literature reveals six types of magnetic materials, i.e., diamagnetic, paramagnetic, ferromagnetic, superparamagnetic, ferromagnetic and antiferromagnetic ( Njagi et al., 2010 ). When the external field is removed, paramagnetic substances lose magnetic momentum and superparamagnetic materials become non-magnetic, but if an external field is placed, these develop a mean magnetic momentum. Magnetic nanoparticles can carry large doses of drugs to achieve high local concentration, avoiding toxic and other adverse side effects arising due to high drug doses in other parts of the organism ( Langer, 1990 ). In vivo studies proved that actual clinical trials are a challenging task due to size control, stability, biocompatibility and coating-layer for drug binding and other physiological parameters.

The objective of developing and/or improving drug delivery systems is to position medications to target parts of the subject's body through a medium that can control the therapy's administration by means of a physiological or chemical trigger ( Mody et al., 2014 ). Polymeric microspheres, micelles and hydrogels proved to be effective in enhancing drug target specificity, systemic drug toxicity lowering, improved treatment absorption rate and protection of pharmaceuticals against biochemical degradation ( Bucak et al., 2012 ; Kharissova et al., 2013 ; Kharisov et al., 2014 ; Hola et al., 2015 ; Jiles, 2015 ; Anselmo and Mitragotri, 2017 ; Seeli and Prabaharan, 2017 ). In addition to these, biodegradable polymer and dendrimers based experimental drug delivery systems displayed exciting signs of promise ( Figure 8 ).

Figure 8 . Transition metal/metal oxides magnetic core-shell nanoparticles [adapted and modified from Kharissova et al. (2013) ].

Dendrimers, due to their size and structure, are suitable carriers and these can be easily processed to good biocompatibility and biodegradation, but these are poor coating materials magnetic nanoparticles ( Yu et al., 2017 ). Suitable materials may be nanoparticles, emulsions, micelles and dendrimers etc.; a typical drug delivery process includes the loading of drugs in biocompatible carrier materials, transferred to bodies for cancer treatment. Biocompatibility, subcellular size and targeting action make nanoparticles excellent carrier materials and several nanosized materials have shown interesting potential for drug delivery; this potential stems from their intrinsic magnetic properties, such as room temperature superparamagnetism, magnetization and high magnetic susceptibility ( Figure 9 ).

Figure 9 . Novel drug-carrier systems depicting different types of coating polymers and copolymers [adapted and modified from Veiseh et al. (2010) ].

Surface functionalization by chemical as well as biological means improve stability and biocompatibility of the magnetic nanoparticles. The most interesting aspect of magnetic nanoparticles in drug delivery is the controlled delivery of drugs to target site under external magnetic fields. Magnetic driving of drugs to the target area is based on the binding of drugs to ferrofluid and desorption from the ferrofluid after reaching the target site by external magnetic field. Still, a lot of work is needed to be done, as successful drug delivery is affected by different factors, for example pH, temperature, osmolality, and so on ( Veiseh et al., 2010 ). The strength of the external applied magnetic field may hamper the magnetic drug delivery process as living cells withstand to a certain extent. The responsive nature of the magnetic nanoparticles carriers to external magnetic fields is due to the presence of incorporated magnetic materials, for example magnetite and some other transition metals and mix-metals ( Figure 10 ).

Figure 10 . Controlled delivery of anti-tumor drug with a new design incorporating a phase-change material in magnetic nanoparticles allowing chemo-photothermal combined tumor therapy with multimodal tumor imaging [adapted and modified from: http://www.advancedsciencenews.com/pent-drug-delivery-tumor-therapy-trimodal-imaging (accessed on July 07, 2018, 2200 PST)].

While designing a magnetic targeted drug delivery system, certain factors must be borne in mind like strength of the applied magnetic field and geometry. There are some other factors like magnetic properties and particles size, magnetic field strength, drug loading capacity, remoteness of the target site and blood flow rate. The aim of the magnetically targeted drug delivery system is to carry the drug to the site of action at a rate needed by the body during the treatment time ( Funke and Szeri, 2017 ).

The most advanced application of nanoscale materials toward human health is the application of iron oxide magnetic nanoparticles-based formulations as a contrasting agent in magnetic resonance imaging ( Fish et al., 2017 ). The past 50 years have seen remarkable improvements in diagnostic imaging procedures; for example in tumor diagnoses, damaged tissues and neurological disorders. Among various diagnostic imaging techniques, Magnetic Resonance Imaging abbreviated as MRI is an established tool in biomedical applications; exhibit stronger contrast of tissues makes it a favorable diagnostic test in medicine. In other diagnostic techniques like X-ray, the contrast quality is hindered leading to the misdiagnosis of several medical conditions. Looking at the superior contrast properties of MRIs, developments are needed and are made possible using a special medium called contrast agent ( Hyeon et al., 2016 ). Contrast agent consists of a metal-based core with an external coating of a biocompatible material; the contrast agent intensifies the contrast of images obtained from MRI for accurate diagnoses. MRI equipment exerts a strong magnetic field within the CAs as well as other magnetic particles of biological significance respond ( Hachani et al., 2016 ). MRI contrasting agents are classified into five categories as: T 1 , T 2 / T 2 * , CEST, 19 F-based and hyperpolarized agents (T 1 and T 2 are relaxation rates) ( Sood et al., 2017 ).

T1 agents include paramagnetic Gd III or Mn II complexes capable of enhancing the magnetic resonance water signal known as “signal brightening.” The benefits of using T 1 contrasting agents relies on the high versatility of the interesting contrast mechanism that is dependent on their structures and biological aspects; for example, the use of paramagnetic complexes to see the delivery as well as the drug release from liposomes ( Xiao et al., 2016 ). However, these systems have got limited sensitivity based on the local concentration. To tackle this problem, scientists proposed the use of nanoscale materials which will aggravate numerous contrasting unit's necessary to detect a T 1 contrast. T 1 / T 2 * contrasting agents are mostly superparamagnetic iron oxide nanoparticles capable of shortening T 1 / T 2 * of water protons than T 1 signal; in fact, they darken the MRI due to signal loss. T 1 / T 2 * show higher intrinsic sensitivity than T 1 contrasting agents which make them highly helpful in cellular imaging; this signal loss is undesirable as in the case of intrinsically low signal locations such as the lungs, while r 2 is the relaxivity of the CA as a function of effect of concentration of the solution on the relaxation rates reflects the ( Figure 11 ). This can be explained by classical outer-sphere relaxation theory that, with the increase in particle size, the relaxavity ratio ( r 1 / r 2 ) increases while decrease in particle's size lead to better T1-shortening ( Taboada et al., 2007 ; Xiao et al., 2016 ).

Figure 11 . T 2 -weighted contrasts and r 2 color maps for iron oxide nanoparticles of different sizes (Nanoparticles in magnetic resonance imaging: from simple to dual contrast agents) [adapted and modified from Estelrich et al. (2015) and Xu et al. (2016) ].

CEST (Chemical Exchange Saturation Transfer) is the future of MRI contrasting agents; the principal governing CEST imaging is that these agents generate MRI contrast signals through chemical exchange of saturated protons from donor (CEST) to acceptor (water) ( Taboada et al., 2007 ; Xiao et al., 2016 ). The uniqueness of using CEST agents is that the contrasting signal can be detected by irradiating with the characteristic NMR resonance of the donor. The 19 F nucleus is the most sensitive spin after proton so needs no enrichment, bearing similar detection sensitivity to CEST. Fluorinated agents are preferred over other media agents, due to possible correlation of signal to agent concentration ( Bünzli, 2016 ). Hyper polarized agents are the most sensitive media contrasting agents using polarization techniques which dramatically increase the population difference between the spin energy levels. These have got limited use because of the signal loss over time.

