Cover
Chapter 1: Introduction
1. 1.1 History of Metal Complexes
2. 1.2 Nanotechnology
3. 1.3 Nanoparticles
4. 1.4 Nanotechnology‐Supported Metal Nanoparticles
5. Acknowledgment
6. References
Chapter 2: Methods for Preparation of Metal Nanoparticles
1. 2.1 Introduction
2. 2.2 Methods for Preparation of Metallic NPs
3. 2.3 Conclusion
4. References
Chapter 3: Metal Nanoparticles as Therapeutic Agents: A Paradigm Shift in Medicine
1. 3.1 Introduction
2. 3.2 Metal Nanoparticles in Diagnostics
3. 3.3 Advanced Drug Delivery
4. 3.4 Nanoparticle‐Mediated Gene Transfer
5. 3.5 Nanotechnology in Regenerative Therapies
6. 3.6 Nanoparticles–Essential Oils Combination Against Human Pathogens
7. 3.7 Conclusion
8. Acknowledgment
9. References
Chapter 4: Soft‐Oxometalates: A New State of Oxometalates and Their Potential Applications as Nanomotors
1. 4.1 Introduction to Soft‐Oxometalates (SOMs)
2. 4.2 Application of Soft‐Oxometalates
3. 4.3 Active Nano/micro Motors
4. 4.4 Micro‐Optomechanical Movement (MOM) in Soft‐Oxometalates
5. 4.5 Autonomous Movements Induced in Heptamolybdate SOMs
6. 4.6 SOMs as Water Oxidation Catalysts
7. 4.7 Conclusion
8. Acknowledgment
9. References
Chapter 5: Medicinal Applications of Metal Nanoparticles
1. 5.1 Overview
2. 5.2 Introduction and Background
3. 5.3 Biomedical Applications of Metal Nanoparticles
4. 5.4 Pharmacokinetics of Metal Nanoparticles
5. 5.5 Status of Metal Nanoparticles in Clinical Study
6. 5.6 Future Prospect of Metal Nanoparticles in Medicine
7. Acknowledgment
8. References
Chapter 6: Metal Nanoparticles in Nanomedicine: Advantages and Scope
1. 6.1 Introduction
2. 6.2 Advantages Associated with Metal Nanosystems
3. 6.3 Applications and Scope
4. 6.4 Concluding Remarks
5. Acknowledgments
6. References
Chapter 7: Applications of Metal Nanoparticles in Medicine/Metal Nanoparticles as Anticancer Agents
1. 7.1 Advantages of Metal Nanoparticles
2. 7.2 Metal Nanoparticles as Anticancer Agents
3. 7.3 Gold Nanoparticles
4. 7.4 Silver Nanoparticles (AgNPs)
5. 7.5 Copper Nanoparticles
6. 7.6 Conclusion
7. Acknowledgments
8. References
Chapter 8: Noble Metal Nanoparticles and Their Antimicrobial Properties
1. 8.1 Introduction
2. 8.2 Synthesis of Antibacterial Noble Metal Nanoparticles
3. 8.3 Antibacterial Nanomaterials and Their Antibacterial Mechanism
4. 8.4 Concluding Remarks and Future Outlook
5. References
Chapter 9: Metal Nanoparticles and Their Toxicity
1. 9.1 Introduction to Metal Nanoparticles Toxicity
2. 9.2 Metal Nanoparticle Internalization and Biodistribution
3. 9.3 Physicochemical Properties of Metal Nanoparticles
4. 9.4 Nanoparticle Size and Toxicity
5. 9.5 Nanoparticle Composition and Toxicity
6. 9.6 Nanoparticle Morphology and Toxicity
7. 9.7 Nanoparticle Crystalline Structure and Toxicity
8. 9.8 Nanoparticle Surface and Toxicity
9. 9.9 Nanoparticle Magnetism and Toxicity
10. 9.10 Interaction of Nanoparticles Within Organisms
11. 9.11 Other Novel Properties of Metal Nanoparticles
12. 9.12 Conclusions
13. References
Index
End User License Agreement

