Contents

Cover

Title page

Copyright page

Preface

Chapter 1: Introduction

References

Chapter 2: Nanomaterials

2.1 Physical Properties of Nanomaterials
2.2 Nanomaterials: An Overview
References

Chapter 3: Promising Applications in Medicine

3.1 Diagnostics
3.2 Therapy
References

Chapter 4: Interactions of Nanomaterials with Biological Systems

4.1 Cellular Level (in vitro)
4.2 Body Level (in vivo)
References

Chapter 5: Nanomaterials in the Market or in the Way of

5.1 Approval Pipeline (FDA and EMA)
5.2 Nanotherapeutics
5.3 Nanodiagnostics
References

Chapter 6: Avoiding the Persistence of Metal Nanomaterials

6.1 Ultrasmall-in-Nano Approach
6.2 Porphyrin-Based Nanomaterials
References

Chapter 7: Conclusions and Perspectives

References

Index

End User License Agreement

List of Illustrations

Chapter 2

Figure 2.1 Portion of a three-dimensional cubic crystal lattice. First, second and third nearest neighbors, with respect to the central atom, are marked with different gray levels.
Figure 2.2 Solid/liquid phase diagram for bulk (dash-dotted straight line) and nano materials (solid and dashed curves) [2].
Figure 2.3 Melting temperatures (top) and heat of fusion (down) vs particle radius for Sn NPs [5]. Reprinted with permission from [5]. Copyright 1996 by the American Physical Society.
Figure 2.4 Silver (a) and gold (b) nanostructures with plasmonic response finely tunable in the UV/NIR range [13, 14]. a) is reproduced from [13] with permission of The Royal Society of Chemistry. b) is reproduced from [14] with permession of John Wiley & Sons Inc.
Figure 2.5 Excitation and emission spectra of Ag clusters (a) and Au clusters (b) with emission tunable over a wide range of visible wavelengths. [16, 17]. a) is reproduced from with permission from [16]. Copyright 2008 American Chemical Society. b) is reproduced from [17] with permission of the Royal Society of Chemistry.
Figure 2.6 (Top) TEM images of size tunable PbSe quantum dots of (a) 11 nm, (b) 13 nm and (c) 16 nm. (Bottom) Normalized photoluminescence spectra of size tunable PbSe quantum dots. [20]. Reprinted with permission from [20]. Copyright 2004 American Chemical Society.
Figure 2.7 Scheme of domain wall creation between two opposite-spin magnetic domains.
Figure 2.8 Langevin plot of magnetization (M) vs applied magnetic field (H) for ferromagnetic, paramagnetic, and superparamagnetic materials. M_S and M_R denote saturation magnetization and retentivity, respectively.
Figure 2.9 Magnetic behavior of bare gold NPs. Electron microscopy characterization of NPs (left) and magnetic response to applied magnetif field at different temperatures (right) [26]. Reprinted with permission from [25]. Copyright 2011 by the American Physical Society.
Figure 2.10 Schematic rappresentation of low-dimensional carbon materials [27]. “Reprinted with permission from [26]. Copyright 2015 American Chemical Society”.
Figure 2.11 Surface functionalization of carbon nanomaterials by self-assembly of amphiphilic molecules (a) and by pi-stacking interactions (b). a) is reprinted with permission from [156]. Copyright 2015 American Chemical Society. b) is reprinted with permission from [27]. Copyright 2015 American Chemical Society.
Figure 2.12 Scheme of Prato reaction for fullerene covalent functionalization.
Figure 2.13 Scheme of liposome structures from self-assembly of phospholipids [47].
Figure 2.14 Convergent (a) and divergent (b) approaches for dendrimers synthesis [57].
Figure 2.15 Scheme of strategies for synthesis of carbohydrates NPs either by self assembly of amphiphilic polymers (left) or by chemical (right) or physical (bottom) crosslinking [62]. Reprinted from [62] with permission from Elsevier.
Figure 2.16 Electron microscopy images of dextran NPs obtained in aqueous solution (c) and in water/ethanol mixtures (a), (b) and (d) [67]. Reprinted from [67] with permission of John Wiley & Sons Inc.
Figure 2.17 PLGA hydrolisis into lactic acid and glycolic acid.
Figure 2.18 Schematic representation of nanoprecipitation technique [82]. Reprinted with permission from [82]. Copyright 2016 Springer Nature.
