Nanobiomaterials in Medical Imaging: Applications of Nanobiomaterials

Turkey

Preface of the series

Ecaterina Andronescu, Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, Bucharest, Romania

The era of nanosized materials is now considered the center of the evolution of future tools and emerging technologies with wide applications in industry, research, health, and beyond. Despite recent scientific progress, biological applications of nanomaterials are far from being depleted and current knowledge is limited by the poor access to significant data, but also by widespread and usually unfounded speculation. Although exhaustive, the current literature is difficult to reach and understand because of the specificity and strict focuses of researchers investigating different applications of nanomaterials.

In this context, the scientific series entitled Applications of Nanobiomaterials was motivated by the desire of the Editor, Alexandru Mihai Grumezescu, and others to bring together comprehensive, up-to-date and relevant findings on the field of biological applications of nanostructured materials, to promote the knowledge and expand our vision regarding future perspectives. Even though the approached domain is quite specific and research-oriented, this multivolume set is easily intelligible for a wide audience including: undergraduate and postgraduate students, engineers, researchers, academic staff, pharmaceutical companies, biomedical sector, and industrial biotechnologies. However, some basic knowledge of the field of materials science (nanobiomaterials, pharmaceutical industry, products for medicinal treatments, nanoarchitectonics for delivery of biological active molecules and release, bone implants and stomatology) and engineering is a requisite for understanding technical aspects.

The selected authors of each chapter are outstanding specialists in the field of nanobiomaterials, who have made impressive contributions in a specific area of research or applied area within the scope of this book.

Each of the 11 volumes of the series contains 15 chapters, addressing the most relevant and recent matters on the field of the volume.

The first volume, Fabrication and Self-Assembly of Nanobiomaterials, introduces the reader to the amazing field of nanostructured materials and offers interesting information regarding the fabrication and assembly of these nanosized structures. In Volume II, entitled Engineering of Nanobiomaterials, readers can easily find the most commonly investigated methods and approaches for obtaining tailored nanomaterials for a particular application, especially those with a great deal of significance in the biomedical field. In the following step, readers will discover the importance and the ways of modifying the surface of nanostructured materials to obtain bioactive materials, by reading Volume III, Surface Chemistry of Nanobiomaterials. Starting with Volume IV Nanobiomaterials in Hard Tissue Engineering and Volume V Nanobiomaterials in Soft Tissue Engineering the biomedical applications of engineered nanomaterials are revealed and discussed, focusing on one of the most impacted fields, tissue engineering. Volume VI, Nanobiomaterials in Antimicrobial Therapy, highlights the potential of different nanostructured materials to be utilized in the development of novel efficient antimicrobial approaches to fight the global crisis of antibiotic inefficiency and emerging infectious diseases caused by resistant pathogens. Volume VII moves on to another key biomedical domain—cancer therapy. This volume, Nanobiomaterials in Cancer Therapy, describes current issues of cancer therapy and discusses the most relevant findings regarding the impact of nanobiomaterials in cancer management. Medical Imaging represents the focus of Volume VIII, while Volume IX deals with applications of Nanobiomaterials in Drug Delivery. Volume X, entitled Nanobiomaterials in Galenic Formulations and Cosmetics, refers to the perspectives highlighted by the utilization of nanosized functional biomaterials in the development of improved drugs and active principles for different biomedical industries. Finally, Volume XI is dedicated to the impact of Nanobiomaterials in Dentistry, which currently represents one of the most investigated and controversial domains related to the biomedical applications of nanostructured materials.

Due to their specific organization, each volume can be treated individually or as a part of this comprehensive series, which aims to bring a significant contribution to the field of research and biomedical applications of nanosized engineered materials.

Preface

Alexandru Mihai Grumezescu

http://grumezescu.com/

Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, University Politehnica of Bucharest, Bucharest, Romania

Department of Biomaterials and Medical Devices, Faculty of Medical Engineering, University Politehnica of Bucharest, Bucharest, Romania

About the Series (Volumes I–XI)

The increased fabrication of nanosized materials with applications in the biomedical field by using biomimetic and bio-inspired processes and formulations, has recently led to a new concept, named Nanobiotechnology. This complex research brings together significant knowledge from physical, chemical, biological, and technological sciences in an applicative field.