List of Illustrations

Chapter 1
1. Figure 1.1 Applications of Nanotechnology.
2. Figure 1.2 Various features of engineered nanoparticles.
Chapter 2
1. Figure 2.1 Some important examples of physical, chemical, and green sustainable methods for preparation of metallic NPs.
2. Figure 2.2 Some important advantages of using green chemistry methods.
3. Figure 2.3 Advantages and disadvantages of green and biogenic synthesis of metal NPs.
4. Figure 2.4 Advantages of microwave‐assisted synthetic approach.
5. Figure 2.5 Some important examples of organisms in metal nanoparticle synthesis.
6. Figure 2.6 Plants in nanoparticle synthesis: the reducing and capping agents.
Chapter 3
1. Figure 3.1 Schematic representation of passive and active targeting of cancer cells by ligand modified nanoparticle‐drug complex and nanoparticle‐drug complex without ligand.
2. Figure 3.2 Nanoparticulate transfer of genetic material.
Chapter 4
1. Figure 4.1 Polyoxometalates that can form SOMs [2].
2. Figure 4.2 (a) Example of spontaneously formed SOMs: [PMo₁₂] peapods observed under TEM Ref. [14]. (Reproduced with permission of American Chemical Society.) (b) Two examples of designed SOMs: Case I: Schematic model showing a gibbsite nanocrystal (left) that is used as a template for forming designed phosphomolybdate Keggin superstructure Ref. [15]. (Reproduced with permission of Royal Society of Chemistry.) Case II: Schematic model of spherical DOTAP template (left) and DOTAP‐scaffold designed soft‐oxometalate supersphere (right) Ref. [16].
3. Figure 4.3 (A) TEM images of AuNP‐SOM (left), SAED pattern (inset), lattice spacing in nanoparticles (right) at ψ = 35. (B) TEM images of AuNP‐SOM (a–d), SAED pattern (e), lattice spacing in nanoparticles (f) at ψ = 20. (Adapted from Ref. [28].) (C) Schematic representation of conversion of nanorods to nanospheres (a–c). SEM images (d–f). DLS size distribution plots (g and h). Hydrodynamic radius versus time plot (i) Ref. [29]. (Reproduced with permission of John Wiley & Sons.) (D) SEM images of SD‐SOM at different time intervals: At t = 0 (a), at t = 4 h (b), at t = 5 h (c), and at t = 13 h (d) after preparation of dispersion.
4. Figure 4.4 (A) Polystyrene microspheres obtained by varying loading of monomer concentrations (a) 200 µl, (b) 500 µl, (c) 700 µl, and (d) 1000 µl Ref. [28]. (Reproduced with permission of John Wiley & Sons.) (B) SEM images and radii plot of polystyrene nanospheres by varying the ratio of water and DMSO. Points 1–5 refer to the ratios 8.5 : 1.5, 7 : 3, 6 : 4, 5 : 5, and 4 : 6, respectively Ref. [31].
5. Figure 4.5 (A) Schematic of the patterning technique. (B) Pattern “IISER” written with SOM crystals using single bubble on a slide. (C) Schematic representation of phenomenon involved in patterning Ref. [26]. (Panels (A–C) Reproduced with permission of American Chemical Society.) (D) (a) Close‐up image of SOM‐POF (i). EDX‐TEM of SOM‐POF (ii). Atomic abundance of different materials present in the dispersion (iii). (b): Time‐resolved Raman spectroscopic study showing catalytic oxidation of benzaldehyde using SOM‐POF composite as the catalyst and DMSO as the external standard. (c): I_{benzoic acid}/I_DMSO versus time plot confirming formation of benzoic acid.
6. Figure 4.6 (a) SOM peapods as catalyst carrier. AFM images of single peapod (left) and showing topological as well as dimensional changes of [PMo₁₂O₄₀]³‐loaded catalyst (right). (b) Controlled motion of an optically trapped particle along the periphery of the ring having diameter 1, 3.5, and 4.5 µm, respectively. (c) Quantified values of particle trajectories as obtained from a commercial software. (d) Catalytic activity of the catalyst as a function of catalyst loading on peapod from spectroscopic analysis.
7. Figure 4.7 (A) Schematic of autonomous movement induced in heptamolybdate SOMs. (B) Time lapse images of moving SOM in 0.014 mol l⁻¹ dithionite. (C) Plot of velocity of SOMs versus concentration of dithionite (left) and trajectories of moving SOM at different dithionite concentrations obtained using commercial tracking software.
8. Figure 4.8 (a) Schematic diagram of water splitting by SOM composite. (b) Comparative oxygen evolution of the SOM composite and the POM alone. (c) Raman spectra of the SOM composite before and after reaction. (d) Catalytic recyclability of the SOM composite catalyst.
Chapter 5
1. Figure 5.1 Representation of application of metal nanoparticles in various biomedical fields.
2. Figure 5.1 (a) Schematic illustration of doxorubicin (DOX)‐tethered responsive gold nanoparticles. (b) Schematic illustration of the cooperation between enhanced doxorubicin cellular entry and a responsive intracellular release of doxorubicin into the cells to overcome drug resistance. The fluorescence of doxorubicin tethered to gold nanoparticles is quenched (Fluorescence “OFF”), while recovered when it is released with response to cellular acid conditions (Fluorescence “ON”) Ref. [156].
3. Figure 5.2 Nanocomposite formulation process (a) and NIR laser induced targeted thermo‐chemotherapy using the nanocomposite Ref. [47] (b)
4. Figure 5.3 CEA assay with ZnO nanoflowers for in vivo angiogenesis assay. (a, a1) Untreated chicken egg yolks were considered as control; (b, b1) TE (Tris–EDTA) buffer; ZnO nanoflowers at different concentrations (1–20 mg) (c, c1; d, d1; e, e1); and VEGF (10 ng) as positive control experiment (f, f1), respectively. Dose dependent increase of matured blood vessel formation was observed with increasing concentration of ZnO nanoflowers. Black arrows marked indicate the formation of new vasculature. Three angiogenesis parameters were quantified: vessel length (g), vessel size (h), and Junction (i) Ref. [83].