Before extending our discussion about nanoscale magnetic materials as contrasting media, some in vivo considerations must be discussed like toxicity, size and shape, and charge. Iron oxide magnetic nanoparticles are regarded as harmless for in vivo applications; based on iron's concentration inside the human body. Iron becomes toxic at a concentration level of 60 mg/kg; iron oxide magnetic nanoparticles have been used as contrasting agents for more than two decades in clinics are below 1 mg/kg. However, iron oxide magnetic nanoparticles have been reported to have adverse effects on cell cultures based on the proposal that the internalization of nanoparticles alters the fate of the cells. Iron oxide magnetic nanoparticles consist of two components, namely magnetic core and organic coatings, and the role of the contribution of either of these is difficult to assess. Moreover, the toxicity of iron oxide magnetic nanoparticles is not dependent only on organic coating but cell type as well. Iron oxide magnetic nanoparticles can induce oxidative stress by disturbing oxidant/antioxidant balance.

Based on the size, charge and shape, the potential toxicity of iron oxide magnetic nanoparticles has been closely related to two factors, their size and charge, while less is reported about the relation to shape. Sizes between 10 and 100 nm have longer half-lifes in the blood and are small enough to go through capillaries; these considerations are to be kept in mind while cancer imaging is under discussion relevant to size ( Estelrich et al., 2015 ; Xu et al., 2016 ). Organic polymers of molecular weights above 50 kDa has been found to have an effective blood half-life of 6 h. The in vivo effect of shape on the toxic behavior of iron oxide magnetic nanoparticles is difficult to assess because of the difficulty in the preparation of comparable samples of nanoparticles with different shapes ( McMahon and Bulte, 2018 ).

Theranostics

Theranostic is the seamless integration of therapy and diagnosis into one step; it is perhaps one of the trend setters in modern day research. The pivotal idea behind theranostic is that nanoparticles are unique in nature, i.e., these are capable of imaging and treating a lesion simultaneously ( Khandhar et al., 2017 ). A careful survey of the literature revealed it was 2006 when this term was coined for the first time in scientific literature; theranostics was described as “Future nanotechnology developments will most likely include the capability of designing and fabricating multifunctional nanoparticles to combine imaging and therapeutic capabilities (“theranostics”)” ( Sun et al., 2016 ). In this regard, iron oxide magnetic nanoparticles have attracted interest due to their unique magnetic properties which make these excellent MRI contrasting agents and effective cytotoxic agents against tumors.

The use of nanoparticles allows imaging and treatment to be achieved simultaneously, in addition it also assists multiple treatment modalities in combination. This multi-modal approach was observed during the use of cisplatin-bonded gold nanospheres to administer chemo-radiotherapy in GBM cell models, leading to apoptic cell death after the intracellular uptake ( Li et al., 2017 ). During the experiment, it was observed that due exposure to radiation in either of the metals started functioning as high atomic number radiosensitising agents and initiated the release of photoelectrons and Auger electrons. Radiosensitisation of the nanoparticle's formulations enhanced the in vitro cytotoxic effects of chemo- and radiotherapy and contributed to the photoablation of tumor cells ( Bissonnette and Bergeron, 2006 ). These results upstretched the prospect of concomitant administration of diagnostics and multiple forms of therapy.

Photoablation therapy is used for cancer treatment and is divided into two types, photothermal therapy (PTT) and photodynamic therapy (PDT) ( Zheng et al., 2008 ). Among these, PTT is an excellent contender for cancer treatment and focuses on the use of photo-induced heat to kill cancer cells ( Her et al., 2017 ). While in PDT treatment, a poorly soluble drug and visible light irradiations are used at certain wavelengths for generating reactive oxygen species such as singlet oxygen to kill cancer cells ( McNamara and Tofail, 2017 ). PTT is an attractive method owing to advantages such as the safety of non-target regions, its minimally invasive nature, fast recovery, and so on. Magnetic nanoparticles generate heat when placed in a varying magnetic field due to magnetic hysteresis loss (Neel-relaxation and Brown-relaxation). This led scientists to apply these magnetic in hyperthermia treatment which is considered as a supplementary treatment to radiation, chemotherapy and surgery in cancer therapy ( Marangon et al., 2017 ). Magnetic induction hyperthermia is based on the fact that when alternating magnetic field is applied to magnetic nanoparticles, induced currents are generated and consequently heat is produced in magnetic nanoparticles. Based on this principal, when magnetic fluids are exposed to alternating magnetic field, the fluids turn into powerful heat sources, destroying tumor cells, since these cells are more sensitive to temperatures more than 41°C than their normal counterparts ( Gomer et al., 2016 ). PTT has certain disadvantages as well, like the need for high-power lasers and the thermal destruction of cancer selective cell lines. Recently, PDT has attracted considerable attention in cancer treatment, as it is a non-invasive method, low energy light, site-specific tumor targeting and negligible side effects. Due to the poor solubility of drugs in water, these tend to accumulate in physiological media, hence indicating the need to work on developing improved drug delivery systems.

Photoacoustic imaging is a new method which is a combination of optical and acoustic imaging of burns, studying blood vessels, melanoma sites etc. This technique gives in-depth analysis of various tissues, e.g., breast cancer cells, brain cancer cells and tumor monitoring ( Sakellari et al., 2016 ). In photoacoustic tomography, the laser system used for photoacoustic imaging (532 nm) has great promise for non-invasive early diagnosis and the imaging of tumor cells and tissues. Gold nanoparticles have proven to be excellent non-invasive contrasting agents for early diagnosis of tumor by photoacoustic imaging. Computed tomography is one of the most common hospital's diagnostic tools; it is another excellent imaging method for grabbing anatomical information. It is a choice made for clinical applications because of cost, efficiency, availability, deep tissue penetration and high spatial resolution. In this method, gold nanoparticles can be used as contrasting agents because of the high X-ray absorption, lower toxicity and slow clearance in the body. it was also suggested that gold nanoparticles may replace conventional iodine based contrasting agents as these reagents display renal toxicity and fast excretion. Gold nanoparticles displayed excellent biocompatibility, enhanced stability and increased accumulation in computed tomography tumor imaging ( Kobayashi et al., 2016 ). Ultrasound imaging is a clinical diagnostic tool extensively used due to interesting features such as being non-invasive, cost-effective and portable. Like all the other diagnostic imaging methods, contrasting agents can be adopted to enhance imaging precision in ultrasound imaging. In this method, microscale fluorocarbon bubbles are typically used as contrasting agents: in literature, ultrasound imaging contrasting agents should feature four characteristics, easy fabrication, easy administration, high biosafety and excellent echogenicity.

Atherosclerosis

Atherosclerosis, a complex disease and one of the leading causes of death in the developed world ( Chen et al., 2016 ). It is a chronic inflammation and remodeling processes which leads to the stenosis of the aorta; generally, it's a gradual process spanning over decades, but under certain conditions, it grows rapidly leading to an ischaemia.

In recent years, an extraordinary number of research projects have been funded to make advances in the diagnosis, prognosis and treatment of this fatal disease ( Yildirim et al., 2016 ). Pathological detection of atherosclerosis has improved significantly with the use of magnetic resonance imaging due to contrasting agents and their excellent spatial resolution and average sensitivity; modern-day research in this area is probing new contrasting agents for improved imaging ( Fernández-Ruiz, 2016 ). Other techniques used to detect early-stage atherosclerosis include computed tomography, photoacoustic tomography, positron emission tomography, single-photon emission computed tomography and fluorescence molecular tomography and every technique has pluses as well as minuses. For example, some methods give outstanding sensitivity but low resolution while others have excellent resolution but lower sensitivity. Magnetic nanomaterials have shown the promise to implement magnetic nanomaterials binding to specific surfaces to reduce the detection time ( Brown et al., 2016 ).