Medical applications of nanobiomaterials range from the development of adequate scaffolds for tissue engineering to therapeutic nanostructures, such as targeted drug delivery systems. The purpose of this multivolume set entitled Applications of Nanobiomaterials is to offer a broad, updated, and interdisciplinary point of view regarding the applications of these materials of the future medicine, starting with their fabrication, specific engineering, and characterization, but also discussing about their impact in tissue engineering, antimicrobial and cancer therapies, and also the development of different medical and cosmetic products. These books bring together the work of outstanding contributors who have significantly enhanced the basic knowledge and applicative concepts of this research field in their respective disciplines.

The multivolume set Applications of Nanobiomaterials contains 165 chapters, organized in 11 volumes, which are ready to present a novel and up-to-date approach related to this intriguing domain. Each chapter was carefully composed and illustrated to highlight the relevance of nanobiomaterials on most biomedical fields, revealing the most recent applications on a specific domain. The whole set represents a great material for the academic community, starting with undergraduate and postgraduate students, researchers, engineers, and medical doctors, but also pharmaceutical companies and innovative biotechnologies.

These 11 volumes cover all relevant aspects related to the Applications of Nanobiomaterials as it follows:

Volume I: Fabrication and Self-Assembly of Nanobiomaterials

Volume II: Engineering of Nanobiomaterials

Volume III: Surface Chemistry of Nanobiomaterials

Volume IV: Nanobiomaterials in Hard Tissue Engineering

Volume V: Nanobiomaterials in Soft Tissue Engineering

Volume VI: Nanobiomaterials in Antimicrobial Therapy

Volume VII: Nanobiomaterials in Cancer Therapy

Volume VIII: Nanobiomaterials in Medical Imaging

Volume IX: Nanobiomaterials in Drug Delivery

Volume X: Nanobiomaterials in Galenic Formulations and Cosmetics

Volume XI: Nanobiomaterials in Dentistry

About Volume VIII

Volume VIII, entitled Nanobiomaterials in Medical Imaging, presents the recent progress and a comprehensive summary of the state-of-the-art related to (i) synthesis and surface modification of multimodal imaging agents, (ii) popular examples of nanoparticles (quantum dots, iron oxide nanoparticles, silver nanoparticles, gold nanoparticles, carbon nanotubes), with applications in different imaging techniques such as fluorescence imaging, magnetic resonance imaging, computed tomography, and other various techniques, and (iii) combinatorial therapy for the development of multifunctional nanocarriers.

Volume VIII contains 15 chapters, prepared by outstanding researchers from Canada, Argentina, Portugal, France, Romania, Turkey, Saudi Arabia, India, China, Taiwan, Malaysia, Singapore, and South Korea.

In the Chapter 1, entitled Specifically targeted imaging using functionalized nanoparticles, Roxana Cristina Popescu et al., discuss the most popular examples of nanoparticles that are currently used in different imaging techniques: quantum dots utilized in fluorescence imaging, iron oxide nanoparticles for magnetic resonance imaging or computer tomography, and silver nanoparticles adapted for various techniques and applications.

James C. L. Chow et al., in Chapter 2, Photon and electron interactions with gold nanoparticle: a Monte Carlo study on gold nanoparticle-enhanced radiotherapy, present an up-to-date review regarding the rapid progress of gold nanoparticle-enhanced radiotherapy. In this chapter, the utility of Monte Carlo simulations to predict the photon and electron interactions with gold nanoparticles in a tissue/water equivalent medium is described.

Chapter 3, Quantum dots: dynamic tools in cancer nanomedicine, prepared by S.K. Tripathi et al., discusses the architecture and various approaches used for functionalization of quantum dot (QD) probes. The authors highlight the role of QDs as antitumor theranostic agents in drug delivery, gene therapy, recently emerged photodynamic therapy, safety concerns, and futuristic perspectives.

In Chapter 4, Basics to different imaging techniques, different nanobiomaterials for image enhancement, Radhakrishnan Narayanaswamy et al., present an up-to-date review regarding major insights and current status of nanotechnology and nanobiomaterials and their various applications in medical imaging.

Juan C. Fraire et al., in Chapter 5, Design of plasmonic probes through bioconjugation and their applications in biomedicine: from cellular imaging to cancer therapy, describe the following aspects: (i) the main factors that control the optical properties of noble metal nanoparticles and the most commonly used approaches currently applied for the synthesis of stable colloidal dispersions of these nanostructures; (ii) the most relevant strategies for their functionalization with biomolecules and how the combination of the biorecognition properties of biomolecules with the plasmonic properties of noble metal nanoparticles can be used for sensing; (iii) specific detection of target molecules for the development of promising nanomedicine tools especially for biospectroscopy and cancer therapy.