5. Figure 5.4 (a) Redox signaling in angiogenesis by Eu(OH)₃ nanorods in endothelial cells (EC). Generation of ROS, especially H₂O₂ by Eu(OH)₃ nanorods, in the cytosolic part of the EC function as signaling molecules. (b) HUVEC cell proliferation assay. The effect of europium hydroxide [Eu^III(OH)₃] nanorod‐induced HUVEC cell proliferation in the presence and absence of MnTBAP (SOD mimetic) and catalase was observed using radioactive [³H]‐thymidine, with the results represented as fold stimulation. MnTBAP (10 μM) was incubated with cells in the presence or absence of nanorods and catalase in serum‐starved EBM medium. Initially, MnTBAP (10 μM) was incubated with the cells for 15 min, and then, catalase was added and the cells incubated for another 5 min. Finally, Eu^III(OH)₃ nanorods (10 µg ml⁻¹) were added, and the cells incubated for another 24 h. After 24 h, 1 μCi [³H]‐thymidine was added into each well. Four hours later, the cells were washed with cold PBS, fixed with 100% cold methanol, and collected for the measurement of trichloroacetic acid precipitable radioactivity. Experiments were performed in triplicate. C, catalase (1200 units ml⁻¹); M, MnTBAP (10 μM); and Eu, Eu^III(OH)₃ (10 µg/ml⁻¹). The data are statistically significant with p ≤ 0.05. The mean ± SD of three separate experiments, each performed in triplicate, was calculated. (c–f) In vivo angiogenesis study in a transgenic FLI‐1. EGFP zebrafish model. Nanorods in combination with MnTBAP induce ectopic sprouting from the SIV: lateral view of embryos at 72 hpf. The vehicle control was Tris‐EDTA (TE), to which was added 4.5 ng of MnTBAP and/or 50 ng of nanorods. (g) The number of embryos showing normal SIVs, and ectopic sprouting from SIVs is summarized Ref. [84].
6. Figure 5.5 MRI of the polysaccharide biomaterials seeded with 2 million stem cells labeled with the three different doses of GdNPs or seeded with 2 million endothelial cells labeled with IONPs. T2‐ and T1‐weighted sequences were acquired with the same acquisition parameters (described in section “Materials and Methods”). A 3D T1 sequence was also used to allow volume reconstruction. Prior to MRI, the same scaffolds were imaged by confocal microscopy at a four magnification. GdNP1‐MSCs were detected in green because of FITC molecules embedded in the silica shell, whereas GdNP2‐MSCs were counterstained at the membrane with PKH67 marker. Similarly, the HUVEC‐C plasma membrane was stained in red by PKH26 marker. Single cells (circled in white as an example in the confocal imaging zoomed part on the right) appeared densely packed within the pores of the biomaterials Ref. [96].
7. Figure 5.6 In vivo MRI of labeled 9 l cells 24 h after transplantation in the striata of rat brain. (a–c) Spin echo image (TR = 1000 ms, TE = 14.1 ms). (d–f) R1 maps. (g–i) R2 maps. (j–l) R1/R2 mergedmaps. Shown are representative images of three out of seven rats, two injected with MnO‐ and FeO‐labeled cells (a,b), and one with FeO‐labeled cells and unlabeled cells (c; control). Note the simultaneous double contrast in (j–l) Ref. [98].
8. Figure 5.7 Effect of apatite‐coated TiO₂ suspensions on microbial morphology. (a1 and a2) S. aureus, (b1 and b2) MRSA, (c1 and c2) E. coli, (d1 and d2) M. luteus. Selected SEM images of cell structure show untreated cells (a1–d1) and treated cells with apatite‐coated TiO₂ suspensions after black‐light activation for 24 h (a2–d2) (×200 000). After treatment with apatite‐coated TiO₂ (black arrows), cell morphology changes (white arrows) are seen Ref. [229].
9. Figure 5.8 Study of anti‐bacterial activities: (a) liquid growth inhibition kinetics of E. coli using different concentrations of b‐AgNPs. b‐AgNP‐30 (at 30 μM) shows almost 100% growth inhibition. Ampicillin has been used as a positive control (PC) and NC: negative control or untreated E. coli. The numerical number indicates the concentration of b‐AgNPs in μM, (b–e) optical images of bacterial colonies formed by E. coli cells, that is, colony counting assay (after 24 h): (b) Control, (c) Ampicillin (100 µg ml⁻¹), (d) b‐AgNPs (18 μM), (e) b‐AgNPs (30 μM), and (f–h) SEM images of E. coli cells (f) without being treated (control), (g) treated with Olax for 1 h, (h) treated with b‐AgNPs (30 μM) for 1 h. The SEM images show the silver nanoparticles damages the bacterial cell membrane (marked by blue arrow), whereas, the bacterial membranes of untreated and treated E. coli with Olax is intact.
Chapter 6
1. Figure 6.1 (A) Normalized extinction spectra of spherical Ag (38 ± 12 nm diameter), Au (25 ± 5 nm), and Cu (133 ± 23 nm) particles showing their respective LSPR peaks along with the solar spectrum (solar radiation data for air mass 1.5). Contributions from interband transitions are shown as dashed portions in the metal extinction spectra (no surface plasmon resonance in these regions). (Reproduced with permission from Ref. [68] © 2011 Macmillan Publishers Limited.) (B) The tunability of noble metal nanoparticles. Left: Transmission electron micrographs of typical (a) Au nanospheres, (b) Au nanorods, and (c) Ag nanoprisms formed by the citrate reduction, seed growth, and DMF reduction methods, respectively. Right: Photographs showing color variations in the colloidal dispersions of (d) AuAg alloy nanoparticles with increasing Au concentration, (e) Au nanorods of increasing aspect ratio, and (f) Ag nanoprisms with increasing lateral size.
2. Figure 6.2 LSPRs of nonspherical plasmonic nanoparticles. Normalized extinction spectra of Ag wire (90 ± 12 nm diameter and >30 aspect ratio), cube (79 ± 12 nm edge length) and spherical (38 ± 12 nm diameter) nanoparticles Ref. [68].
3. Figure 6.3 FDTD‐simulated spatial distribution of the electric field intensity at the LSPR peak wavelength (420 nm) of (a) a 75 nm Ag nanocube and (b) two 75 nm Ag nanocubes separated by a distance of 1 nm and one cube is rotated by 45°. (c) and (d) show the enhancement in the electric field intensity with respect to the incident field at the LSPR peak wavelength as a function of the distance, d, along the dashed lines at the edges of the cubes in (a) and (b), respectively. The field is enhanced and localized at the corners and interparticle junction. Comparison of (c) and (d) shows that the field intensity varies as interparticle junction > corners > edges > surface Ref. [68].
