Hybrid Nanostructures for Cancer Theranostics

Korea

Chapter 1

Introduction and Types of Hybrid Nanostructures for Medical Applications

Raghvendra A. Bohara¹,²,    ¹CÚRAM, Centre for Research in Medical Devices, National University of Ireland Galway, Galway, Ireland,    ²Centre For Interdisciplinary Research, D.Y. Patil University, Kolhapur, Maharashtra, India

Abstract

Nanoscience and nanotechnology are a relatively recent developing trend and showing widespread activities in scientific research and have gained many of applications, especially in the medical field. This science deals with size and the size-based properties of these materials. The word nano-biotechnology comes from the simultaneous interface of the nanoworld, biosystems, and technology leading to the nano-biotechnology. This branch encompasses devlopment of nanomaterials for different medical medical applications. Many different nanomaterials have been established to date. Magnetic nanoparticles have received a special place in the world of nanoscience. Because of its intrinsic and tailormade properties it is envisaged to have widespread applications. Not only this, the system allows combination with different materials, either organic or inorganic, by different synthesis strategies for better medical applications. Such systems are said to hybrid nanostructures. This chapter deals with the basic concepts of hybrid nanostructures, synthesis methods, and their applications.

Keywords

Design; nanoscience; hybrid nanotechnology; medical applications

1.1 Introduction to Nanotechnology

Nanoscience and nanotechnology are a relatively recent developing trend and show widespread activities in scientific research. They have their roots in ideas from scientists in the 20th century. In 1959, Richard Feynman, the American physicist, assertively delivered a legendary talk entitled There’s Plenty of Room at the Bottom. This inspired others to discover new revelations in the field of nanotechnology. The process which enables the manipulation of individual atoms and molecules by using proper tools and techniques resulting in another proportionally smaller set on the desired scale had been described by Feynman [1,2]. The term nanotechnology was originally coined by the Japanese scientist, Norio Taniguchi of the Tokyo University of Science, in 1974 [3]. However, the term was unused until 1981, when Eric Drexler published his first paper on nanotechnology. He was unaware of the fact that the term nanotechnology had previously been used by Taniguchi [4–6]. The concept of nanotechnology had been developed and popularized by K. Eric Drexler. He founded the field of molecular nanotechnology, which includes engineered nanosystems operating on the molecular scale and associates of the molecular assembler [7]. His ideas about nanotechnology can be quoted as: it is the principle of manipulation of an atom by an atom, through control of the structure of matter at the molecular level, which entails the ability to build molecular systems with atom-by-atom precision, yielding a variety of nanomachines. With respect to this reality, in 1998, the National Science and Technology Council of the USA created a working group on nanoscience, technology, and engineering. Succeeding this, they also started the National Nanotechnology Initiative in 2001 with the objective of initiation to create a common platform for the academic institute, industries, and private sector for working on this new technology. Following this example, nowadays, the field of nanoscience and nanotechnology is being rapidly developed and being heavily invested in in most of the advanced countries in the world and also many developing countries including China and India [8]. The word nano originates from the Greek word nanos, which means dwarf or extremely small. Nanotechnology and nanoscience are defined by various means, which are often interchangeable. Nanotechnology could be defined as: The science involving designing, synthesis, characterization, and application of materials which are characterized by at least one dimension in the nanometer range where 1 nm=10−9 m. In nanotechnology, two perspectives, bottom-up and top-down, are used. With the bottom-up approach, nanoscale materials are created by breaking down larger materials physically or chemically. Meanwhile, in the top-down perspective, nanoscale objects are assembled atom-by-atom or molecule-by-molecule. Nanotechnology includes the production and application of physical, chemical, and biological systems at scales which range from individual atoms or molecules to submicron dimensions. It is also concerned with the integration of the resulting nanostructures into larger systems [9–11].

By merging nanoscience with technology, new, improved, potential nanotechniques are developed, replacing older ones. Nanotechnology has been of tremendous interested since nanoscale materials possess novel functionalities, leading to them having many imminent technological applications. There is an expanding attempt at creating new knowledge, which explains the size-dependent evolution of various physical properties and previously unnoticed features. Various basic and applied scientific disciplines have been promptly enrolled within the empirical discipline of nanotechnology. It has recently become one of the most important areas with potential to aid existing technologies with more efficiency and better outcome [8]. Nanotechnology shows great promise for providing us soon with many breakthroughs that will change the direction of technological advances in a wide range of applications. Improved and more desirable products can be made using nanosystems than with conventional materials. Nanotechnology is surely going to have a huge impact in areas such as electronics, communication, medical devices, medicine, cosmetics, architecture, textiles, agriculture, food, metallurgy, defense and security, space, and many more [12].