Figure 2.19 Transmission electron microscopy images of citrate-capped gold nanospheres with diameters ranging from 3.6 nm to 200 nm [91, 92]. Upper panel reprinted with permission friom [91]. Copyright 2016 American Chemical Society. Lower panel reprinted with permission from [92]. Copyright 2011 American Chemical Society.
Figure 2.20 Extinction spectra (a) and TEM images (b-d) of gold nanostars with tunable size and branch length [98]. Reproduced from [97] with permission of The Royal Society of Chemistry.
Figure 2.21 Template-free synthesis of hollow gold nanoshells with tunable diameter. Extinction spectra (a) and TEM images (b-f) [100]. Reproduced from [100] with permission of Elsevier.
Figure 2.22 TEM images of polygonal gold nanoplates: pentagons (a), hexagons (b), triangles (c) and squares (d) produced by varying the synthetic conditions [101]. Reproduced from [101] with permission from The Royal Society of Chemistry.
Figure 2.23 TEM images of edge length – tunable triangular gold nanoplates [102]. Reprinted with permission from [102]. Copyright 2014 American Chemical Society.
Figure 2.24 Scheme of ligand-exchange technique for gold NPs functionalization [103]. Reproduced from [103] with permission from The Royal Society of Chemistry.
Figure 2.25 Extinction spectra (a) and colloidal solution photographs (b) of size-tunable silver nanospheres [109]. Reprinted with permission from [109].
Figure 2.26 Size dispersion hystograms and TEM images (insets of size-tunable silver NPs of 26 nm (a), 33 nm (b), 40 nm (c) 59 nm (d), 96 nm (e) and 118 nm (f). [110].
Figure 2.27 (a) Absorbance spectra of silver nanoplates synthesized with different concentrations of poly(sodium 4-styrene sulfonate) (PSS). (b) Absorbance maxima vs PSS concentration and (c) photograph of silver nanoplates colloidal solutions [113]. Reprinted from [113] with permission of Elsevier.
Figure 2.28 TEM images and size dispersion (top, right) of nearly-monodisperse platinum nanospheres [120]. (Left panel) Reprinted with permission from [170]. Copyright 1999 American Chemical Society. (Right panel) Reprinted with permission from [120]. Copyright 2008 American Chemical Society.
Figure 2.29 (a) Reproduced with permission from [157]. Copyright 2010 American Chemical Society. (b,c,e,f) Reproduced with permission from [158]. Copyright 2013 American Chemical Society. (d) Reproduced with permission from [159]. Copyright 2008 American Chemical Society. (g) Reproduced from [160] with permission of The Royal Society of Chemistry. (h) Reproduced with permission from [161]. Copyright 2005 American Chemical Society. (i) Reproduced from [162] with permission of John Wiley & Sons Inc.
Figure 2.30 Examples of condensation steps to synthesize metal oxide NPs [138]. Reproduced from [137] with permission of Elsevier.
Figure 2.31 TEM images of monodisperse maghemite nanospheres with diameter ranging from 6 to 13 nm [140]. Reproduced with permission from [140]. Copyright 2001 American Chemical Society.
Figure 2.32 TEM images and 3D structure (insets) of anisotropic iron oxide NPs [141]. Reproduced with permission from [141]. Copyright 2015 American Chemical Society.
Figure 2.33 TEM image of monodisperse silica NPs synthesized by Stöber protocol [145]. Reproduced from [145] with permission of Elsevier.
Figure 2.34 Size-dependent optical behavior of (a) InP, (b) CdTe, (c) PbS and (d) PbSe quantum dots. (a) Reproduced from [163] with permission of John Wiley & Sons Inc. (b) Reproduced with permission from [164]. Copyright 2004 American Chemical Society. (c) Reproduced with permission from [165]. Copyright 2003 American Chemical Society. (d) Reproduced with permission from [166]. Copyright 1996 American Chemical Society.
Figure 2.35 TEM images of Cu based quaternary chalcogenides [151]. (a) Reprinted with permission from [167]. Copyright 2013 American Chemical Society. (b) Reprinted with permission from [168]. Copyright 2012 American Chemical Society. (c) Reprinted with permission from [169]. Copyright 2012 American Chemical Society.