4. Figure 6.4 Glutathione‐triggered controlled release of the drug, thiolated doxorubicin (DOX‐SH), within cancer cells. Confocal laser scan microscopy images of HeLa cells (a cervical cancer cell line) incubated for 2 h with DOX‐SH (bottom row), and DOX‐SH‐loaded dendrimer‐encapsulated gold nanoparticles (G5‐OH/Au NPs) (middle and top rows). The cells of the middle row were preincubated with 20 mM GSH‐OEt. Left‐most column: DOX‐SH‐loaded G5‐OH/Au NPs showed weaker fluorescence as compared to DOX‐SH‐treated cells. The red fluorescence intensity of DOX in DOX‐SH‐loaded G5‐OH/Au NPs‐treated cells is quenched by the Au NPs due to the closeness of DOX to the nanoparticle surface. This shows the slow and sustained release of DOX‐SH from the nanoparticles due to the strong Au‐S linkage. When the cells were pretreated with GSH‐OEt, the fluorescence of the cells treated with DOX‐SH‐loaded nanoparticles significantly increased. This is attributed to the intracellular GSH‐triggered release of the drug, DOX‐SH, from the DOX‐SH‐loaded G5‐OH/Au NPs. Second to fourth columns: The nucleus and cytoskeleton of the cells were stained with DAPI (diamidino‐2‐phenylindole, a blue fluorescent probe) and phalloidin‐FITC (green), respectively. It shows that most of the drugs were observed in the nucleus of HeLa cells, suggesting that G5‐OH/Au NPs are able to deliver anticancer drugs such as DOX to its active sites in the nucleus Ref. [207].
5. Figure 6.5 Photothermal localized destruction of cells. Left Column: Cells irradiated in the absence of nanoshells maintain both viabilities, as depicted by (a) calcein fluorescence, and membrane integrity, as indicated by the (c) lack of intracellular fluorescein dextran uptake. Cells irradiated in the presence of nanoshells show well‐defined circular zones of cell death, as shown by (b) the calcein fluorescence study and (d) cellular uptake of fluorescein dextran resulting from increased membrane permeability Ref. [229].
6. Figure 6.6 Live cell SERS images showing the distributions of gold nanoparticles for their targeted sites such as cytoplasm, mitochondria, or nucleus of HSC‐3 cells. Raman images obtained after incubating with subcellular targeting spherical gold nanoparticles with highly narrow intra‐nanogap structures (responding to NIR excitation at 785 nm and high‐speed confocal Raman microscopy). Three different Raman‐active molecules placed in the narrow intra‐nanogap showed a strong and uniform Raman intensity in solution even under transient exposure time (10 ms) and low input power of incident laser (200 μW), which led to obtaining high‐resolution single cell image within 30 s without inducing significant cell damage. The narrow gap gives high Raman intensity due to “hot‐spot” effect. Left column: Cartoons showing gold nanoparticles with various Raman‐active molecules placed in the narrow intra‐nanogap. Right column: Representative Raman spectra from cells incubated with 4,4′‐dipyridyl (44DP)‐coded NPs for mitochondria targeting, methylene blue (MB)‐coded NPs for cytoplasm targeting, and 4,4′‐azobis (pyridine) (AB)‐coded NPs for nucleus targeting Ref. [311].
Chapter 7
1. Figure 7.1 Different metal nanoparticles easily uptook and metabolized by related metal iron transporter.
2. Figure 7.2 The type and biofunction of different metal nanoparticles.
3. Figure 7.1 Generalized scheme for the biomedical application of AuNPs.
Chapter 9
1. Figure 9.1 Schematics of the most important physicochemical properties of metal nanoparticles.
2. Figure 9.2 Field emission gun‐transmission electron microscopy images of silver nanoparticles that have different sizes: (a) 5 ± 0.7 nm; (b) 7 ± 1.3 nm; (c) 10 ± 2.0 nm; (d) 15 ± 2.3 nm; (e) 20 ± 2.5 nm; (f) 30 ± 5.1 nm; (g) 50 ± 7.1; (h) 63 ± 7.6; (i) 85 ± 8.2; (j) 100 ± 11.2 nm. The upper inset for each image is the high‐resolution HRTEM image and lattice fringes (d‐spacing). The lower right side shows particle size distribution histograms.
3. Figure 9.3 Scanning and transmission electron microscopic images of gold nanoparticles obtained by laser irradiation at various laser fluences from original octahedral nanoparticles. Laser fluences are (a, b), 1.76 mJ cm⁻² (c, d), 2.87 mJ cm⁻² (e, f), 3.84 mJ cm⁻² (g, h), and 5.50 mJ cm⁻² (i, j) Ref. [71].
4. Figure 9.4 (a) The uptake of gold nanoparticles with various sizes by HeLa cells. (b) Cellular uptake of gold nanoparticles versus the incubation time for gold nanoparticles with diameters of 14, 50, and 74 nm Ref. [27].
5. Figure 9.5 TEM images of nanoparticles with various compositions: (a) Ag, (b) Au, (c) CdS‐rich quantum dots, (d) ZnSe rich quantum dots, (e) CuO, (f) TiO₂, (g) ZnO, (h) Fe₂O₃, (i) Fe₃O₄, (j) Al‐O, (k) Bi‐O, (l) Co‐O, (m) Cr‐O, (n) In‐O, (o) La‐O, (p) Mn‐O, (q) Ni‐O, (r) Sn‐O, (s) W‐O, (t) Zr‐O.
6. Figure 9.6 Composite nanoparticles with different degrees of symmetry, Ag and Al₂O₃ nano‐barcodes, Au‐TiO₂‐Si‐Ni nano‐zigzags, and Au‐Al₂O₃‐Cu nanohooks with defined chirality. Upper part shows schematics with structure models while lower part has TEM images Ref. [89].
7. Figure 9.7 Spherical composite nanoparticles. (a) HRTEM image of a Ni particle encapsulated by a graphite shell Ref. [90]. (Reproduced with permission of Elsevier.) (b) Rattle‐type Au/CdS composite nanoparticles Ref. [91]. (Reproduced with permission of John Wiley & Sons.) (c, d) TEM images of polymer‐coated cobalt nanoparticle chains at different magnifications Ref. [92].
8. Figure 9.8 (a) Cytotoxicity of various metal oxides in cultured A549 cells after exposure to 20 and 40 µg cm⁻² nanoparticles for 18 h. (b) A comparison of cytotoxicity of CuO nanoparticles and Cu ions for increasing concentrations Ref. [85].
9. Figure 9.9 Nanoparticles with different morphologies, with long and short aspect ratio. Transmission and scanning electron microscope images of (a) Au nanowires Ref. [130], (Reproduced with permission of John Wiley & Sons.) (b) Ag nanowires Ref. [131], (Reproduced with permission of Elsevier.) (c) Pd nanotubes, (d) Pd nanosprings (inset shows a drawing of real spring structure) Ref. [128], (Reproduced with permission of American Chemical Society.) (e) Au nanopyramids, and (f) Au nanocubes Ref. [132].