1.1.1 Fundamentals of Nano-Biotechnology

Nano-biotechnology is the simultaneous interface of the nanoworld, biosystems, and technology, as presented in Fig. 1.1.

Figure 1.1 The simultaneous interface of the nanoworld, biosystems, and technology leading to nano-biotechnology.

Nano-biotechnology is that branch of nanotechnology which deals with biological and biochemical applications or uses. Nano-biotechnology takes most of its fundamentals from nanotechnology. Nano-biotechnology often studies existing elements of living organisms and nature to fabricate new nano-devices. Nano-biotechnology can be defined as the ways that nanotechnology is used to create devices to study biological systems. On the other hand, bio-nanotechnology can be defined as the study of how nanotechnology is incorporated into the study of biological systems and adapting these biological motifs into improving existing nanotechnologies or creating new ones. It can be stated, that nano-biotechnology is a specific application of nanotechnology, whereas the bio-nanotechnology is an essential branch of biotechnology [13–15]. For example, many new medical technologies, which involve nanoparticles (NPs) as delivery systems or as sensors are categorized under nano-biotechnology, since they use nanotechnology to advance the goals of biology. Conversely, DNA nanotechnology or cellular engineering would be categorized under bio-nanotechnology, since they involve working with biomolecules on the nanoscale. Molecular behavior at nanometer scales governs living systems, where the disciplines of chemistry, physics, and biology all converge. Such a multidisciplinary approach will stimulate progress in nano-biotechnology. The nanosystems in biology are the most complex and highly functional nanoscale materials and machines that occur in nature. Incredible precision regarding regulation and control of biological systems is seen due to the proteins and nucleic acids. The molecular building blocks of cells, such as lipids, carbohydrates, and similar nonbiological molecules, are examples of materials that possess unique properties due to their size and folding patterns in the nanosize range. Many nanotechnologists are approaching new materials and devices by being inspired by nanosystems within biology [16–18]. Understanding of biological processes on the nanoscale level is a strong driving force behind the development of nano-biotechnology [19]. The cells are the fundamental unit of the living organisms, which are about 10 μm. Within the cell, the cell parts are much smaller and are in the submicron size. The comparison of these cells with manmade nanomaterials raised the idea to use nanotechnology for nano-bio applications (Fig. 1.2). For example, the nanosized protein of 5 nm, is comparable with the dimensions of the smallest manmade NPs, which can be used as very small probes to observe at the cellular level [20].

Figure 1.2 Comparison of nanomaterials and nanoscale biosystems [21] Copyright 2013 ChemSoc Rev.

1.2 Design Rationales of Hybrid Nanostructures

Among the different types of nanomaterials, magnetic nanoparticles (MNPs) are being focused on due to their various exciting properties that make them useful in a wide range of biomedical applications. The use of MNPs through nanotechnology for biomedical applications is currently gaining huge attention since the MNPs have immense potential for applications in diverse areas of biology and medicine. Scientific communities are widely reporting the potentiality of MNPs for diagnostic and therapeutic purposes. Among different magnetic nanomaterials iron oxide-based magnetic nanomaterial is determined to be one of the most well-established nanomaterials in the biomedical field, considering its benign biocompatibility, controllable size, high stability, and the potential applications in different aspects of the biomedical field, including drug delivery, hyperthermia, and MRI sensing [22]. Comparable size scales of MNPs and biological materials promote themselves to be used in biological and biomedical applications. At the nanometer scale, the properties of materials seem to be different from those at the macro scale. The distinctive physical and chemical characteristics of nanomaterials, such as a high surface-area-to-volume ratio, tunable optical emission, unique electrical and magnetic behavior, and many more other novel properties can be exposed to gain a wide spectrum of medical applications. In addition, magnetic nanomaterials provide an excellent nanoplatform to integrate different components into one single entity as hybrid magnetic nanomaterials (HMNs) to achieve multifunctional properties without losing the individual properties of each component [22]. A combination of different components in the same structure not only sums up the properties of separate components but, in some cases, endows the hybrid structure with new properties due to the synergistic effect. In recent years, numerous HMNs have been investigated for biomedical applications, such as noble metal, high-Z elements, quantum dots, isotopes, and polymers [23,24] for better imaging properties, better cargo release, and heating capacity. By varying the component set, ratio, composition, size, shape, and structure, it is possible to design hybrid materials with a broad range of functional properties [25]. This chapter covers the functional properties and considers the possible applications of hybrid nanostructures. The presence of magnetic components provides the function of directed motion and spatial control of hybrid nanomaterials. Owing to plasmonic properties, there is the possibility of enhancing luminescence and Raman signals. By combining magnetic and/or plasmonic nanostructures with other nanocomponents, it is possible to extend the range of properties with maintenance of functions set by the major component.