In Chapter 6, Multifunctional nanocarriers for codelivery of nucleic acids and chemotherapeutics to cancer cells, Vítor M. Gaspar et al. outline the concepts underlying combinatorial therapy and the development of multifunctional nanocarriers specifically designed for codelivery of drug–gene combinations to cancer cells. Various examples of multifunctional nanobiomaterials employed in multifunctional particle assemblies are also discussed.

Bahar Guler et al., in Chapter 7, Targeting and imaging of cancer cells using nanomaterials, reveal the most commonly investigated functionalization techniques utilized for the design of bioactive nanoparticles. The chapter describes a variety of biological molecules utilized in order to prepare nanocarrier systems and their impact in targeting and imaging of cancer cells.

In Chapter 8, Multimodal inorganic nanoparticles for biomedical applications, Timur Sh. Atabaev et al. introduce recent developments in the synthesis and surface modification of multimodal imaging agents, and focus on their potential applications in biomedical areas.

Chapter 9, Iron oxide nanomaterials for functional imaging, by Alexandru Mihai Grumezescu and Mariana Carmen Chifiriuc highlights the current solutions offered by nanotechnology and magnetic nanoparticles for the improvement of cancer imaging and theranostics platforms.

Chapter 10, Nanobiomaterials involved in medical imaging technologies, prepared by Raj K. Keservani et al., discusses the potential advantages and applications of nanobiomaterials in the field of medical imaging.

Suresh K. Kailasa et al., in Chapter 11, Applications of carbon nanomaterials in biosensing and cellular imaging, describe the photo- and electron properties of carbon dots and their applications as optical probes for biomolecules sensing. The authors also present many other applications of these nanomaterials, such as the development of fluorescent probes for biomolecule-sensing and cell labels for imaging of various cells.

Chapter 12, Inorganic nanobiomaterials for medical imaging, by Hemant Kumar Singh Yadav et al., covers the field of nanosized materials extensively used in medical engineering and for imaging purposes.

Xin Liu et al., in Chapter 13, Nanobiomaterials in X-ray luminescence computed tomography (XLCT) imaging, introduce the XLCT imaging system, the computational method, and reveal future directions of its use. The authors discuss the advantages and challenges of the XLCT technique. The diverse XLCT imaging systems are classified and summarized. Finally, the authors predict an attractive prospect for XLCT.

Neelesh K. Mehra et al., in Chapter 14, Multifunctional carbon nanotubes in cancer therapy and imaging, provide a critical update on the applications of multifunctional carbon nanotubes in cancer therapies and imaging. The drug delivery aspects embodying the safety and efficacy of carbon nanotubes are also reviewed to address the regulatory considerations.

Chapter 15, Functionalized carbon nanotubes and their promising applications in therapeutics and diagnostics, prepared by Bhupinder Singh et al., describes various types of carbon nanotubes and discuss the methods utilized for their commercial production, and the functionalization approaches employed in drug-delivery applications.

Chapter 1

Specifically targeted imaging using functionalized nanoparticles

Roxana Cristina Popescu¹,², Mariana Oana Mihaela Fufă¹,³, Ecaterina Andronescu¹ and Alexandru Mihai Grumezescu¹,    ¹Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, Politehnica University of Bucharest, Bucharest, Romania,    ²Department of Life and Environmental Physics, Horia Hulubei National Institute of Physics and Nuclear Engineering, Magurele, Bucharest, Romania,    ³Lasers Department, National Institute for Laser, Plasma and Radiation Physics, Magurele, Bucharest, Romania

Abstract

Since the discovery of quantum dots (QDs) and their optical properties, many attempts have been made in order to obtain more efficient nanosystems, to be used as a tool in an easier diagnostic or for higher-resolution detection of molecules/intracellular components. Nowadays, these attempts have been channeled toward specificity and targeting. These can be done by applying specific functionalizing agents to less toxic nanoparticles which are actively transported at the site of action. This chapter focuses on some popular examples of nanoparticles which are currently used in different imaging techniques: QDs in fluorescence imaging, iron oxide nanoparticles in magnetic resonance imaging or computer tomography, and respectively silver nanoparticles in various techniques.