10. Figure 9.10 Nanoparticles made of the same material with various morphologies. TEM images of gold nanoparticles with different shapes: (a–d) nanoplates with triangle, hexagon, pentagon, and so on shape, (e) spherical, (f) urchin shaped. These nanoparticles were synthesized under different reaction conditions by manipulating their growth parameters, such as gold ion concentration, solution pH, and reaction time by using a cell‐free extract of the fungal strain Rhizopus oryzae interaction with chloroauric acid. The lower right hand inset for images (b–f) shows selected‐area electron diffraction pattern Ref. [130].
11. Figure 9.11 Comparison of the number of gold nanoparticle internalized by HeLa cells as a function of nanoparticle shape. Aspect ratio 1 : 1 denotes spherical nanoparticles, while size is specified at the top of each column in the graph. Aspect ratio of 1 : 3 is for nanoparticles with rod‐like morphologies with the length of 40 nm and diameter of 14 nm, while aspect ratio of 1 : 5 is related to gold nanorods with length of 74 nm and diameter of 14 nm Ref. [27].
12. Figure 9.12 (Color online). TEM images of titanium dioxide TiO₂ in (a) anatase and (b) rutile forms. Inset shows schematics of crystalline structure Ref. [136].
13. Figure 9.13 Calculated number of atoms in bulk and on the surface versus nanoparticle size Ref. [138].
14. Figure 9.14 TEM images of human fibroblast cells incubated with gold nanoparticles functionalized with anionic and cationic ligands. Images show increased cellular uptake of cationic bioconjugates. Anionic nanoparticles showed no significant uptake (a, b), while cationic nanoparticles were localized in endocytic vesicles (c, d, e, f) and nucleus (g, h, i, j) Ref. [148].
15. Figure 9.15 (a) Types of magnetic dipoles and their behavior in the absence and presence of external magnetic fields: diamagnetic, paramagnetic, ferromagnetic, ferrimagnetic, antiferromagnetic Ref. [150]. (Reproduced with permission of John Wiley & Sons.) (b) The magnetization of ferromagnetic and superparamagnetic nanoparticles under an external magnetic field; the domains of a ferromagnetic nanoparticle as well as the magnetic moment of single domain superparamagnetic nanoparticle align with the applied field. (Akbarzadeh et al. 2012 [151], https://link.springer.com/article/10.1186/1556‐276X‐7‐144. Licensed under CC BY 2.0.) (c) The magnetization of ferromagnetic and superparamagnetic nanoparticles in the absence of an external magnetic field; the ferromagnetic nanoparticles will have a net magnetization, and superparamagnetic nanoparticles will have no net magnetization due to rapid reversal of the magnetic moment. (d) Schematic illustration of the coercivity versus nanoparticle size and their domain configuration.
16. Figure 9.16 Cell uptake of nanoparticles with their localization in (A). cytoplasm, (B) vacuoles, (C) mitochondrion, and (D) nucleus. Images (a), (b), (c), (d), (e), and (g) represent 5–10 nm silver nanoparticles in TK6 cells. (Huk et al. 2015 [197]. https://particleandfibretoxicology.biomedcentral.com/articles/10.1186/s12989‐015‐0100‐x. Licensed under CC BY 4.0.) (f) 40 nm gold nanoparticles in mouse embryonic stem cells. (Sathuluri et al. 2011 [198], http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022802. Licensed under CC BY 4.0.) (h) 4 nm gold nanoparticles in human fibroblast 1BR3G cells Ref. [148]. (Reproduced with permission of American Chemical Society.) The notations in image (f) G, M, L, N, and C represent gold nanoparticle, mitochondria, secondary lysosome, nucleus, and cytoplasm, respectively.
17. Figure 9.17 Environmental scanning electron microscopy (ESEM) images showing nanoparticles in blood of patients with blood diseases. Tissue was collected from explanted vena cava filters in patients with deep‐vein thrombosis or pulmonary embolism. The right side of the figures shows the energy dispersive spectroscopy (EDS) images identifying the composition of nanoparticles entrapped in the tissue. Images show thrombus with nanoparticles of (a) Pb and Cu [37], (b) Fe, Cr, and Ni [37], (c) W and Cu [214], (d) Al, Fe, Cr, and Ni [214].
18. Figure 9.18 The mass percentages of prevalent chemical elements in particles with a coarse, fine and ultrafine size measured in the Shanghai atmosphere during the summer of 2008 Ref. [217].
19. Figure 9.19 Environmental scanning electron microscopy (ESEM) images showing nanoparticles in colon samples of patients with cancer and in thrombi collected from filters in patients affected by blood disorders. The right side of the figures shows the energy dispersive spectroscopy (EDS) images identifying the composition of nanoparticles entrapped in the tissue. Panel (a) shows nanoparticles of stainless steel in a colon tumor from a young female patient; Panel (b) silver nanoparticles in a colon cancer sample Ref. [61]. (Reproduced with permission of Elsevier.) (c) Silver nanoparticles in ameloblastoma, tumor of odontogenic origin Ref. [65].
20. Figure 9.20 (Color online) Figure 9.17. The absorbance spectra of gold nanoparticles with different aspect ratio. Inset shows TEM images of gold nanoparticles for each absorbance curve Ref. [83].
21. Figure 9.21 (a) The normalized circular dichroism (CD) spectra of left‐handed and right‐handed gold helices. Inset: TEM images of helices with left (top) and right (bottom) chirality (image dimensions: 85 nm × 120 nm). (b) Schematics of Au nanohelix with two turns showing dimensions Ref. [89].
22. Figure 9.22 (Color online) The variation of melting temperature with nanoparticle size. (a) The melting point, T_m, as a function of nanoparticle size for Ag, Sn, and Pb; Data for the plot were taken from: Ag [238], Sn [239], and Pb [241]. (b) Upper panel: Na clusters with icosahedral growth pattern. Lower panel: Variation of the melting temperature (black), the latent heat of fusion per atom (q, red), and the entropy change (Δs, blue) versus the number of atoms per cluster, N. The three data show maxima around the same N. The cluster sizes are indicated for some peaks Ref. [244].