As discussed earlier, iron oxide magnetic nanoparticles' magnetic moments rotate rapidly when exposed to external magnetic field and the magnetic flux gets enhanced; and upon the removal of the magnetic field, Brownian motion causes randomization of the magnetic field; this condition is superparamagentism which is observable only at nanoscale. Commonly used as good contrasting agents are gadolinium-based substances; with adverse characteristics including cytotoxicity and the persistent accumulation of gadolinium. Iron oxide magnetic nanoparticles have better results as magnetic resonance imaging contrasting agents when compared with gadolinium and manganese oxide nanoparticles ( Li et al., 2016 ). Gadolinium-based formulations are still dominating contrasting agents; however, after a careful survey of literature and recent clinical trials evidences, the future of iron oxide magnetic nanoparticles is highly promissory for diagnostic imaging guided therapy with the suitable incorporation of specific ligands to well-defined pathologies. So far, we have learnt that atherosclerosis may occur anywhere in the vascular system and the lack of sensitivity in the use of commercially available contrasting agents is a major challenge for the early diagnosis of the plaque which usually possesses a thickness and length. Positron emission tomography has low resolution for the detection of atherosclerotic plaque while the magnetic resonance imaging technique has excellent resolution but lacks sensitivity for pertinent screening. Superparamagnetic iron oxide nanoparticles synthesized by polyol method were successfully applied to mice as an MRI contrasting agent with promising results 5 h after post-injection treatment ( Wang et al., 2016 ). More recently, the in vivo application of magnetic nanoparticles in the range of 90 nm allowed for excellent visuals of atherosclerotic plaque in mice; similarly, the NIR-fluorescence based method approach have also been applied with interesting results ( Cuadrado et al., 2016 ; Yoo et al., 2016 ; Schneider and Lassalle, 2017 ). In all three techniques, it was observed that the magnetic nanoparticles got accumulated in the atherosclerotic area.

Concluding Remarks

Magnetic nanoparticles possess a great promise in drug-delivery systems due to their unique properties to overcome some of the problems to efficiently target diverse cell types. The future is encouraging as well as challenging and novel research ideas are needed to be worked out to prevent its limitations for the therapy of more diseases. Iron oxide magnetic nanoparticles possess a strong candidature for aqueous/non-aqueous phase solubility with great potential in medical applications. To achieve this, several factors play a key-role including suitable precursors, pH of the medium, coating agents and solvents for the synthesis of magnetic nanoparticles. Aqueous phase solubility can be significantly improved by using water-soluble surface functionalization agents via thermal decomposition, co-precipitation, microwave and high-temperature methods.

MRI is a non-invasive imaging technique used to study anatomical site and biologically compatible nanomaterials aid in detailed images for more accurate diagnosis. Magnetic nanoparticles act as contrasting agents which are advantageous to improve the contrast in these images. Magnetic iron oxide nanoparticles have been the key focus in this review article; which are stabilized by increasing the hydrophilicity through coatings onto the metal surface followed by the attachment of additional ligands like antibodies etc. Next is the specific linking to signal-secreting cells which permits specific agglomeration of nanoparticles to the inflamed/tumor bearing site. Contrast is still a challenge in MRI and new improvements are being sought through labeled magnetic nanoparticles with a fluorescent protein, such as green fluorescent protein or red fluorescent protein; giving rise to a distinct color of the target area under investigation. This research requires more intense in vivo studies which will lead to improve the biological compatibilities and any possible negative side effects associated with the injection of magnetic nanoparticles. Magnetic iron oxide nanoparticles comparatively proved to be a highly reliable and better theranostic option as gadolinium complexes gives excellent contrast, but these are nephrotoxic.

Finally, the scientific information collected here while compiling this review opens novel insights into the role of magnetic nanoparticles to develop nanocarriers enabled to increase the efficiency of the modern-day theranostics.

Author Contributions

SG compiled this review article with collective scholarly contribution of all the co-authors.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: iron oxide magnetic nanoparticles, synthetic routes, drug delivery, imaging, theranostic, atherosclerosis

Citation: Gul S, Khan SB, Rehman IU, Khan MA and Khan MI (2019) A Comprehensive Review of Magnetic Nanomaterials Modern Day Theranostics. Front. Mater. 6:179. doi: 10.3389/fmats.2019.00179

Received: 12 February 2019; Accepted: 09 July 2019; Published: 31 July 2019.

Reviewed by:

Copyright © 2019 Gul, Khan, Rehman, Khan and Khan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: M. I. Khan, gorikhan@kust.edu.pk

This article is part of the Research Topic

Functional Materials for Bio-Applications

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Nanoscience and Nanotechnology

p-ISSN: 2163-257X    e-ISSN: 2163-2588

2013;  3(3): 62-74

doi:10.5923/j.nn.20130303.06

Semiconductor Nanomaterials, Methods and Applications: A Review

Sagadevan Suresh

Department of Physics, Sree Sastha Institute of Engineering and Technology, Chembarambakkam, Chennai, 600123

Copyright © 2012 Scientific & Academic Publishing. All Rights Reserved.

When the size of semiconductor materials is reduced to nanoscale, their physical and chemical properties change drastically, resulting in unique properties due to their large surface area or quantum size effect. Currently, semiconductor nanomaterials and devices are still in the research stage, but they are promising for applications in many fields, such as solar cells, nanoscale electronic devices, light-emitting nano devices, laser technology, waveguide, chemicals and biosensors. Further development of nanotechnology will certainly lead to significant breakthroughs in the semiconductor industry. This paper deals with the some of the current initiatives and critical issues in the improvement of semiconductors based on nanostructures and nanodevices.

Keywords: Semiconductors, Nanomaterials, Solar Cells, Light Emitting Nano Devices

Cite this paper: Sagadevan Suresh, Semiconductor Nanomaterials, Methods and Applications: A Review, Nanoscience and Nanotechnology , Vol. 3 No. 3, 2013, pp. 62-74. doi: 10.5923/j.nn.20130303.06.

Article Outline

1. introduction, 2. introductions to nanoscience and nanotechnology, 3. semiconductor nanoparticles, 4. classifications of semiconductor nanostructures, 4.1. zero dimensional (0d) nanostructures, 4.2. quasi one dimensional (1d) nanostructures, 4.3. two dimensional (2d) nanostructures, 4.4. three dimensional (3d) nanosystems, 5. core-shell nanostructures, 5.1. types of core-shell nanocrystals, 6. quantum confinement effects, 6.1. weak confinement regime, 6.2. moderate confinement regime, 6.3. strong confinement regime, 7. nanoparticles synthesis methods, 7.1. wet chemical methods, 7.2. sol-gel, 7.3. solvothermal/hydrothermal method, 7.3.1. main parameters governing solvothermal reactions, 7.4. surface modification of nanocrystals and interparticle forces in solution, 7.5. van der waals forces, 7.6. magnetic dipolar forces, 7.7. electrostatic forces, 7.8. steric forces, 7.9. solvation forces, 8. application of semiconductor nanomaterials, 9. semiconductor nanomaterials for hydrogen production, 10. silicon semiconductor nanomaterials and devices, 11. research on nano optoelectronic sensors and photovoltaic devices, 12. organic optoelectronic materials and devices, 13. conclusions, acknowledgements.

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Nanomedicine: Principles, Properties, and Regulatory Issues

Sara soares.

1 Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

João Sousa

2 REQUIMTE/LAQV, Group of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal

Alberto Pais

3 Department of Chemistry, Coimbra Chemistry Centre, University of Coimbra, Coimbra, Portugal

Carla Vitorino

4 Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal

Several scientific areas have benefited significantly from the introduction of nanotechnology and the respective evolution. This is especially noteworthy in the development of new drug substances and products. This review focuses on the introduction of nanomedicines in the pharmaceutical market, and all the controversy associated to basic concepts related to these nanosystems, and the numerous methodologies applied for enhanced knowledge. Due to the properties conferred by the nanoscale, the challenges for nanotechnology implementation, specifically in the pharmaceutical development of new drug products and respective regulatory issues are critically discussed, mainly focused on the European Union context. Finally, issues pertaining to the current applications and future developments are presented.

Introduction

Over the last years, nanotechnology has been introduced in our daily routine. This revolutionary technology has been applied in multiple fields through an integrated approach. An increasing number of applications and products containing nanomaterials or at least with nano-based claims have become available. This also happens in pharmaceutical research. The use of nanotechnology in the development of new medicines is now part of our research and in the European Union (EU) it has been recognized as a Key Enabling Technology, capable of providing new and innovative medical solution to address unmet medical needs (Bleeker et al., 2013 ; Ossa, 2014 ; Tinkle et al., 2014 ; Pita et al., 2016 ).