Keywords

Biomedical imaging; specific; targeting; functionalized nanoparticles

1.1 Introduction

Healthcare practice has various obstacles in current therapeutic strategies; the main reasons for such an alarming situation being the improper diagnostic or (un)recommended treatment. The human genetic complexity plays a significant role during the development and evolution of new emerging pathologies. In the case of microbial-related pathologies, there is worldwide acknowledgment of the hazardous phenomenon of conventional therapy resistance that has been developed and enhanced due to the improper or irrational use of antimicrobial medication (Alharbi and Al-Sheikh, 2014; Heffernan and Fox, 2014; Roca et al., 2015). Healthcare professionals did and still do their utmost to devise novel therapeutic strategies for such conditions, and nanotechnology-related results reported now are promising in terms of accurate diagnostic and efficient targeted therapy. For microbial-related diseases, the personalized therapeutic approach seems closer than originally expected, but there are still manifold pathologies that raise serious issues. Except for human genetics (that are strongly affected by age, gender, case history, collateral heredity, residency, and workplace), various factors are responsible for typical pathophysiological behavior. Herein, we must mention the impressive structural, genetic and behavioral diversity found in various types of cells that are responsible for complex pathologies, such as metabolic disorders (Frye, 2015; Tudor and Georgescu, 2013; Verma et al., 2015), autoimmune conditions (Aguilar-Nájera et al., 2015; Al-Ajlan et al., 2014; Effraimidis et al., 2012; Ishimaru, 2012; Ngo et al., 2014), degenerative pathologies (Aikawa and Schoen, 2014; Farshad-Amacker et al., 2015; Gendelman et al., 2015; Glaab and Schneider, 2015; Sousa et al., 2015), genetic disorders (Assou et al., 2014; Chen et al., 2015a,b; Evans et al., 2015; Wright et al., 2015), and various cancers (Davidson and Tropé, 2014; Esfahani et al., 2015; Grover et al., 2015; Jin et al., 2015; Kourou et al., 2015; Marengo and Robotti, 2014; Popper et al., 2014).

The complex pathophysiological mechanism of such conditions has alarmed the medical community, resulting in the promotion of less conventional therapeutic strategies, despite starting with an accurate diagnostic result. Thus, the emergent requirement for such specific detection systems involves the distinctive detection of biological and chemical structures and molecular markers, in order to provide a sensitive and specific diagnosis. The occurrence of such an unusual therapeutic strategy would not have been possible without the tremendous technological substruction given by nanotechnology. Thanks to the impressive progress recently reported in this novel and powerful direction—which allows molecular and atomic manipulation of matter—there are already reported data regarding potential biomedical applications of nanotechnologies, such as targeted and controlled drug delivery systems (Khadka et al., 2014; Kim et al., 2013; Safari and Zarnegar, 2014), gene therapy (Ibraheem et al., 2014; Yu and Chen, 2012) and antitumor therapy (Bose and Wong, 2015; Kang et al., 2015), tissue engineering (Shajkumar, 2015; Sampogna et al., 2015), and biomedical imaging (Cabral et al., 2014; Dukes et al., 2014; Kumar and Kumar, 2014).

Metallic materials represent ideal candidates for nanoscale technological manipulation, thanks to their specific physical and chemical properties. In terms of synthesis techniques, there are plenty of successful methods that provide manifold possibilities to design nanodimensional metal-based structures. The physical, chemical, biological, and biomimetic synthetic approaches provide unimaginable possibilities to design metallic nanosized systems (dimensional range lower than 100 nm), with various morphologies (sphere, cube, polyhedron, triangle, hexagon, polygon, plate, rod, wire, ribbon, inflorescence), and tunable properties (Edmundson et al., 2014; Kuppusamy et al., 2015; Rai et al., 2011; Schröfel et al., 2014). Given the specific high surface/volume ratio, metallic nanomaterials exhibit unique structural and morphological features, but also specific physical-chemical and functional peculiarities, which enable auspicious interactions with molecular structures (either physiological or pathological). Furthermore, the nanoscale-related surface physics and chemistry also offer remarkable functionalizing strategies, by means of a natural or synthetic coating, composite or hybrid encapsulation, inorganic or organic shell, superficial binding of biomolecules (such as amino acids, peptides, proteins, enzymes, polysaccharides, nucleic acids, or specific antibodies) (Cabral et al., 2014; Edmundson et al., 2014; Kuppusamy et al., 2015; Maldonado et al., 2013). The specific properties of metallic nanostructures strongly recommend them for the unconventional development of metallic nanosystems used for the benefit of novel medical diagnosis strategies. As will be revealed during the following paragraphs, various metal-based nanosized systems have been engineered and assessed as potential diagnostic tools.