1
Introduction

Sreekanth Thota^1,2,3 and Debbie C. Crans³

¹Fundação Oswaldo Cruz – Ministério da Saúde, National Institute for Science and Technology on Innovation on Neglected Diseases (INCT/IDN), Center for Technological Development in Health (CDTS), Av. Brazil 4036 – Prédio da Expansão, 8 Andar – Sala 814, Manguinhos, Rio de Janeiro, 21040‐361, Brazil

²Universidade Federal do Rio de Janeiro, Programa de Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Av. Carlos Chagas Filho, Rio de Janeiro, RJ, 21941‐902, Brazil

³Colorado State University, Department of Chemistry, Fort Collins, Colorado, 80523, USA

1.1 History of Metal Complexes

1.1.1 Introduction

Pharmaceutical science, which studies the design, action, delivery, and disposition of drugs, is an important field in drug research. Humans have made several sincere attempts for the search of new drugs in order to cure and control different diseases. Although possible remedial measures are available at present to tackle any disease, scientists are increasingly trying to find superior and more effective drugs [1]. Over the last 50 years some “wonder drugs” have played a crucial role in diminishing the global burden of infectious diseases. New drugs are constantly being screened for their potential biological properties. Among the category of new drugs that are receiving much attention are metal‐based drugs [2]. Precious metals have been used for medicinal purposes for at least 3500 years. Among them, gold has played a crucial role in a variety of medicines in China and Arabia [3].