The application of nanotechnology for medical purposes has been termed nanomedicine and is defined as the use of nanomaterials for diagnosis, monitoring, control, prevention and treatment of diseases (Tinkle et al., 2014 ). However, the definition of nanomaterial has been controversial among the various scientific and international regulatory corporations. Some efforts have been made in order to find a consensual definition due to the fact that nanomaterials possess novel physicochemical properties, different from those of their conventional bulk chemical equivalents, due to their small size. These properties greatly increase a set of opportunities in the drug development; however, some concerns about safety issues have emerged. The physicochemical properties of the nanoformulation which can lead to the alteration of the pharmacokinetics, namely the absorption, distribution, elimination, and metabolism, the potential for more easily cross biological barriers, toxic properties and their persistence in the environment and human body are some examples of the concerns over the application of the nanomaterials (Bleeker et al., 2013 ; Tinkle et al., 2014 ).

To avoid any concern, it is necessary establishing an unambiguous definition to identify the presence of nanomaterials. The European Commission (EC) created a definition based on the European Commission Joint Research Center and on the Scientific Committee on Emerging and Newly Identified Health Risks. This definition is only used as a reference to determine whether a material is considered a nanomaterial or not; however, it is not classified as hazardous or safe. The EC claims that it should be used as a reference for additional regulatory and policy frameworks related to quality, safety, efficacy, and risks assessment (Bleeker et al., 2013 ; Boverhof et al., 2015 ).

Nanomaterial

According to the EC recommendation, nanomaterial refers to a natural, incidental, or manufactured material comprising particles, either in an unbound state or as an aggregate wherein one or more external dimensions is in the size range of 1–100 nm for ≥50% of the particles, according to the number size distribution. In cases of environment, health, safety or competitiveness concern, the number size distribution threshold of 50% may be substituted by a threshold between 1 and 50%. Structures with one or more external dimensions below 1 nm, such as fullerenes, graphene flakes, and single wall carbon nanotubes, should be considered as nanomaterials. Materials with surface area by volume in excess of 60 m 2 /cm 3 are also included (Commission Recommendation., 2011 ). This defines a nanomaterial in terms of legislation and policy in the European Union. Based on this definition, the regulatory bodies have released their own guidances to support drug product development.

The EMA working group introduces nanomedicines as purposely designed systems for clinical applications, with at least one component at the nanoscale, resulting in reproducible properties and characteristics, related to the specific nanotechnology application and characteristics for the intended use (route of administration, dose), associated with the expected clinical advantages of nano-engineering (e.g., preferential organ/tissue distribution; Ossa, 2014 ).

Food and Drug Administration (FDA) has not established its own definition for “nanotechnology,” “nanomaterial,” “nanoscale,” or other related terms, instead adopting the meanings commonly employed in relation to the engineering of materials that have at least one dimension in the size range of approximately 1 nanometer (nm) to 100 nm. Based on the current scientific and technical understanding of nanomaterials and their characteristics, FDA advises that evaluations of safety, effectiveness, public health impact, or regulatory status of nanotechnology products should consider any unique properties and behaviors that the application of nanotechnology may impart (Guidance for Industry, FDA, 2014 ).

According to the former definition, there are three fundamental aspects to identify the presence of a nanomaterial, which are size, particle size distribution (PSD) and surface area (Commission Recommendation., 2011 ; Bleeker et al., 2013 ; Boverhof et al., 2015 ).

The most important feature to take into account is size, because it is applicable to a huge range of materials. The conventional range is from 1 to 100 nm. However, there is no bright line to set this limit. The maximum size that a material can have to be considered nanomaterial is an arbitrary value because the psychochemical and biological characteristics of the materials do not change abruptly at 100 nm. To this extent, it is assumed that other properties should be taken in account (Lövestam et al., 2010 ; Commission Recommendation., 2011 ; Bleeker et al., 2013 ; Boverhof et al., 2015 ).

The pharmaceutical manufacturing of nanomaterials involves two different approaches: top down and bottom down. The top down process involves the breakdown of a bulk material into a smaller one or smaller pieces by mechanical or chemical energy. Conversely, the bottom down process starts with atomic or molecular species allowing the precursor particles to increase in size through chemical reaction (Luther, 2004 ; Oberdörster, 2010 ; Boverhof et al., 2015 ). These two processes of manufacturing are in the origin of different forms of particles termed primary particle, aggregate and agglomerate (Figure ​ (Figure1). 1 ). The respective definition is (sic) :

Schematic representation of the different forms of particles: primary particle, aggregate, and agglomerate (reproduced with permission from Oberdörster, 2010 ).

“particle is a minute piece of matter with defined physical boundaries” (Oberdörster, 2010 ; Commission Recommendation., 2011 );

“aggregate denotes a particle comprising strongly bound or fused particles”—and the external surface can be smaller than the sum of the surface areas of the individual particles (Oberdörster, 2010 ; Commission Recommendation., 2011 );

“agglomerate means a collection of weakly bound particles or aggregates where the resulting external surface area are similar to the sum of the surface areas of the individual components” (Oberdörster, 2010 ; Commission Recommendation., 2011 ).

Considering the definition, it is understandable why aggregates and agglomerates are included. They may still preserve the properties of the unbound particles and have the potential to break down in to nanoscale (Lövestam et al., 2010 ; Boverhof et al., 2015 ). The lower size limit is used to distinguish atoms and molecules from particles (Lövestam et al., 2010 ).

Particle size distribution

The PSD is a parameter widely used in the nanomaterial identification, reflecting the range of variation of sizes. It is important to set the PSD, because a nanomaterial is usually polydisperse, which means, it is commonly composed by particles with different sizes (Commission Recommendation., 2011 ; Bleeker et al., 2013 ; Boverhof et al., 2015 ).

Surface area

The determination of the surface area by volume is a relational parameter, which is necessary when requested by additional legislation. The material is under the definition if the surface area by volume is larger than 60 m 2 /cm 3 , as pointed out. However, the PSD shall prevail, and for example, a material is classified as a nanomaterial based on the particle size distribution, even if the surface area by volume is lower than the specified 60 m 2 /cm 3 (Commission Recommendation., 2011 ; Bleeker et al., 2013 ; Boverhof et al., 2015 ).

Dynamic behavior of nanomaterials and applications in nanomedicine

Nanomaterials can be applied in nanomedicine for medical purposes in three different areas: diagnosis (nanodiagnosis), controlled drug delivery (nanotherapy), and regenerative medicine. A new area which combines diagnostics and therapy termed theranostics is emerging and is a promising approach which holds in the same system both the diagnosis/imaging agent and the medicine. Nanomedicine is holding promising changes in clinical practice by the introduction of novel medicines for both diagnosis and treatment, having enabled to address unmet medical needs, by (i) integrating effective molecules that otherwise could not be used because of their high toxicity (e.g., Mepact), (ii) exploiting multiple mechanisms of action (e.g., Nanomag, multifunctional gels), (iii) maximizing efficacy (e.g., by increasing bioavailability) and reducing dose and toxicity, (iv) providing drug targeting, controlled and site specific release, favoring a preferential distribution within the body (e.g., in areas with cancer lesions) and improved transport across biological barriers (Chan, 2006 ; Méndez-Rojas et al., 2009 ; Zhang et al., 2012 ; Ossa, 2014 ).

This is a result of intrinsic properties of nanomaterials that have brought many advantages in the pharmaceutical development. Due to their small size, nanomaterials have a high specific surface area in relation to the volume. Consequently, the particle surface energy is increased, making the nanomaterials much more reactive. Nanomaterials have a tendency to adsorb biomolecules, e.g., proteins, lipids, among others, when in contact with the biological fluids. One of the most important interactions with the living matter relies on the plasma/serum biomoleculeadsorption layer, known as “corona,” that forms on the surface of colloidal nanoparticles (Pino et al., 2014 ). Its composition is dependent on the portal of entry into the body and on the particular fluid that the nanoparticles come across with (e.g., blood, lung fluid, gastro-intestinal fluid, etc.). Additional dynamic changes can influence the “corona” constitution as the nanoparticle crosses from one biological compartment to another one (Pearson et al., 2014 ; Louro, 2018 ).