There are some requirements that need to be satisfied when using nanoparticles (NPs) in biomedical applications such as medical imaging; these are given by their direct interaction with living tissue and blood flow: (i) nontoxicity; (ii) colloidal stability; (iii) low absorption of plasma proteins; (iv) controlled surface charge; (v) nonaggregation tendency; and (vi) controlled hydrodynamic dimension and stability. However, there must be equilibrium between these properties, because very low nanoparticle dimensions can determine their uncontrolled distribution, permeation, and accumulation inside many cells. Usually, the use of bare nanoparticles in applications which assume their interaction with biological structures is avoided, in order to have better control of the previously listed properties. Also, by functionalizing, one can facilitate the transport of the nanosystem at the site of action. This property is known as targeting of the NPs and can be done in several ways: (i) passive targeting, when the NPs are randomly transported in the blood flow and deposited in organs such as the liver or spleen; in case of cancer passive targeting, this is facilitated by enhanced permeability and retention effect; (ii) active magnetic targeting, when using magnetic nanoparticles (MNPs) such as iron oxide nanoparticles (IONPs), which can be transported in magnetic flux; and (iii) active targeting, by applying different functionalizing agents, specifically binding to certain receptors on the surface of the targeted cells (Figure 1.1).

Figure 1.1 Specifically targeted imaging using functionalized nanoparticles: (1) active targeting using small molecules or antibodies that are specifically recognized by the receptors on a certain type of cells; (2) operating principle by magnetic field activation or photon activation.

1.2 Functionalized Quantum Dots for Imaging

1.2.1 Introduction

Quantum dots (QDs) are defined as inorganic nanoparticles with semiconductor properties, composed of elements from the groups III–V and II–VI from the Periodic Table (Volkov, 2015). Their properties were reported for the first time in 1988 (Reed et al., 1988). In the literature, the term is improperly associated with nanoparticles having diameters smaller than 10 nm, made from C, Si, Au, and Mo, and exhibiting quantum confinement phenomena at these dimensions.

The quantum confinement effect appears in semiconductor crystallites smaller in size than twice the size of the excitation Bohr radius and is manifested by a fluorescent appearance when excited electrons relax to the ground state and are combined with a hole.

The main reason for using QDs in imaging applications is their optical properties, including (i) the broad absorption spectra; (ii) the narrow light emission bands, which depend on the nanoparticle size; (iii) the resistance to photo-bleaching; and (iv) large effective Stoke shift (Karakoti et al., 2015).

Currently, the use of QDs in different biomedical imaging refers to applications such as: (i) in vitro and in vivo imaging of biological probes; (ii) detection of pathogens and toxins; (iii) gene profiling; and (iv) Fourier resonance energy transfer (FRET) (Stanisavljevic et al., 2015).

The FRET effect is the transfer of energy between the excited fluorophore and the nonexcited fluorophore, through a long-range dipole–dipole coupling (Onoshima et al., 2015). This method is intensively used in biomedical and biotechnological applications, due to its high sensitivity: it can generate fluorescence signal changes in the range of 1–10 nm. Other approaches using QDs consist of targeting the desired biological structures, followed by an exterior excitation with penetrating radiation.

1.2.2 Obtaining Methods for Functionalized Quantum Dots

The main approaches to synthesize QDs are the following: (i) the colloidal method, which includes the use of precursor salts, surfactants, and solvents (Li et al., 2015f; Ayele et al., 2014; Niu et al., 2015); (ii) plasma synthesis (Kumar, 2012); and (iii) electrochemical method (Freitas et al., 2014; Gopalakrishnan et al., 2015).