1.1.2 Metal Complexes

Medicinal inorganic chemistry is in the early days of its development, although there are now a significant number of clinical trials involving metal compounds or other agents that interfere with metabolic pathways for metals, both for therapy and for diagnosis [4]. In chemistry, metal complexes are nothing but reactions between metals and ligands [5]. Biomedical applications of several metal coordination compounds in recent years have provided a substantial contribution to the augmentation of more impressive diagnostic and therapeutic agents [6]. Metal coordination compounds and metal ions are known to effect cellular processes in a dramatic way [7]. Metal coordination complexes offer biological and chemical diversity that is distinct from that of organic drugs.

1.1.3 Metal Complexes in Medicine

In the ancient history of medicine, extraordinarily, many metal‐based drugs played a crucial role as anti‐infective agents. The increasing medicinal application of metals and metal complexes day by day is gaining clinical and commercial significance [8]. The development of metals containing anticancer drugs has been in the 1960s with the synthesis of Platinum compounds. Cisplatin is one of the most extensively used antineoplastic drugs, specifically for the treatment of ovarian and testicular cancers [9, 10]. The success of cisplatin and its analogs has accelerated a resurgence of inorganic medicinal chemistry and the search for complexes of other precious metals [Ru, Va, Zn, Cu, Ag, Gold, Pd] with interesting biological properties [11–17]. Among them, particularly ruthenium compounds have attracted significant attention with two compounds, namely, NAMI‐A and KP1019, advancing through clinical trials [18]. Many precious metals and metal compounds have succeeded in the clinic over the last few decades. Platinum compounds are the most extensively used chemotherapeutic agents, silver compounds have been useful as antimicrobial agents, and gold compounds are used widely in the treatment of rheumatoid arthritis. Scientists have been investigating over the past 25 years several metal‐based compounds and such return of interest in metal‐based drugs can be witnessed in several recent articles [19–24].

1.2 Nanotechnology

1.2.1 Introduction

In today's world, nanotechnology is a relatively new field, but its structural nanometer dimensions and functional devices are not new, and in fact, these materials have much significance. In recent years, we found a plethora of literature explaining the recent advances in nanotechnology [25–33]. Nanotechnology has the potential to provide novel, paradigm‐shifting solutions to medical problems. Nanotechnology, which has been defined as the engineering and manufacturing of materials at the atomic and molecular scale, offers exclusive tools for developing safer and more efficient medicines (nanomedicines), and provides several potential advantages in drug formulation and delivery. Nanotechnology refers to an emerging field of science that includes preparation and development of various nanomaterials. Nowadays, nanomaterials are widely used in many fields including biomedicine, consumer goods, and energy production [34–37]. The purpose of nanomaterials in biotechnology combines the fields of material science and biology.

1.2.2 Development of Nanotechnology

In recent years, disparate products of nanotechnology have played a key role in adding a novel armamentarium of therapeutics to the pipelines of pharmaceutical industries. The nanotechnology fever we are experiencing now began when the United States launched the National Nanotechnology Initiative [38], the world's first program of its kind, in 2000. Nanotechnology usage may possibly achieve many advantages: (i) improved delivery of poorly water‐soluble drugs; (ii) targeted delivery of drugs in a cell‐ or tissue‐specific manner; (iii) drugs transcytosis beyond the tight endothelial and epithelial barriers; (iv) improved delivery of large macromolecule drugs to intracellular sites of action; (v) co‐delivery of multiple drugs or therapeutic modality for combination therapy; (vi) improvement in drug delivery through visualization of sites by combining therapeutic agents with imaging modalities [39]; and (vii) real‐time read on the in vivo efficacy of an agent [40]. Nanotherapeutics has the potential to actively target tumors, increasing the therapeutic effectiveness of a treatment while limiting side effects. This improved therapeutic index is one of the great promises of nanotechnology [41].

1.2.3 Nanotechnology in Medicine

In pharmaceutical trade, a new molecular entity (NME) that exhibits significant biological activity but meager water solubility, or a very terse circulating half‐life, will likely face significant challenges in progress or will be assumed undevelopable [42]. Nanotechnology may revolutionize the rules and possibilities of drug discovery and change the landscape of pharmaceutical industries. In medicine, nanotechnology application may be referred to as nanomedicine that explains various intriguing possibilities in the healthcare sector. The major current and promising applications of nanomedicine include, but are not limited to, drug delivery, in vivo imaging, in vitro diagnostics, biomaterials, therapy techniques, and tissue engineering [28]. In oncology, nanomaterials can enable targeted delivery of imaging agents and therapeutics to cancerous tissues; nanoscale devices enable multiplexed sensing for early disease detection and therapeutic monitoring. The drug delivery field application of nanotechnology is widely expected to change the landscape of pharmaceutical and biotechnology industries in the foreseeable future [40, 43–45]. Nanotechnology attracts scientists because of a wide variety of applications, which includes drugs and medicines, energy, nanoparticles, nanodevices, nanobiotechnology, optical engineering, bioengineering, nanofabrics, and cosmetics (Figure 1.1).

Illustration of Applications of Nanotechnology. — Figure 1.1 Applications of Nanotechnology.