Furthermore, optical, electrical and magnetic properties can change and be tunable through electron confinement in nanomaterials. In addition, nanomaterials can be engineered to have different size, shape, chemical composition and surface, making them able to interact with specific biological targets (Oberdörster et al., 2005 ; Kim et al., 2010 ). A successful biological outcome can only be obtained resorting to careful particle design. As such, a comprehensive knowledge of how the nanomaterials interact with biological systems are required for two main reasons.

The first one is related to the physiopathological nature of the diseases. The biological processes behind diseases occur at the nanoscale and can rely, for example, on mutated genes, misfolded proteins, infection by virus or bacteria. A better understanding of the molecular processes will provide the rational design on engineered nanomaterials to target the specific site of action desired in the body (Kim et al., 2010 ; Albanese et al., 2012 ). The other concern is the interaction between nanomaterial surface and the environment in biological fluids. In this context, characterization of the biomolecules corona is of utmost importance for understanding the mutual interaction nanoparticle-cell affects the biological responses. This interface comprises dynamic mechanisms involving the exchange between nanomaterial surfaces and the surfaces of biological components (proteins, membranes, phospholipids, vesicles, and organelles). This interaction stems from the composition of the nanomaterial and the suspending media. Size, shape, surface area, surface charge and chemistry, energy, roughness, porosity, valence and conductance states, the presence of ligands, or the hydrophobic/ hydrophilic character are some of the material characteristics that influence the respective surface properties. In turn, the presence of water molecules, acids and bases, salts and multivalent ions, surfactants are some of the factors related to the medium that will influence the interaction. All these aspects will govern the characteristics of the interface between the nanomaterial and biological components and, consequently, promote different cellular fates (Nel et al., 2009 ; Kim et al., 2010 ; Albanese et al., 2012 ; Monopoli et al., 2012 ).

A deeper knowledge about how the physicochemical properties of the biointerface influence the cellular signaling pathway, kinetics and transport will thus provide critical rules to the design of nanomaterials (Nel et al., 2009 ; Kim et al., 2010 ; Albanese et al., 2012 ; Monopoli et al., 2012 ).

Challenges in pharmaceutical development

The translation of nanotechnology form the bench to the market imposed several challenges. General issues to consider during the development of nanomedicine products including physicochemical characterization, biocompatibility, and nanotoxicology evaluation, pharmacokinetics and pharmacodynamics assessment, process control, and scale-reproducibility (Figure ​ (Figure2) 2 ) are discussed in the sections that follow.

Schematic representation of the several “barriers” found throughout the development of a nanomedicine product.

Physicochemical characterization

The characterization of a nanomedicine is necessary to understand its behavior in the human body, and to provide guidance for the process control and safety assessment. This characterization is not consensual in the number of parameters required for a correct and complete characterization. Internationally standardized methodologies and the use of reference nanomaterials are the key to harmonize all the different opinions about this topic (Lin et al., 2014 ; Zhao and Chen, 2016 ).

Ideally, the characterization of a nanomaterial should be carried out at different stages throughout its life cycle, from the design to the evaluation of its in vitro and in vivo performance. The interaction with the biological system or even the sample preparation or extraction procedures may modify some properties and interfere with some measurements. In addition, the determination of the in vivo and in vitro physicochemical properties is important for the understanding of the potential risk of nanomaterials (Lin et al., 2014 ; Zhao and Chen, 2016 ).

The Organization for Economic Co-operation and Development started a Working Party on Manufactured Nanomaterials with the International Organization for Standardization to provide scientific advice for the safety use of nanomaterials that include the respective physicochemical characterization and the metrology. However, there is not an effective list of minimum parameters. The following characteristics should be a starting point to the characterization: particle size, shape and size distribution, aggregation and agglomeration state, crystal structure, specific surface area, porosity, chemical composition, surface chemistry, charge, photocatalytic activity, zeta potential, water solubility, dissolution rate/kinetics, and dustiness (McCall et al., 2013 ; Lin et al., 2014 ).

Concerning the chemical composition, nanomaterials can be classified as organic, inorganic, crystalline or amorphous particles and can be organized as single particles, aggregates, agglomerate powders or dispersed in a matrix which give rise to suspensions, emulsions, nanolayers, or films (Luther, 2004 ).

Regarding dimension, if a nanomaterial has three dimensions below 100 nm, it can be for example a particle, a quantum dot or hollow sphere. If it has two dimensions below 100 nm it can be a tube, fiber or wire and if it has one dimension below 100 nm it can be a film, a coating or a multilayer (Luther, 2004 ).

Different techniques are available for the analysis of these parameters. They can be grouped in different categories, involving counting, ensemble, separation and integral methods, among others (Linsinger et al., 2012 ; Contado, 2015 ).

Counting methods

Counting methods make possible the individualization of the different particles that compose a nanomaterial, the measurement of their different sizes and visualization of their morphology. The particles visualization is preferentially performed using microscopy methods, which include several variations of these techniques. Transmission Electron Microscopy (TEM), High-Resolution TEM, Scanning Electron Microscopy (SEM), cryo-SEM, Atomic Force Microscopy and Particle Tracking Analysis are just some of the examples. The main disadvantage of these methods is the operation under high-vacuum, although recently with the development of cryo-SEM sample dehydration has been prevented under high-vacuum conditions (Linsinger et al., 2012 ; Contado, 2015 ; Hodoroaba and Mielke, 2015 ).

Fractionation methods

These methods involve two steps of sample treatment: the separation of the particles into a monodisperse fraction, followed by the detection of each fraction. Field-Flow Fractionation (FFF), Analytical Centrifugation (AC) and Differential Electrical Mobility Analysis are some of the techniques that can be applied. The FFF techniques include different methods which separate the particles according to the force field applied. AC separates the particles through centrifugal sedimentation (Linsinger et al., 2012 ; Contado, 2015 ; Hodoroaba and Mielke, 2015 ).

Ensemble methods

Ensemble methods allow the report of intensity-weighted particle sizes. The variation of the measured signal over time give the size distribution of the particles extracted from a combined signal. Dynamic Light Scattering (DLS), Small-angle X-ray Scattering (SAXS) and X-ray Diffraction (XRD) are some of the examples. DLS and QELS are based on the Brownian motion of the sample. XRD is a good technique to obtain information about the chemical composition, crystal structure and physical properties (Linsinger et al., 2012 ; Contado, 2015 ; Hodoroaba and Mielke, 2015 ).

Integral methods

The integral methods only measure an integral property of the particle and they are mostly used to determine the specific surface area. Brunauer Emmet Teller is the principal method used and is based on the adsorption of an inert gas on the surface of the nanomaterial (Linsinger et al., 2012 ; Contado, 2015 ; Hodoroaba and Mielke, 2015 ).

Other relevant technique is the electrophoretic light scattering (ELS) used to determine zeta potential, which is a parameter related to the overall charge a particle acquires in a particular medium. ELS measures the electrophoretic mobility of particles in dispersion, based on the principle of electrophoresis (Linsinger et al., 2012 ).

The Table ​ Table1 1 shows some of principal methods for the characterization of the nanomaterials including the operational principle, physicochemical parameters analyzed and respective limitations.

Some of the principal methods for the characterization of the nanomaterials, operation principle, physicochemical parameters analyzed, and respective limitations (Luther, 2004 ; Linsinger et al., 2012 ; Lin et al., 2014 ; Contado, 2015 ; Hodoroaba and Mielke, 2015 ).

Process control—understanding the critical manufacturing steps

Another challenge in the pharmaceutical development is the control of the manufacturing process by the identification of the critical parameters and technologies required to analyse them (Gaspar, 2010 ; Gaspar et al., 2014 ; Sainz et al., 2015 ).

New approaches have arisen from the pharmaceutical innovation and the concern about the quality and safety of new medicines by regulatory agencies (Gaspar, 2010 ; Gaspar et al., 2014 ; Sainz et al., 2015 ).

Quality-by-Design (QbD), supported by Process Analytical Technologies (PAT) is one of the pharmaceutical development approaches that were recognized for the systematic evaluation and control of nanomedicines (FDA, 2004 ; Gaspar, 2010 ; Gaspar et al., 2014 ; Sainz et al., 2015 ; European Medicines Agency, 2017 ).