Chapter 3

Figure 3.1 Scheme of photoelectric effect followed by emission of an X-ray photon (a) and attenuation coefficients of typical X-ray contrast agents in the range 0–150 keV (b) [2]. Reprinted from [2] with permission of Elsevier.
Figure 3.2 Micro CT images of mice before (a) and 6h after the injection of PEGylated Au NPs as contrast agents (b). Image (c) is the 3D volume rendered image [10].
Figure 3.3 X-ray mammogram (a) of 69 year old woman infiltrating ductal carcinoma compared with ultrasonography scan image (b) and photoacoustic image (c) and 3D volume rendering (d) of the selected ROI [19]. Reprinted with permission from [19].
Figure 3.4 Photoacoustic imaging in vivo of mouse tumor (a) and ischemia (b) enhanced by silica coated gold nanorods [20]. Reproduced from [20] with permission of The Royal Society of Chemistry.
Figure 3.5 Nuclear spin precession about external static magnetic field axis (a), magnetization flip after the application of an RF pulse (b) and longitudinal and transversal magnetization relaxation law (c) and (d), respectively [49]. Reproduced from [49] with permission of John Wiley & Sons Inc.
Figure 3.6 (Left) TEM images and size histograms of PVP-coated iron oxide NPs of sizes ranging from 7.6 to 65.3 nm and (Right) in vivo mouse liver MRI at different time steps after intravenous administration of the IONPs and the commercial contrast agent Feridex [56]. Reprinted with permission from [56]. Copyright 2010 American Chemical Society
Figure 3.7 Jablonski diagram showing vibrational energy levels involved in Raman scattering (top) and Raman spectrum of CCl₄ (bottom) [73]. Reprinted with permission from [73]. Copyright 2016 Springer Nature.
Figure 3.8 SERS spectra of gold based nanoprobes incubated with cultured breast epithelial cells during 24 h (a) and SERS mapping on a single cell (b). SERS spectra of nanoprobes over time in vivo after intratumoral injection (c). Experimental setup for in vivo SERS (d) [95]. Reproduced from [95] with permission of The Royal Society of Chemistry
Figure 3.9 (a) Scheme of the synthesis and self-destruction mechanisms with subsequent drug release of doxorubicin (DOX)-loaded mesoporous silica NPs (DS) coated with CD-PGEA targeting agent (DS-DOX-PGEA). (b) TEM images of DS-DOX-PGEA in ethanol (top) and their degradation after 1 day (center) and 4 days (bottom) in a PBS solution of glutathione. (c) Tumor relative shrinking (left) and average weight (center) after 10 days of treatment with PBS (black), free doxorubicin (red), DS-PGEA coated with p53 gene for inhibiting tumor proliferation (blue), DS-DOX-PGEA (green) and DS-DOX-PGEA coated with p53 (yellow), and picture of the treated tumors ex vivo (right) [131]. Reproduced from [131] with permission of John Wiley & Sons Inc.
Figure 3.10 (a) Extinction cross section spectra of gold nanorods of different aspect ratio and (b) clockwise, comparison between simulated extinction, scattering and absorption cross sections of gold nanorods, nanoshells, nanocages and nanostars of representative sizes [147]. Reproduced from [147] with permission of The Royal Society of Chemistry
Figure 3.11 Upper panel: TEM image of cyanine/peptide/glucosamine-functionalized gold nanorods (Pep-Acy/Glu@AuNRs, left) and their absorbance spectra at neutral and acidic pH compared to absorbance of CTAB coated gold nanorods (right). Bottom panel: representative thermal images of mice treated with Pep-Agy/Glu@AuNRs or with PBS upon exposure to 808 nm laser irradiation (left) and relative tumor size variation for each group of mice (right) [155]. Reproduced from [155] with permission of John Wiley & Sons Inc.
Figure 3.12 (a) Scheme of the synthesis of nanoplatforms bearing both plasmonic and magnetic features (MagPlasmNP), (b) HAADF image and EELS elemental analysis of MagPlasmNP and (c) temperature map of mouse model subjected to HT treatments upon intratumoral injection of MagPlasmNP due to laser stimulation (PLASM), RF magnetic field (MHT) or synergistic applications of the two (MHT+PLASM). (d) Plot of temperature variation at tumor site containing MagPlasmNP (T+) and at control tumor (T-) [187]. Reproduced from [187] with permission of The Royal Society of Chemistry.
Figure 3.13 (a) In vivo gamma imaging after injection of free ¹³¹I (up), ¹³¹I-HAS (center) and ¹³¹I-HAS-MnO₂ (down); (b) relative tumor volume after internal RT treatment and (c) relative mice body weight following RT [238]. Reproduced from [238] with permission of John Wiley & Sons Inc.