1.2.1 Classification and Synthesis Methods of Hybrid Magnetic Nanostructures (HMNs)

In the last few decades, the synthesis of MNPs has been intensively pursued because of their many technological possibilities. The synthesis of HMNs has gained importance due to the properties that depend on synthesis of the material. This synthesis can be classified into three types, as shown in Fig. 1.3. The reader is directed to read a special review article for a more detailed approach to the synthesis of HMNs [25]. HMNs can be broadly classified into two types (Fig. 1.3).

Figure 1.3 Summary of the synthesis methods and classification of HMNs.

1.2.2 Heterodimer HMNs

Heterodimer HMNs are the class of material which contains two different molecules within one structure. Common examples are Fe3O4-Au/Ag/Pt. [26–30]. This structure shows immense advantages in biomedical application, as compared to iron oxide alone. The optical properties of Ag/Au/Pt can be an additional advantage and this system has more functions such as multimodal imaging and multifunctional disease therapy. Moreover, these two integrated parts do not have any evident passive effects on each other, but can bring about benefits such as a catalytic effect on formation [31]. Xu’s group reported a facile method to fabricate heterodimers based on the colloidosome approach at a liquid–liquid interface, which controlled the sizes and compositions of heterodimers as well as attached functional molecules on specific parts of the heterodimers [32]. Different kinds of functional molecules could bind to specific parts of heterodimers through ligand exchange, thus producing heterodimer MHNs with good stability, biocompatibility, and functionality.

1.2.3 Core–shell HMNs

HMNs with core–shell structures can contain different material components and offer different properties in a single particle, providing many medical application possibilities. A range of Fe3O4@Ag and Au magnetic plasmonic materials have been prepared using a silica layer. The silica provides a basis for further functionalization and is biocompatible in nature. In some case, 3-aminopropyl triethoxysilane has been used to functionalize the surface with amino groups which help facilitate the attachment of the plasmonic metal NPs and drug for a better therapeutic and diagnostic approach (Fig. 1.4) [33,34].

Figure 1.4 A diagram illustrating the structure of the Fe3O4@Au nanoparticles [34,35]. silica sphere; magnetic NPs; gold NPs; PEG NPs; curcumin Copyright 2010 Macromol. Rapid Commun., 2018 Appl. Sci.

Three synthesis methods for hybrid nanostructures have been created. These are the aggregation, chronological, and equivalent synthesis methods. The first deals with the arrangement of NPs and supplementary aggregation to create a solitary arrangement. Essentially, this advance is an expansion of the bottom-up synthetic trick which does not prevent the configuration of solitary nanostructures but also embraces the consequent formation of multifaceted multicomponent substances upon aggregation of the preliminary nanostructures to provide the final hybrid. The second advance comprises a progression of response, creating a multilayer film arrangement, with NPs in the core–shell nanostructures. The third advance implies equivalent synthesis of hybrid nanostructures without pretreatment of the ingredients [36].

The HMNs can also be classified depending on the natural history of the interface combining the biological/organic or inorganic components [37]. These are divided into class I and class II:

Class I are hybrid coordinations where the biological, mineral, and organic components interrelate by weak bonds such as van der Waals, hydrogen, and electrostatic bonds.

Class II correspond to hybrid nanostructures in which these components are associated by stronger ionic interactions, such as covalent or chemical attachment.

Numerous hybrid nanostructures have both types of interactions, weak and strong, but due to the implications of the existence of strong chemical attachments on the ultimate hybrid nanostructure properties, these kinds of hybrids are placed into class II [38].