Note that some of the physicochemical characteristics of nanomaterials can change during the manufacturing process, which compromises the quality and safety of the final nanomedicine. The basis of QbD relies on the identification of the Quality Attributes (QA), which refers to the chemical, physical or biological properties or another relevant characteristic of the nanomaterial. Some of them may be modified by the manufacturing and should be within a specific range for quality control purposes. In this situation, these characteristics are considered Critical Quality Attributes (CQA). The variability of the CQA can be caused by the critical material attributes and process parameters (Verma et al., 2009 ; Riley and Li, 2011 ; Bastogne, 2017 ; European Medicines Agency, 2017 ).

The quality should not be tested in nanomedicine, but built on it instead, by the understanding of the therapeutic purpose, pharmacological, pharmacokinetic, toxicological, chemical and physical properties of the medicine, process formulation, packaging, and the design of the manufacturing process. This new approach allows better focus on the relevant relationships between the characteristics, parameters of the formulation and process in order to develop effective processes to ensure the quality of the nanomedicines (FDA, 2014 ).

According to the FDA definition “PAT is a system for designing, analzsing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring final product quality” (FDA, 2014 ). The PAT tools analyse the critical quality and performance attributes. The main point of the PAT is to assure and enhance the understanding of the manufacturing concept (Verma et al., 2009 ; Riley and Li, 2011 ; FDA, 2014 ; Bastogne, 2017 ; European Medicines Agency, 2017 ).

Biocompatibility and nanotoxicology

Biocompatibility is another essential property in the design of drug delivery systems. One very general and brief definition of a biocompatible surface is that it cannot trigger an undesired' response from the organism. Biocompatibility is alternatively defined as “the ability of a material to perform with an appropriate response in a specific application” (Williams, 2003 ; Keck and Müller, 2013 ).

Pre-clinical assessment of nanomaterials involve a thorough biocompatibility testing program, which typically comprises in vivo studies complemented by selected in vitro assays to prove safety. If the biocompatibility of nanomaterials cannot be warranted, potentially advantageous properties of nanosystems may raise toxicological concerns.

Regulatory agencies, pharmaceutical industry, government, and academia are making efforts to accomplish specific and appropriate guidelines for risk assessment of nanomaterials (Hussain et al., 2015 ).

In spite of efforts to harmonize the procedures for safety evaluation, nanoscale materials are still mostly treated as conventional chemicals, thus lacking clear specific guidelines for establishing regulations and appropriate standard protocols. However, several initiatives, including scientific opinions, guidelines and specific European regulations and OECD guidelines such as those for cosmetics, food contact materials, medical devices, FDA regulations, as well as European Commission scientific projects (NanoTEST project, www.nanotest-fp7.eu ) specifically address nanomaterials safety (Juillerat-Jeanneret et al., 2015 ).

In this context, it is important to identify the properties, to understand the mechanisms by which nanomaterials interact with living systems and thus to understand exposure, hazards and their possible risks.

Note that the pharmacokinetics and distribution of nanoparticles in the body depends on their surface physicochemical characteristics, shape and size. For example, nanoparticles with 10 nm in size were preferentially found in blood, liver, spleen, kidney, testis, thymus, heart, lung, and brain, while larger particles are detected only in spleen, liver, and blood (De Jong et al., 2008 ; Adabi et al., 2017 ).

In turn, the surface of nanoparticles also impacts upon their distribution in these organs, since their combination with serum proteins available in systemic circulation, influencing their cellular uptake. It should be recalled that a biocompatible material generates no immune response. One of the cause for an immune response can rely on the adsorption pattern of body proteins. An assessment of the in vivo protein profile is therefore crucial to address these interactions and to establish biocompatibility (Keck et al., 2013 ).

Finally, the clearance of nanoparticles is also size and surface dependent. Small nanoparticles, bellow 20–30 nm, are rapidly cleared by renal excretion, while 200 nm or larger particles are more efficiently taken up by mononuclear phagocytic system (reticuloendothelial system) located in the liver, spleen, and bone marrow (Moghimi et al., 2001 ; Adabi et al., 2017 ).

Studies are required to address how nanomaterials penetrate cells and tissues, and the respective biodistribution, degradation, and excretion.

Due to all these issues, a new field in toxicology termed nanotoxicology has emerged, which aims at studying the nanomaterial effects deriving from their interaction with biological systems (Donaldson et al., 2004 ; Oberdörster, 2010 ; Fadeel, 2013 ).

Evaluation methods

The evaluation of possible toxic effects of the nanomaterials can be ascribed to the presence of well-known molecular responses in the cell. Nanomaterials are able to disrupt the balance of the redox systems and, consequently, lead to the production of reactive species of oxygen (ROS). ROS comprise hydroxyl radicals, superoxide anion and hydrogen peroxide. Under normal conditions, the cells produce these reactive species as a result of the metabolism. However, when exposed to nanomaterials the production of ROS increases. Cells have the capacity to defend itself through reduced glutathione, superoxide dismutase, glutathione peroxidase and catalase mechanisms. The superoxide dismutase converts superoxide anion into hydrogen peroxide and catalase, in contrast, converts it into water and molecular oxygen (Nel et al., 2006 ; Arora et al., 2012 ; Azhdarzadeh et al., 2015 ). Glutathione peroxidase uses glutathione to reduce some of the hydroperoxides. Under normal conditions, the glutathione is almost totally reduced. Nevertheless, an increase in ROS lead to the depletion of the glutathione and the capacity to neutralize the free radicals is decreased. The free radicals will induce oxidative stress and interact with the fatty acids in the membranes of the cell (Nel et al., 2006 ; Arora et al., 2012 ; Azhdarzadeh et al., 2015 ).

Consequently, the viability of the cell will be compromised by the disruption of cell membranes, inflammation responses caused by the upregulation of transcription factors like the nuclear factor kappa β, activator protein, extracellular signal regulated kinases c-Jun, N-terminal kinases and others. All these biological responses can result on cell apoptosis or necrosis. Distinct physiological outcomes are possible due to the different pathways for cell injury after the interaction between nanomaterials and cells and tissues (Nel et al., 2006 ; Arora et al., 2012 ; Azhdarzadeh et al., 2015 ).

Over the last years, the number of scientific publications regarding toxicological effects of nanomaterials have increased exponentially. However, there is a big concern about the results of the experiments, because they were not performed following standard and harmonized protocols. The nanomaterial characterization can be considered weak once there are not standard nanomaterials to use as reference and the doses used in the experiences sometimes cannot be applied in the biological system. Therefore, the results are not comparable. For a correct comparison, it is necessary to perform a precise and thorough physicochemical characterization to define risk assessment guidelines. This is the first step for the comparison between data from biological and toxicological experiments (Warheit, 2008 ; Fadeel et al., 2015 ; Costa and Fadeel, 2016 ).

Although nanomaterials may have an identical composition, slight differences e.g., in the surface charge, size, or shape could impact on their respective activity and, consequently, on their cellular fate and accumulation in the human body, leading to different biological responses (Sayes and Warheit, 2009 ).

Sayes and Warheit ( 2009 ) proposed a three phases model for a comprehensive characterization of nanomaterials. Accordingly, the primary phase is achieved in the native state of the nanomaterial, specifically, in its dry state. The secondary characterization is performed with the nanomaterials in the wet phase, e.g., as solution or suspension. The tertiary characterization includes i n vitro and in vivo interactions with biological systems. The tertiary characterization is the most difficult from the technical point of view, especially in vivo , because of all the ethical questions concerning the use of animals in experiments (Sayes and Warheit, 2009 ).

Traditional toxicology uses of animals to conduct tests. These types of experiments using nanomaterials can be considered impracticable and unethical. In addition, it is time-consuming, expensive and sometimes the end points achieved are not enough to correctly correlate with what happens in the biological systems of animals and the translation to the human body (Collins et al., 2017 ).

In vitro studies are the first assays used for the evaluation of cytotoxicity. This approach usually uses cell lines, primary cells from the tissues, and/or a mixture of different cells in a culture to assess the toxicity of the nanomaterials. Different in vitro cytotoxicity assays to the analysis of the cell viability, stress, and inflammatory responses are available. There are several cellular processes to determine the cell viability, which consequently results in different assays with distinct endpoints. The evaluation of mitochondrial activity, the lactate dehydrogenase release from the cytosol by tretazolium salts and the detection of the biological marker Caspase-3 are some of the examples that imposes experimental variability in this analysis. The stress response is another example which can be analyzed by probes in the evaluation of the inflammatory response via enzyme linked immunosorbent assay are used (Kroll et al., 2009 ).