Chapter 4

Figure 4.1 Scheme of the possible endocytic pathways and intracellular fate following internalization. Reproduced with permission from [2]. Reproduced with permission from [194]. Copyright 2007 Springer Nature.
Figure 4.2 (Top) Cellular uptake histogram of gold NPs in the range 14–100 nm (left) and TEM images of the of 14 nm (center), 30 nm (right), 50 nm (bottom, left), 74 nm (bottom, center) and 100 nm (bottom, right) NPs trapped in vesicles in HeLa cells [33]. Reproduced with permission from [33]. Copyright 2006 American Chemical Society. Reproduced with permission from [32]. Copyright 2006 American Chemical Society
Figure 4.3 (a) Individual components employed for the simulation and (b) kinetics of spontaneous uptake for a cationic gold NP (top) and HIV-1 Tat peptide (bottom) [52]. Reprinted with permission from [52]. Copyright 2003 American Chemical Society. Reprinted with permission from [51]. Copyright 2003 American Chemical Society
Figure 4.4 (a) SEM images of particles tested for vasculature adhesion assessment and (b) results of adhesion assay (S = spheres, ED = elliptical disks, CD = circular disk, R = rods) [124]. Adapted from [124] with permission of Elsevier
Figure 4.5 (a) Schematic depiction of the immune system recognition of hidden epitopes that become exposed following protein corona formation. (b) interleukins (left) and tumor necrosis factors (right) secretion by THP-1 cells following exposure to fibrinogen and gold NPs of 5 and 20 nm [162, 163]. (a) reproduced with permission from [162]. (b) Reproduced with permission from [163]. Copyright 2010 Springer Nature.
Figure 4.6 Biodistribution examples of nanomaterials with different chemical composition, size and shape in mice, including gold NPs (a), iron oxide NPs (b) and silica NPs (c), displaying preferential accumulation in the RES organs. Schematic depiction of a liver sinusoid in cross-section showing the main components in fluorescence microscopy images (d) [167, 168, 170, 171]. (a) Reproduced from [167] with permission of Elsevier. (b) Reproduced from [168] with permission of The Royal Society of Chemistry. (c) Reproduced with permission from [170]. Copyright 2017 Springer Nature. (d) Reproduced with permission from [171]. Copyright 2013 Springer Nature.
Figure 4.7 (a) Fluorescence imaging of silica NPs accumulating in mouse liver 15 minutes after systemic injection and subsequently migrating to the gastrointestinal tract. (b) Ex vivo fluorescence imaging of organs harvested from silica NPs treated mouse 3 hours after tail injection show NPs sequestration by the liver and migration in the intestine and stomach. (c) Fluorescence imaging of feces and urine collected from treated mouse respectively 0 days and 1 day after injection. (d) Presence of silicon in the feces is confirmed by mass spectroscopy analyses 3 days after NPs injection [180]. Reproduced from [180] with permission of Elsevier.
Figure 4.8 (a) Scheme of the glomerular filtration barrier separating the blood capillary from Bowman’s space, showing the three components that dictate the size threshold for renal clearance: fenestrated endothelium, basement membrane and podocytes. (b) TEM images of glomerular filtration barrier in mice (top) showing that high aspect ratio carbon nanotubes can effectively cross the barrier and translocate to Bowman’s space [183, 191]. (a) Reprinted from [183] with permission of John Wiley & Sons Inc. (b) Reprinted from [191] with permission of John Wiley & Sons Inc