1.3 Medical Applications of HMNs

Hybrid nanostructured materials can be defined as those with at least one dimension falling in the nanometer range, and which include NPs, nanowires, and nanotubes, bulk materials made of nanoscale building blocks or consisting of nanoscale structures. This material has been created to either uplift, enhance, or enable the desired property in the material for specific applications. Because of their unique advantages, magnetic nanomaterials provide an excellent nanoplatform to integrate different components into a single entity to achieve multifunctional properties without losing the individual properties of each component. These HMNs provide many attractive possibilities for multimodal imaging and multiple therapeutic functions. The following sections deal with different medical applications of HMNs [39].

1.3.1 HMNs for Hyperthermia

As compared to conventional therapy including radiotherapy, surgery, and chemotherapy, hyperthermia-based cancer therapy has received much attention due to its several advantages. For hyperthermia treatment, a number of potential NPs have been investigated. In recent years the development of hyperthermia therapy has shown great promise [40]. Magnetic hybrid NPs convert their magnetic energy into thermal energy due to their magnetic properties. Magnetic hybrid NPs contain heavy metal materials, such as Au and Bi, which are used as photothermal agents [41]. The applications of magnetic hybrid NPs for hyperthermia therapy are briefly discussed below. Magnetic hyperthermia therapy is an extensively used method for hyperthermia. Through Néel and Brownian relaxation mechanisms magnetic hyperthermia NPs release thermal energy with good capability when an external alternating magnetic field is exposed to it. Magnetic hyperthermia NPs have superior potential in hyperthermia-based cancer therapy because of their magnetic stimulated heat generation property. Numerous magnetic hyperthermia NPs for hyperthermia have emerged with massively different structures and compositions. The synthesis of magnetic iron oxide nanomaterials with Zn ion dopant has been done: [(Zn0.4Mn0.6) Fe2O4]. When this material is compared with iron-based Feridex contrast agents, it showed lower biological toxicity and higher magnetothermal capability. After hyperthermia treatment, the Zn-doped nanomaterial and Feridex differed in cell viability. The superior hyperthermic efficacy is showed by (Zn0.4Mn0.6). This doping process gave high performance and satisfying tenability for the interrelated study of therapeutics [42] (Fig. 1.5).

Figure 1.5 (a) Release of thermal energy through Néel and Brownian relaxation mechanisms. (b) Images of fluorescence microscopy HeLa cells after the treatment of hyperthermia with (Zn0.4Mn0.6) Feridex (right) and Fe2O4 nanoparticles (left) [43] Copyright 2017 Wiley Periodicals, Inc.

1.3.2 HMNs for Photothermal Therapy

Photothermal therapy is the most significant aspect of nanotechnology in utilization of hyperthermia. Materials with strong absorption in the near-infrared region for therapy in real situations are more suitable as compared with other materials, as it reduces the energy loss which is caused due to intrinsic absorption of tissue [44]. Magnetic hybrid NPs contain Pt@Fe2O3 nanorods in which noninvasive antitumor therapy is combined with photothermal therapy, and is called radiation therapy. For better efficacy the magnetic hybrid NPs combined two diverse cancer treatment methods. The role of radiosensitizer is here played by Pt to decrease the dose of radiation needed because of its deep nondistinctive killing effect upon cancer cells and healthy cells. Without any environment limitations iron oxide exhibits elevated performance in photothermal therapy. Iron oxide has weak near-infrared penetrability ane therefore it works only when it is close to the body surface. Therefore this nanohybrid avoids this weakness. A smaller dose of material can be used due to its similar curative effect and synergistic effect. An analysis of cell viability was done before and after treatment, by which staining of cells was done by propidium iodide and calcein acetoxymethyl and the MNPs were visually revealed to show the killing effect on 4T1 cells. Magnetic hybrid NPs are also used in CT imaging, and iron oxide is also used as a superior contrast agent. When the integration of treatment and imaging was done, the highest utilization of each type of material is achieved, and this is known as theranostics [45] (Fig. 1.6).

Figure 1.6 An image of Pt@Fe2O3 nanorods for radiation and photothermal combined therapy [46] Copyright 2016 Nanoscale.