Of the QDs developed for bioimaging purposes, carbon dots attracted the greatest interest due to their biocompatibility and low cytotoxicity, and also due to their fluorescence properties. Zhuo et al. (2015) obtained carbon dots using citric acid and glutathione as precursors. The resultant nanoparticles exhibit blue fluorescence under UV excitation at low concentrations, the phenomenon being due to an n–π* transition of C=O and C=N, emphasized with UV-Vis spectroscopy. The emission was independent of the excitation, due to the fact that there was no shift in the emission peak and the intensity of the fluorescence decreased with the excitation wavelength. The stability of these nanoparticles was good for different pH and ionic strength media, however, under pH=7, a redshift in the emission spectra was observed and, also, the fluorescence intensities decreased with the values of the pH. The in vitro cytotoxicity and performance of the systems were assessed for A549 human lung cancer cells, proving that the carbon dots are safe for in vivo use, even at high doses, and are suitable for cell imaging.

The need to apply surface functionalizing agents to QDs comes from the following shortcomings: (i) the surface defects that can appear in the case of bare QDs and affect their fluorescence properties; (ii) surface oxidation and photochemical degradation of QDs; (iii) metal ion release in physiologic media; (iv) increasing the stability in physiologic media; (v) the opsonization process and the immune reactions, due to the surface hydrophobicity of the bare QDs; and (vi) nonspecificity and necessity of active targeting.

The most commonly encountered methods for QD functionalizing are: (i) the ligand exchange method; (ii) surface silanization; (iii) the amphiphilic combination method; (iv) absorption of biomolecules; and (v) the covalent functionalizing method. Table 1.1 gives some examples of differently functionalized QDs, using each of these methods.

Table 1.1

Functionalizing Methods for QDs

The ligand exchange method refers to the substitution of the existing ligands on the QDs surface with other hydrophilic ligands offering higher biocompatibility, system solubility, and the possibility of secondary functionalizing. This is possible due to the fact that in the process of obtaining QDs, some agents are used in order to: (i) prevent aggregation of the dots; (ii) prevent excessive QD growth in the synthesis process; and (iii) passivate the surface defects (Karakoti et al., 2015). One of the main disadvantages of this method is the low stability of the capping agent–nanoparticle interaction, however this can be improved by disulfide linkage approaches.

Surface silanization means the attachment of silane groups on the surface of QDs. The crosslinking process which occurs in these layers determines high adherence and stability. The terminal groups also offer the possibility of secondary functionalizing. The main advantage of employing this type of capping method is its high stability even at large pH variations and particle concentrations, an effect given by the string steric repulsions.

When using the amphiphilic combination method, we actually employ a secondary functionalizing of the natively functionalized QDs. The usually hydrophobic layer interacts with other hydrophobic groups from more biocompatible capping agents. Such functionalized nanoparticles provide more stability at temperature fluctuations.

The absorption strategy is based on the high surface area and reactivity of the nanoparticles, and can be done through the following mechanisms: (i) electrostatic interaction and (ii) hydrogen bonding.

The covalent functionalizing approach can be done using the following methods: (i) amide coupling, which is achieved using a ligand (carbodiimide hydrochloride) to provide a secondary functionalizing through the forming of amide bonds with peptides, proteins, and antibodies; (ii) thiol binding using an intermediary step of peptide disulfide binding at the QD surface; and (iii) click chemistry, combinatorial methods employing catalyzing agents and direct functionalizing steps.

1.2.3 Quantum Dots in Biomedical Imaging

Most of the targeted imaging applications involving QDs refer to their use in cancer diagnosis. Table 1.2 gives a brief summary of some recent studies of functionalized QDs used in specifically targeted imaging of cancer cells; as one can clearly see, most involve the capping of small molecules (like folic acid, monoclonal antibodies—antihuman epidermal growth factor receptor 2 [HER2], aptamers—antinucleolin aptamer (AS1411), etc.), which can be recognized by certain receptors on the surface of expressing cancer cells.

Table 1.2

Brief Description of Some Examples of QDs Used in Cancer Cell Imaging

The efficiency of QD-based imaging systems has been evaluated using both in vitro (Ertas and Kara, 2015; Liu et al., 2015a,b,c; Xu et al., 2015; Onoshima et al., 2015; Maguire et al., 2014; Li et al., 2014a, 2015a; Yang et al., 2015b; Casas et al., 2014) and in vivo (Chen et al., 2015a,b; Lin et al., 2015; Li et al., 2015b; Alaraby et al., 2015; Si et al., 2014; Li et al., 2014b,c; Lu et al., 2013; Wang et al., 2015; Liu et al., 2012, 2014; Wang et al., 2013a; Su et al., 2011; Tang et al., 2013; Praetner et al., 2010) approaches. There are many studies testing the interaction of these nanoparticles with living tissues and their properties in an environment closer to the final purpose. For example, Tan et al. (2015) developed AgInS2 QDs functionalized with a multidentate polymer (MDP) with photoluminescent properties in near infrared (NIR). In this regards, the as-designed systems proved to have low cytotoxicity for HeLa cells and then were in vivo evaluated on nude mice for biocompatibility: the administering was done by a subcutaneous injection of 0.1 mg/ml of QDs in PBS/intravenous injection in the tail vein of 10 µg QDs.