Chapter 5

Figure 5.1 Overview of the FDA approval pipeline [7].
Figure 5.2 (a) Overview of the established nanomedicines either on the market or under clinical investigation. (b) Approved nanodrugs already available for clinical use and (c) nanodrugs under clinical investigations [20, 12]. (a) Reprinted with permission from [20]. (b,c) Data from [12].

Chapter 6

Figure 6.1 Examples of ultrasmall-in-nano constructs produced by encapsulating ultrasmall NPs in (clockwise order): polymeric micelles, silica capsules, biological vesicles (red blood cells) and lipid vesicles [5, 13, 15, 16]. (Top, left) Adapted from [5] with permission of Elsevier. (Bottom, left) Adapted with permission from [16]. Copyright 2015 American Chemical Society. (Bottom, right) Adapted with permission from [13]. Copyright 2018 American Chemical Society.
Figure 6.2 (a) Scheme of the nanoplatform composed by an engineered hepatitis B virus capsid decorated with gold USNPs and targeting moieties (left) and representative TEM images of the nanostructure at different magnifications. (b) NIR fluorescence imaging of the Cy5.5 dye-labeled nanoplatforms displaying preferential tumor accumulation (dotted red circles) when exposing targeting peptide (aff +) with respect to non-functionalized ones (aff -) and the control (PBS only). (c) Photos of cancerous livers treated with alternating magnetic field either with (top) or without (bottom) nanoplatforms injection. (d) MRI employing the nanoplatforms as contrast agent in healthy (left) and tumor-bearing mice (right) showing increased contrast in the tumor region (yellow dotted regions indicate the liver). Reprinted from [34] with permission of John Wiley & Sons Inc.
Figure 6.3 (a) Scheme of the synthesis of PEG-TCPP and TEM images of NPs synthesized with PEG of different molecular weight. (b) PET imaging of the biodistribution of PEG-TCPP over 24h in tumor-bearing mice. (c) Fluorescence imaging of PEG-TCPP during at different time steps after systemic administration in tumor-bearing mice (top) and of the explanted organs and tumor 24 h after administration (bottom) [63]. Reprinted from [63] with permission of John Wiley & Sons Inc.
Figure 6.4 (a) Scheme of porphysome self-assembly and TEM image of the vesicle and a detail of the lipid membrane at higher magnification. (b) Photothermal efficiency benchmark of porphysomes against gold nanorods and the two controls PBS and liposomes. (c) Thermal images of tumor bearing mice injected with porphysomes or PBS 24 h prior to exposure to laser irradiation. (d) Photos of photothermal therapy efficiency on tumor bearing mice using porphysomes. (e) Scheme of the enzymatic biodegradation of porphysomes indicating the fate of each building block [68]. Reprinted with permission from [68]. Copyright 2011 Springer Nature.

Scrivener Publishing
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Advances in Nanotechnology & Applications

Series Editor: Madhuri Sharon

The unique properties of nanomaterials encourage the belief that they can be applied in a wide range of fields, from medical applications to electronics, environmental sciences, information and communication, heavy industries like aerospace, refineries, automobile, consumer and sports good, etc.

This book series will focus on the properties and related applications of nanomaterials so as to have a clear fundamental picture as to why nanoparticles are being tried instead of traditional methods. Since nanotechnology is encompassing various fields of science, each book will focus on one topic and will detail the basics to advanced science for the benefit of all levels of researchers.