As a first approach, in vitro assays can predict the interaction of the nanomaterials with the body. However, the human body possesses compensation mechanisms when exposed to toxics and a huge disadvantage of this model is not to considered them. Moreover, they are less time consuming, more cost-effective, simpler and provide an easier control of the experimental conditions (Kroll et al., 2009 ; Fadeel et al., 2013b ).

Their main drawback is the difficulty to reproduce all the complex interactions in the human body between sub-cellular levels, cells, organs, tissues and membranes. They use specific cells to achieve specific endpoints. In addition, in vitro assays cannot predict the physiopathological response of the human body when exposed to nanomaterials (Kroll et al., 2009 ; Fadeel et al., 2013b ).

Another issue regarding the use of this approach is the possibility of interaction between nanomaterials and the reagents of the assay. It is likely that the reagents used in the in vitro assays interfere with the nanomaterial properties. High adsorption capacity, optical and magnetic properties, catalytic activity, dissolution, and acidity or alkalinity of the nanomaterials are some of the examples of properties that may promote this interaction (Kroll et al., 2009 ).

Many questions have been raised by the regulators related to the lack of consistency of the data produced by cytotoxicity assays. New assays for a correct evaluation of the nanomaterial toxicity are, thus, needed. In this context, new approaches have arisen, such as the in silico nanotoxicology approach. In silico methods are the combination of toxicology with computational tools and bio-statistical methods for the evaluation and prediction of toxicity. By using computational tools is possible to analyse more nanomaterials, combine different endpoints and pathways of nanotoxicity, being less time-consuming and avoiding all the ethical questions (Warheit, 2008 ; Raunio, 2011 ).

Quantitative structure-activity relationship models (QSAR) were one the first applications of computational tools applied in toxicology. QSAR models are based on the hypothesis that the toxicity of nanomaterials and their cellular fate in the body can be predicted by their characteristics, and different biological reactions are the result of physicochemical characteristics, such as size, shape, zeta potential, or surface charge, etc., gathered as a set of descriptors. QSAR aims at identifying the physicochemical characteristics which lead to toxicity, so as to provide alterations to reduce toxicology. A mathematical model is created, which allows liking descriptors and the biological activity (Rusyn and Daston, 2010 ; Winkler et al., 2013 ; Oksel et al., 2015 ).

Currently, toxigenomics is a new area of nanotoxicology, which includes a combination between genomics and nanotoxicology to find alterations in the gene, protein and in the expressions of metabolites (Rusyn et al., 2012 ; Fadeel et al., 2013a ).

Nanotoxicological classification system

Hitherto, different risk assessment approaches have been reported. One of them is the DF4nanoGrouping framework, which concerns a functionality driven scheme for grouping nanomaterials based on their intrinsic properties, system dependent properties and toxicological effects (Arts et al., 2014 , 2016 ). Accordingly, nanomaterials are categorized in four groups, including possible subgroups. The four main groups encompass (1) soluble, (2) biopersistent high aspect ratio, (3) passive, that is, nanomaterials without obvious biological effects and (4) active nanomaterials, that is, those demonstrating surface-related specific toxic properties. The DF4nanoGrouping foresees a stepwise evaluation of nanomaterial properties and effects with increasing biological complexity. In case studies that includes carbonaceous nanomaterials, metal oxide, and metal sulfate nanomaterials, amorphous silica and organic pigments (all nanomaterials having primary particle sizes smaller than 100 nm), the usefulness of the DF4nanoGrouping for nanomaterial hazard assessment has already been established. It facilitates grouping and targeted testing of nanomaterials, also ensuring that enough data for the risk assessment of a nanomaterial are available, and fostering the use of non-animal methods (Landsiedel et al., 2017 ). More recently, DF4nanoGrouping developed three structure-activity relationship classification, decision tree, models by identifying structural features of nanomaterials mainly responsible for the surface activity (size, specific surface area, and the quantum-mechanical calculated property “lowest unoccupied molecular orbital”), based on a reduced number of descriptors: one for intrinsic oxidative potential, two for protein carbonylation, and three for no observed adverse effect concentration (Gajewicz et al., 2018 )

Keck and Müller also proposed a nanotoxicological classification system (NCS) (Figure ​ (Figure3) 3 ) that ranks the nanomaterials into four classes according to the respective size and biodegradability (Müller et al., 2011 ; Keck and Müller, 2013 ).

Nanotoxicological classification (reproduced with permission from Keck and Müller, 2013 ).

Due to the size effects, this parameter is assumed as truly necessary, because when nanomaterials are getting smaller and smaller there is an increase in solubility, which is more evident in poorly soluble nanomaterials than in soluble ones. The adherence to the surface of membranes increases with the decrease of the size. Another important aspect related to size that must be considered is the phagocytosis by macrophages. Above 100 nm, nanomaterials can only be internalized by macrophages, a specific cell population, while nanomaterials below 100 nm can be internalized by any cell due to endocytosis. Thus, nanomaterials below 100 nm are associated to higher toxicity risks in comparison with nanomaterials above 100 nm (Müller et al., 2011 ; Keck and Müller, 2013 ).

In turn, biodegradability was considered a required parameter in almost all pharmaceutical formulations. The term biodegradability applies to the biodegradable nature of the nanomaterial in the human body. Biodegradable nanomaterials will be eliminated from the human body. Even if they cause some inflammation or irritation the immune system will return to the regular function after elimination. Conversely, non-biodegradable nanomaterials will stay forever in the body and change the normal function of the immune system (Müller et al., 2011 ; Keck and Müller, 2013 ).

There are two more factors that must be taken into account in addition to the NCS, namely the route of administration and the biocompatibility surface. When a particle is classified by the NCS, toxicity depends on the route of administration. For example, the same nanomaterials applied dermally or intravenously can pose different risks to the immune system.

In turn, a non-biocompatibility surface (NB) can activate the immune system by adsorption to proteins like opsonins, even if the particle belongs to the class I of the NCS (Figure ​ (Figure3). 3 ). The biocompatibility (B) is dictated by the physicochemical surface properties, irrespective of the size and/or biodegradability. This can lead to further subdivision in eight classes from I-B, I-NB, to IV-B and IV-NB (Müller et al., 2011 ; Keck and Müller, 2013 ).

NCS is a simple guide to the evaluation of the risk of nanoparticles, but there are many other parameters playing a relevant role in nanotoxicity determination (Müller et al., 2011 ; Keck and Müller, 2013 ). Other suggestions encompass more general approaches, combining elements of toxicology, risk assessment modeling, and tools developed in the field of multicriteria decision analysis (Rycroft et al., 2018 ).

Scale-up and reproducibility

A forthcoming challenge in the pharmaceutical development is the scale-up and reproducibility of the nanomedicines. A considerable number of nanomedicines fail these requirements and, consequently, they are not introduced on the pharmaceutical market (Agrahari and Hiremath, 2017 ).

The traditional manufacturing processes do not create three dimensional medicines in the nanometer scale. Nanomedicine manufacturing processes, as already mentioned above, compromise top-down and bottom-down approaches, which include multiple steps, like homogenization, sonication, milling, emulsification, and sometimes, the use of organic solvents and further evaporation. In a small-scale, it is easy to control and achieve the optimization of the formulation. However, at a large scale it becomes very challenging, because slight variations during the manufacturing process can originate critical changes in the physicochemical characteristics and compromise the quality and safety of the nanomedicines, or even the therapeutic outcomes. A detailed definition of the acceptable limits for the CQA is very important, and these parameters must be identified and analyzed at the small-scale, in order to understand how the manufacturing process can change them: this will help the implementation of the larger scale. Thus, a deep process of understanding the critical steps and the analytical tools established for the small-scale will be a greatly help for the introduction of the large scale (Desai, 2012 ; Kaur et al., 2014 ; Agrahari and Hiremath, 2017 ).