Li et al. (2015b) developed Fe³+ functionalized carbon dots for specific targeting of ascorbic acid in rat brains, via a redox reaction of activation; the evaluation was done by implanting a microdialysis probe into the rat brain, by using a guide cannula and perfused with artificial cerebrospinal fluid, after reaching an equilibration (during 100 min perfusion), 100 µl brain region dialysates were collected, the analysis being done using a 1-cm path length quartz cell.

1.3 Functionalized Iron Oxide Nanoparticles for Imaging

1.3.1 Introduction

IONPs have been extensively used in biomedical applications due to their magnetic properties and biocompatibility.

This type of nanoparticle can be found in numerous mineralogical phases, depending on the valence of the iron in the crystalline structure: (i) FeO, or wüstite, with Fe²+ in the cubic crystalline structure; this compound is thermodynamically unstable and paramagnetic at room temperature; (ii) Fe2O3, or ferric oxide, with Fe³+ions; the polymorphic phases of this compound are: α-Fe2O3, or hematite, with rhombohedrally centered hexagonal crystal structure, β-Fe2O3, with cubic body centered crystal structure, γ-Fe2O3, with cubic inverse spinel crystal structure, ε-Fe2O3, with orthorhombic crystal structure; and (iii) Fe3O4, or magnetite, with Fe²+ and Fe³+ in the cubic inverse spinel crystal structure (Hola et al., 2015). In biomedical applications, Fe3O4 and γ-Fe2O3 are preferred due to their performances regarding the magnetic properties.

1.3.2 Obtaining Methods for Functionalized Iron Oxide Nanoparticles

IONPs can be mainly obtained using the following approaches: (i) the coprecipitation method (Roth et al., 2015; Khalil, 2015; Mahmed et al., 2014; Makovec et al., 2015; Rani and Varma, 2015), which is the most common and consists of the simultaneous addition of ferric and ferrous ion precursors into a basic medium; (ii) the hydrothermal method (Yan et al., 2015; Kriedemann and Fester, 2015; Colombo et al., 2015; Behdadfar et al., 2012; Sinha et al., 2015; Mitchell et al., 2015; Tadic et al., 2014), which uses water-soluble minerals to obtain singular crystals by applying very high pressure; and (iii) the solvothermal method (Li et al., 2013a, 2015c; Stojanović et al., 2013; Zhang et al., 2011), with the use of solvents, which are heated together with the precursors at temperatures higher than the solvent boiling point.

Table 1.3 gives some examples of functionalized IONPs using different approaches. Mostly, the purpose of applying a capping agent is given by the need to reduce the NPs' recognition rate by the reticuloendothelial system. Also, the first capping layer offers the possibility to bind targeting molecules, for specific transport.

Table 1.3

Functionalizing Methods for IONPs

1.3.3 Iron Oxide Nanoparticles in Biomedical Imaging

The use of IONPs in biomedical imaging is in their superparamagnetic properties at low dimensions, the ability to offer a contrast effect in MRI, easy controllable magnetic field gradient, and high response to a relatively low magnetic field (Hola et al., 2015).

MRI is based on the principle that protons align in the magnetic field, having a net magnetization at equilibrium, while becoming excited after receiving a pulse of radiation; this results in a change in the magnetization vector. The revenue is characterized by two relaxation processes: (i) the longitudinal relaxation, T1, or spin–lattice relaxation, given by the transfer of energy from excited nuclei to the environment and (ii) the transverse relaxation, T2, or spin–spin relaxation, produced by the interactions between excited and unexcited nuclei (Williams and Corr, 2013).

This type of nanoparticle is mainly used as a contrast agent, due to its ability to modify the spin–spin relaxation of water molecules (T2 relaxation) in the proximity of the IONPs, enhancing the negative contrast (Hola et al., 2015).