Series Editor: Madhuri Sharon, Director, Walchand Centre for Research in Nanotechnology & Bionanotechnology
W.H. Marg, Ashok Chowk, Solapur 413 006
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India

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Library of Congress Cataloging-in-Publication Data

ISBN 978-1-119-41827-6

Preface

Nanomaterials have demonstrated the potential to revolutionize the way in which neoplasms are diagnosed and treated. Some efficient treatments relying on organic nanomaterials are already on the market, while even more promising ones based on noble metals are still at the bench level. Organism persistence after medical action is a major concern hampering the clinical translation of metal nanoparticles. Today, the most practical way to avoid undesirable toxic effects, while maintaining desirable imaging/therapeutic moieties, is by engineering all-in-one biodegradable nanoplatforms that are excretable through the renal pathway after the designed medical action. Despite the field being very young, in the near future personalized and effective treatments of neoplasms may no longer be a dream but a real possibility. The potentiality of these novel nanotheranostics is impressive, but a lot of work is yet to be done.

In order to introduce you to the “world of nanomaterials,” the scope of this book is outlined in Chapter 1 and a comprehensive review of the behaviors of both organic and inorganic nanomaterials is presented in Chapter 2. In Chapter 3, the promising applications in diagnosis and treatment of neoplasms are discussed. The interactions of nanomaterials with biological systems at both the cellular and body levels are presented in Chapter 4, together with the main drawback of metal nanomaterials—the issue of persistence. In Chapter 5, the actual FDA and EMA approval pipeline for nanotheranostics and the nanomaterials that have reached the market are introduced. Chapter 6 reports the most advanced and promising approaches for avoiding the issue of persistence. Finally, in Chapter 7, along with conclusions drawn from the material presented, the perspectives of this exciting fields are discussed.

This book offers state-of-the-art and comprehensive coverage of nanomaterials ranging from their behaviors to the market. In particular, the issue of persistence is discussed, and the most promising approaches to unlock the potentiality of metal nanomaterials for innovative noninvasive and efficient treatments of neoplasms are presented. General readers of this book will gain complete insight into nanomaterials, physicians will have a guide to the latest information on the novel tools under development, and biologists/chemists/physicists/engineers will have a guide for designing the next generation of nanotheranostics.

Domenico Cassano and Valerio Voliani
Pisa, Italy
March 2018

Chapter 1
Introduction

Industry analysts have been forecasting groundbreaking advances as a result of nanotechnology application in renewable energy, communications, pollution removals, agriculture, and medicine [1]. Clothing, sunscreens, cosmetics, sporting equipment, batteries, food packaging, dietary supplements, and electronics are just a few of the kinds of nanotechnology-enabled goods in use [1]. For example, nanosized: i) silver is used in food packaging, ii) silica is employed in food additives, and iii) titanium dioxide, gold, platinum, and zinc oxide are used in cosmetics, such as sunscreens and toothpastes [2, 3]. Although there are several uses of nanomaterials in daily products, the most promising application is in the medical field [2]. A lot of excitement has been generated during last decades about the medical and economic impact of nano-technological approaches in healthcare [4]. The first medical nanosystem was introduced in human therapy at the end of the last century to increase the efficacy of known, but poorly bioavailable drugs [5]. Today, research on nanomaterials is aimed to decrease the side-effects of therapies while increase their action thanks to the unique physical, chemical and physiological features of the matter at the nanoscale. Such advances include improved early screening and diagnosis, as well as treatment regimens that have reduced off-target toxicity; areas where nanoparticle approach is likely to have significant future impact [6].

The usual target application of nanomaterials is related to diagnosis and therapy of neoplasms, due to a number of keyproperties of nanomaterials. These behaviors include size, payload density, duration of effect, and surface properties/targeting [6]. For example, the pharmacokinetic profile of nanoparticle-incorporated drugs often includes a dramatic increase in circulation half-life (t_1/2) compared to the drug alone [6]. Moreover, nanoparticles show the possibility to insert many functionalities on the same platform in order to develop “multifunctional” nanoparticles (theranostic agents) able to improve delivery, therapeutic efficacy, and ultimately patient outcome [7]. Theranostic agents can simultaneously deliver imaging and therapeutic actions to specific sites or organs, enabling detection and treatment of disease in a single procedure [7].