Another requirement for the introduction of medicines in the pharmaceutical market is the reproducibility of every batch produced. The reproducibility is achieved in terms of physicochemical characterization and therapeutic purpose. There are specific ranges for the variations between different batches. Slight changes in the manufacturing process can compromise the CQA and, therefore, they may not be within a specific range and create an inter-batch variation (Desai, 2012 ; Kaur et al., 2014 ; Agrahari and Hiremath, 2017 ).

Regulatory challenges

Nanomedicines in the pharmaceutical market.

Over the last decades, nanomedicines have been successfully introduced in the clinical practice and the continuous development in pharmaceutical research is creating more sophisticated ones which are entering in clinic trials. In the European Union, the nanomedicine market is composed by nanoparticles, liposomes, nanocrystals, nanoemulsions, polymeric-protein conjugates, and nanocomplexes (Hafner et al., 2014 ). Table ​ Table2 2 shows some examples of commercially available nanomedicines in the EU (Hafner et al., 2014 ; Choi and Han, 2018 ).

Examples of nanomedicines currently approved in the EU market (Hafner et al., 2014 ; Choi and Han, 2018 ; EMA) 1 .

Nanomedicines and nanosimilars

In the process of approval, nanomedicines were introduced under the traditional framework of the benefit/risk analysis. Another related challenge is the development of a framework for the evaluation of the follow-on nanomedicines at the time of reference medicine patent expiration (Ehmann et al., 2013 ; Tinkle et al., 2014 ).

Nanomedicine comprises both biological and non-biological medical products. The biological nanomedicines are obtained from biological sources, while non-biological are mentioned as non-biological complex drugs (NBCD), where the active principle consists of different synthetic structures (Tinkle et al., 2014 ; Hussaarts et al., 2017 ; Mühlebach, 2018 ).

In order to introduce a generic medicine in the pharmaceutical market, several parameters need to be demonstrated, as described elsewhere. For both biological and non-biological nanomedicines, a more complete analysis is needed, that goes beyond the plasma concentration measurement. A stepwise comparison of bioequivalence, safety, quality, and efficacy, in relation to the reference medicine, which leads to therapeutic equivalence and consequently interchangeability, is required (Astier et al., 2017 ).

For regulatory purposes, the biological nanomedicines are under the framework set by European Medicines Agency (EMA) 1 This framework is a regulatory approach for the follow-on biological nanomedicines, which include recommendations for comparative quality, non-clinical and clinical studies (Mühlebach et al., 2015 ).

The regulatory approach for the follow-on NBCDs is still ongoing. The industry frequently asks for scientific advice and a case-by-case is analyzed by the EMA. Sometimes, the biological framework is the base for the regulation of the NBCDs, because they have some features in common: the structure cannot be fully characterized and the in vivo activity is dependent on the manufacturing process and, consequently, the comparability needs to establish throughout the life cycle, as happens to the biological nanomedicines. Moreover, for some NBCDs groups like liposomes, glatiramoids, and iron carbohydrate complexes, there are draft regulatory approaches, which help the regulatory bodies to create a final framework for the different NBCDs families (Schellekens et al., 2014 ).

EMA already released some reflection papers regarding nanomedicines with surface coating, intravenous liposomal, block copolymer micelle, and iron-based nano-colloidal nanomedicines (European Medicines Agency, 2011 , 2013a , b , c ). These papers are applied to both new nanomedicines and nanosimilars, in order to provide guidance to developers in the preparation of marketing authorization applications.The principles outlined in these documents address general issues regarding the complexity of the nanosystems and provide basic information for the pharmaceutical development, non-clinical and early clinical studies of block-copolymer micelle, “liposome-like,” and nanoparticle iron (NPI) medicinal products drug products created to affect pharmacokinetic, stability and distribution of incorporated or conjugated active substances in vivo . Important factors related to the exact nature of the particle characteristics, that can influence the kinetic parameters and consequently the toxicity, such as the physicochemical nature of the coating, the respective uniformity and stability (both in terms of attachment and susceptibility to degradation), the bio-distribution of the product and its intracellular fate are specifically detailed.

Market access and pharmacoeconomics

After a nanomedicine obtains the marketing authorization, there is a long way up to the introduction of the nanomedicine in the clinical practice in all EU countries. This occurs because the pricing and reimbursement decisions for medicines are taken at an individual level in each member state of the EU (Sainz et al., 2015 ).

In order to provide patient access to medicines, the multidisciplinary process of Health Technology Assessment (HTA), is being developed. Through HTA, information about medicine safety, effectiveness and cost-effectiveness is generated so as support health and political decision-makers (Sainz et al., 2015 ).

Currently, pharmacoeconomics studies assume a crucial role previous to the commercialization of nanomedicines. They assess both the social and economic importance through the added therapeutic value, using indicators such as quality-adjusted life expectancy years and hospitalization (Sainz et al., 2015 ).

The EUnetHTA was created to harmonize and enhance the entry of new medicines in the clinical practice, so as to provide patients with novel medicines. The main goal of EUnetHTA is to develop decisive, appropriate and transparent information to help the HTAs in EU countries.

Currently, EUnetHTA is developing the Joint Action 3 until 2020 and the main aim is “to define and implement a sustainable model for the scientific and technical cooperation on Health Technology Assessment (HTA) in Europe.”

Conclusion and prospects

The reformulation of pre-existing medicines or the development of new ones has been largely boosted by the increasing research in nanomedicine. Changes in toxicity, solubility and bioavailability profile are some of the modifications that nanotechnology introduces in medicines.

In the last decades, we have assisted to the translation of several applications of nanomedicine in the clinical practice, ranging from medical devices to nanopharmaceuticals. However, there is still a long way toward the complete regulation of nanomedicines, from the creation of harmonized definitions in all Europe to the development of protocols for the characterization, evaluation and process control of nanomedicines. A universally accepted definition for nanomedicines still does not exist, and may even not be feasible at all or useful. The medicinal products span a large range in terms of type and structure, and have been used in a multitude of indications for acute and chronic diseases. Also, ongoing research is rapidly leading to the emergence of more sophisticated nanostructured designs that requires careful understanding of pharmacokinetic and pharmacodynamic properties of nanomedicines, determined by the respective chemical composition and physicochemical properties, which thus poses additional challenges in regulatory terms.

EMA has recognized the importance of the establishment of recommendations for nanomedicines to guide their development and approval. In turn, the nanotechnology methods for the development of nanomedicines bring new challenges for the current regulatory framework used.

EMA have already created an expert group on nanomedicines, gathering members from academia and European regulatory network. The main goal of this group is to provide scientific information about nanomedicines in order to develop or review guidelines. The expert group also helps EMA in discussions with international partners about nanomedicines. For the developer an early advice provided from the regulators for the required data is highly recommended.

The equivalence of complex drug products is another topic that brings scientific and regulatory challenges. Evidence for sufficient similarity must be gathered using a careful stepwise, hopefully consensual, procedure. In the coming years, through all the innovation in science and technology, it is expected an increasingly higher number of medicines based on nanotechnology. For a common understanding among different stakeholders the development of guidelines for the development and evaluation of nanomedicines is mandatory, in order to approve new and innovative nanomedicines in the pharmaceutical market. This process must be also carried out along with interagency harmonization efforts, to support rational decisions pertaining to scientific and regulatory aspects, financing and market access.

Author contributions

CV conceived the original idea and directed the work. SS took the lead in writing the manuscript. AP and JS helped supervise the manuscript. All authors provided critical feedback and helped shape the research, analysis and revision of the manuscript.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

1 Available online at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/epar_search.jsp&mid=WC0b01ac058001d124

Funding. This work was financially supported by Fundação para a Ciência e a Tecnologia (FCT) through the Research Project POCI-01-0145-FEDER-016648, the project PEst-UID/NEU/04539/2013, and COMPETE (Ref. POCI-01-0145-FEDER-007440). The Coimbra Chemistry Center is supported by FCT, through the Project PEst-OE/QUI/UI0313/2014 and POCI-01-0145-FEDER-007630. This paper was also supported by the project UID/QUI/50006/2013—LAQV/REQUIMTE.

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