For this use, many attempts have been made in order to obtain more biocompatible, yet well-performing, nanosystems based on IONPs. Examples in the implementing of active targeting, by attaching specific molecules, are given in Table 1.4.

Table 1.4

Brief Description of Some Examples of IONPs Used in Biomedical Imaging

Sitthichai et al. (2015) obtained Fe3O4 and carboxymethyl cellulose (CMC)—Fe3O4 and comparatively characterized them to determine the phase, morphology, particle-size distribution, surface chemistry, and weight loss. The functionalized MNPs were magnetically characterized and the relaxation properties (543.3 m/M s) were found to be suitable for MRI. The performances of the resultant system were further determined in vitro, for Hep G2 hepatocellular carcinoma cells.

Another recent example is given by Roy et al. (2015), who developed a multipurpose platform, which acts both as s drug delivery system, and also as a multimodal cancer imaging system: near-infrared (NIR) imaging, magnetic resonance imaging (MRI), and computerized tomography (CT). Thus, Fe3O4-lactoferrin-alginate-chitosan-calcium phosphate-locked nucleic acid is targeted to the epithelial cell adhesion molecule (EpCAM) and nucleolin markers. The targeting efficiency was evaluated on mice with positive colon cancer stem cell (EpCAM, CD133, CD44) xenografts, which were orally administered a suspension of NPs. Complete tumor regression was observed 30 days after the treatment, the implied mechanisms of action were mediated by TRAIL, Fas, Fas-associated protein with death domain (FADD)-mediated phosphorylation of p53, which determines the activation of second mitochondria-derived activator of caspases (SMAC)/DIABLO (inhibiting survivin), and mitochondrial depolarization leading to release of cytochrome C. The recurrence that occurred in treated mice was attributed to secondary alternative pathways like mitogen-activated protein kinases (MAPK)/extracellular signal-regulated kinases (ERK) and Wnt signaling. Besides the direct therapeutic effect of the as-designed nanoparticles, immunomodulatory benefits were also observed.

Fe3O4-glucose transporter protein 1 (GLUT1) antibody (Sohn et al., 2015) proved to be a promising candidate in the diagnosis of infantile hemangioma in a hemangioma animal model. The performance of the system was evaluated in vitro for human umbilical vein endothelial cells in order to assess the cellular uptake. The MRI was done for a BALB/c mice infantile hemangioma model implanted with infantile hemangioma tissue from children. Classical histologic evaluation and immunohistochemical evaluation were done for the subjects exposed to the MNPs.

1.4 Functionalized Silver Nanoparticles for Imaging

1.4.1 Introduction

The historically acknowledged biocide activity assigned to silver metal gave humanity tremendous possibilities for high-quality daily activities for a long time. However, the indisputable progress lately reported in interdisciplinary technologies (especially nanotechnology) alongside the emergent need to design novel materials for present-day requirements led to original engineered nanosized silver-based materials. The physical and chemical features related to bulk silver (such as malleability, ductility, plasticity, good thermal conductivity, low melting point, low toughness) (Głuchowski and Rdzawski, 2008; Smith and Fickett, 1995) drew worldwide attention to the remarkable potential to develop and experience genuine systems based on nanosilver. In this respect, various silver nanoparticles (AgNPs) with distinctive morphologies have been developed and intensively examined in terms of specific properties (which are strongly related to the characteristic high surface/volume ratio) and potential applications. Among the peculiar features of nanosized silver particles, those that recommend such systems in biomedical practice are singular surface physics and chemistry (Le Ouay and Stellacci, 2015; Mwilu et al., 2013; Oćwieja et al., 2015; Ohyama et al., 2014), peculiar electrical conductivity and optical behavior (Chen et al., 2015a,b; Das and Sarkar, 2015; Lekawa-Raus et al., 2014; Liang et al., 2012; Wu et al., 2013; Yu et al., 2012; Zheng et al., 2014), distinctive catalytic action (Banerjee et al., 2014; Déronzier et al., 2014; Jiang et al., 2014), remarkable antibacterial (Ahmed et al., 2015; El-Zahry et al., 2015; Guzman et al., 2012), antifungal (Nedelcu et al., 2014; Lee and Lee, 2015) and antiviral activity (Sironmani and Daniel, 2011; Wei et al., 2015), particular anti-inflammatory action (Hebeish et al., 2014; Martínez-Gutierrez et al., 2012), and antitumor effect (Larguinho and Baptista, 2012; Ravindran et al.,