Nanomaterials can be divided in two class: soft and hard [8]. The first are composed by polymers, lipid vesicles and polymer-protein conjugates, while the latter are based on inorganic materials, and in particular metals. Noble metals, due to the high atomic number and the Localized Plasmon Surface Resonances (LSPRs), intrinsically possess both imaging and therapeutic capabilities. This results in more profound benefits in the design of theranostics, holding the great promise to shift current medical detection and therapy paradigms [9].

To date, more than 40 nanosystems for healthcare applications are in the market. The large majority of these nanosystems are soft nanomaterials [5]. Just four metal-based nanomaterials (iron oxide) are already in the market, following the 1996 approval of Endorem^® (Guerbet) by the FDA for Magnetic Resonance Imaging (MRI) diagnostics [8]. Remarkably, there is still no approved nanomaterials based on noble metals for cancer therapy [5, 8]. The only approved platform using gold nanosphere is a tool for bench diagnostic [5]. The lack of translation of metal nanoparticles to the market is mainly related to the concern of their persistence in organisms after the action, confining all their intriguing feature to the bench-side [8]. Recently, nanomaterials designed by the ultrasmall-in-nano approach able to jointly combine theranostic applications and metal excretion were proposed, holding the promise to unlock the appealing behaviors of metal nanomaterials for groundbreaking cancer treatments.

The purpose of this Volume is to collect and comprehensively discuss the advances in this current and exciting topic in order to promote and enhance its growth. In the first part of the Volume, a general introduction about the main features of both organic and inorganic nanomaterials is provided. Then, the most promising and innovative applications for cancer treatment and diagnostic are introduced.

In the second part, an analysis of the nanomaterials in the market for healthcare applications is presented. The issue of unwanted accumulation of metals in organisms after the designed action is then discussed. Finally, the most recent progresses in the design of nanomaterials that are able to escape from organisms after the selected action are comprehensively described, and the perspectives of this exciting field provided.

This Volume is intended for academics at every stage of career and to professionals interested in nanomaterials.

References

1. Kessler, R. Engineered Nanoparticles in Consumer Products: Understanding a New Ingredient. Environ. Health Perspect. 119, a120–a125, 2011.

2. Fröhlich, E. & Roblegg, E. Models for oral uptake of nanoparticles in consumer products. Toxicology 291, 10–17, 2012.

3. Love, S. a, Maurer-Jones, M. a, Thompson, J. W., Lin, Y.-S. & Haynes, C. L. Assessing nanoparticle toxicity. Annu. Rev. Anal. Chem. 5, 181–205, 2012.

4. Schütz, C. A., Juillerat-Jeanneret, L., Soltmann, C. & Mueller, H. Toxicity data of therapeutic nanoparticles in patent documents. World Pat. Inf. 35, 110–114, 2013.

5. Schütz, C. a, Juillerat-Jeanneret, L., Mueller, H., Lynch, I. & Riediker, M. Therapeutic nanoparticles in clinics and under clinical evaluation. Nanomedicine 8, 449–467, 2013.

6. Heidel, J. D. & Davis, M. E. Clinical developments in nanotechnology for cancer therapy. Pharm. Res. 28, 187–199, 2011.

7. Cheng, Z., Al Zaki, A., Hui, J. Z., Muzykantov, V. R. & Tsourkas, A. Multifunctional Nanoparticles: Cost Versus Benefit of Adding Targeting and Imaging Capabilities. Science (80-.). 338, 903–910, 2012.

8. Etheridge, M. L. et al. The big picture on nanomedicine: The state of investigational and approved nanomedicine products. Nanomedicine Nanotechnology, Biol. Med. 9, 1–14, 2013.

9. Yu, M. & Zheng, J. Clearance Pathways and Tumor Targeting of Imaging Nanoparticles. ACS Nano 9 (7), pp 6655–6674, 2015.