1.3 Nanoparticles

1.3.1 Introduction

Any intentionally produced particle that has a characteristic dimension from 1 to 100 nm and has properties that are not shared by non‐nanoscale particles with the same chemical composition has been called a nanoparticle [46, 47]. Nanoparticles demonstrate a particularly useful platform, describing exclusive properties with potentially wide‐ranging therapeutic applications [48]. The enormous diversity of nanoparticles was described (Figure 1.2). Nanoparticles made of polymers (NPs) are of particular interest as drug delivery systems because of their synthetic versatility as well as their tunable properties (e.g., thermosensitivity and pH response). Nanoparticles offer exciting prospects for improving delivery, cell uptake, and targeting of metallodrugs, especially anticancer drugs, to make them more effective and safer. Transition metal nanoparticles synthesis has been extensively investigated in recent years because of its many unique physical (electronic, magnetic, mechanical, and optical) and chemical properties. Nanoparticles are often in the range 10–100 nm and this is the same size as that of human proteins.

Illustration of Various features of engineered nanoparticles. — Figure 1.2 Various features of engineered nanoparticles.

1.3.2 Development of Nanoparticles

The primary intention in designing nanoparticles as a delivery system is to manage particle size, surface properties, and release of pharmacologically active agents in order to obtain the site‐specific action of the drug at the therapeutically optimal rate and dose regimen [49]. Nanoscale particles developed using organic molecules as building blocks have been widely examined for drug and gene delivery. For example, polymer, polymersome, and liposome constructs for controlled release of proteins and polymeric micelles, macromolecules, and long‐circulating polymeric nanoparticles are in different stages of clinical and preclinical development [29]. In the 1960s, Bangham and Horne produced the first nanoparticle‐based platform for medical application based on liposomes. In the following decades, nanoparticles gathered more scientific and general interest and developed rapidly [50].

1.3.2.1 Liposome‐Based Nanoparticles

Liposomes are small sphere‐shaped particles, formed by one or more phospholipid bilayers that can be made from cholesterol and natural phospholipids. Depending on the design, they can range from 10 nm up to micrometers [51].

1.3.2.2 Polymeric Nanoparticles

Polymeric nanoparticles might be the most widely used nanoparticle carriers and have been extensively investigated in this regard. They could be formed by biodegradable, biocompatible, and hydrophilic polymers such as poly(D,L‐lactide), poly(lactic acid) (PLA), poly(D,L‐glycolide) (PLG), poly(lactide‐co‐glycolide) (PLGA), and poly‐(cyanoacrylate) (PCA) [52–54].

1.3.2.3 Metal Nanoparticles

Metal nanoparticles are attractive materials in many fields ranging from physics (hard or soft magnetic materials, optics, microelectronics) to catalysis [55]. Noble metal nanoparticles with spherical shape and sharp size distribution such as gold were formed progressively by the chemical reduction method supported by ultrasonic device [56]. The capability to integrate metal nanoparticles into biological systems has had a huge impact in biology and medicine. Some noble metal nanoparticles have been attracting huge interest from the scientific community owing to their awesome properties and diversity of applications, which include gold and silver [57]. The three important properties of gold nanoparticles that have attracted intensive interest are that they are easily prepared, have low toxicity, and readily attach to molecules of biological interest [58].

1.3.3 Nanoparticles in Science and Medicine

Over the past few years nanoparticles have emerged as a key player in modern medicine. Nanoparticles have significance ranging from being contrast agents in medical imaging to being carriers for gene delivery into individual cells [59]. Nanoparticles represent an extraordinarily charming platform for a distinct array of biological significance. In cancer therapy there has been an enormous amount of interest in the preparation and significance of nanoparticles [60]. NPs can easily be conjugated with biomolecules, and thus, they can act as labels for signal amplification in biosensing and biorecognition assays. These strategies can significantly enhance detection sensitivity; even a single molecule can be detected in an ideal case [34]. The exclusive properties and adequacy of nanoparticles emerge from a peculiarity of attributes, including the similar size of nanoparticles and biomolecules such as polynucleic acids and proteins. Additionally, nanoparticles can be formed with a huge range of metal and semiconductor core materials that convey favorable properties such as fluorescence and magnetic behavior [40]. Nanoparticles can afford significant improvements in traditional biological imaging of cells and tissues using fluorescence microscopy as well as in modern magnetic resonance imaging (MRI) of various regions of the body. MRI technique is extensively used in modern medicine, specifically in the diagnosis and treatment of most diseases of the brain, spine, and the musculoskeletal system. Superparamagnetic iron oxide (SPIO) nanoparticles can also be used to visualize features that would not otherwise be detectable by conventional MRI [61]. Several such SPIO nanoparticles have been used in modern MRI [62, 63]. Nanoparticles have already been used for a wide range of applications both in vitro and in vivo. Nowadays various nanoparticles are used in biomedicine. A list of some of the applications of nanomaterials in biology or medicine is given below:

Drug and gene delivery [64–75]
Fluorescent biological labels [76–80]
Detection of proteins [81]
Biodetection of pathogens [82]
Medical imaging [83]
Probing of DNA structure [84]
Tissue engineering [85]
Phagokinetic studies [86]
Tumor destruction via heating (hyperthermia) [87]
Separation and purification of biological molecules and cells [88]
Cancer cell imaging [89]
Treatment of cancer [26, 69, 90, 91].

₂₃₃₄92

silver nanoparticleAgNP93

1.4 Nanotechnology‐Supported Metal Nanoparticles

4950in vitroin vivo94107

Acknowledgment

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Metal Nanoparticles

Synthesis and Applications in Pharmaceutical Sciences

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