1.3.3 HMNs for Drug Delivery

To reach the preferred position in the body, pharmaceutical advances in drug delivery and drug release are required. Frequently the nanotechnology has been used in scrupulous, to cancer tissues. Reducing the toxic dosage for noncancerous tissues and in unviable spaces therapeutic consequence of the drug are the main objectives of drug delivery. For drug delivery, NPs are the standard aspirants because for reflexive tumor targeting they act as nanotransporters and by magnetic targeting it can be distributed to cancer tissues [47].

Currently there are hurdles to clinical applications of magnetic targeting. Previously it was reported that to generate a high gradient magnetic field the meshes and magnetic needles were inserted into the target site, because the gradient of the field is directly proportional to the magnetic carriers, facilitating capture at the target in the field gradient of sufficient magnitude. For enhancement of targeting, an evaluation of the probable advantages of periodic magnetic bandages and planar has been demonstrated [48].

The mechanism of innate cell targeting is a substitute approach to tumor targeting. By formation of a seminecrotic and hypoxic tumor core, solid tumors and their blood supply can grow [49]. Intravenously administered chemotherapy drugs are accessible to vascularized regions of the tumor, which may destroy that part of the tumor. However, when there is a deficient supply of blood to the core it will be mostly unaffected. The cells of the core reside in dormant tumor and then chemical signals are sent out and macrophages are recruited into the core. The blood supply then begins to rebuild these macrophages, allowing the tumor to initiate growth again [50].

1.3.4 HMNs for MRI

Diagnosis has become a valuable tool in the clinical field and enables timely treatment options. Noninvasive imaging using a molecular technique is the most popular method as it offers a noninvasive option which allows real-time visualization of the cellular structure and components. Contrast agents enhance the contrast of the medium or tissue during medical imaging. They are basically used to see blood vessels and the digestive tract. Research into contrast agents is increasing and many new contrast agents are available for different imaging modalities. Contrast agents have been developed for X-ray computed tomography (CT) [51], optical imaging, positron emission tomography (PET) [52], single-photon-emission computed tomography (SPECT) [53], and ultrasound and magnetic resonance imaging (MRI) [54]; CT and MRI are widely used as both are noninvasive in nature. MRI uses strong magnetic fields, electric field gradients, and radio waves for image generation. To enhance the images MRI contrast agents are commonly used. Generally, gadolinium and its chelates are used as the 3+ oxidation state, as the metal has seven unpaired electrons. This causes water around the contrast agent to relax quickly, enhancing the quality of the MRI scan. The contrast agents are classified as T1 and T2, based upon the relaxation time of the proton molecule. T1 relaxation time gives a hypersignal, and leads to bright contrast and gives T1-weighted images. On the other hand, T2 contrast agents reduce T2 relaxation times, giving rise to dark contrast called T2-weighted images. T1 contrast agents are paramagnetic in nature, such as gadolinium (Gd³+) and manganese (Mn²+) chelates. Among them, Gd³+ complexes are more widely used for clinical applications such as brain tumor contrast enhancement requiring crossing the blood–brain barrier. Meanwhile superparamagnetic iron oxide NPs are the only T2 contrast agent. Paramagnetic materials are unable to reduce the signal of T2 and cannot be used in deep-seated tumors of the digestive tract. In such a case the unique advantage of the MHNs can be used to design and develop MRI contrast agents that enable both T1 and T2 relaxation times for better tumor visibility. CT adapts an X-ray beam image of high density taken from different angles to produce cross-sectional (tomographic) images. To enhance the contrast of the CT, radio contrasts are used. These contrasts are typically iodine-, barium-sulfate-, or gadolinium-based compounds. Additionally, the linear relationship between the concentration of contrast material and attenuation number in perfusion imaging enables CT to provide quantitative information, which is an advantage over MRI. Therefore, the development of the contrast based upon MRI and CT contrast agent will be an additional tool for the clinician to obtain a better understanding of disease progression. Recently our group has shown the development of superparamagnetic gadolinium-doped Fe3O4 (GdIO) NPs with a low TC for magnetochemotherapy. The T1 and T2 relaxometric properties were investigated, and we found that the synthesized GdIO NPs showed T1 and T2 relaxation effectively and produced heat in response to an externally applied alternating current magnetic field. Furthermore, we loaded the anticancer drug doxorubicin (DOX) onto the GdIO NPs to combine chemotherapy and hyperthermia to destroy MCF7 breast cancer cells [55] (Fig.