Open access peer-reviewed chapter

Theranostic Nanoparticles and Their Spectrum in Cancer

Written By

Anca Onaciu, Ancuta Jurj, Cristian Moldovan and Ioana Berindan-Neagoe

Submitted: 02 May 2019 Reviewed: 17 June 2019 Published: 12 October 2019

DOI: 10.5772/intechopen.88097

From the Edited Volume

Engineered Nanomaterials - Health and Safety

Edited by Sorin Marius Avramescu, Kalsoom Akhtar, Irina Fierascu, Sher Bahadar Khan, Fayaz Ali and Abdullah M. Asiri

Chapter metrics overview

1,196 Chapter Downloads

View Full Metrics

Abstract

Nanoparticles offer a lot of advantageous backgrounds for many applications due to their physical, chemical and biological properties. Their different composition (metals, lipids, polymers, peptides) and shapes (spheres, rods, pyramids, flowers and so on) are influenced by the synthesis methods and functionalization procedures. However, in the medical field, researchers focus on the biocompatibility and biodegradability of the nanoparticles in their attempts for a targeted therapy in which the nanocarriers need to bypass certain biological barriers. Moreover, the increased interest in molecular imaging has brought nanoparticles in the spotlight for their applications in two distinct directions: therapy and diagnosis. Furthermore, recent advances in nanoparticle designs have introduced novel nano-objects suitable as both detection and delivery systems at the same time, thus providing theranostic applications.

Keywords

  • nanoparticles
  • nano-oncology
  • targeted therapy
  • molecular imaging
  • diagnosis

1. Introduction

Nanomedicine is able to study the organism and especially the disease at the nanoscale level and offers a lot of structural and functional information for the development of new therapeutics and diagnosis strategies [1]. Nano-oncology refers to the applications of nanotechnology in the oncology medical field.

Oncological malignancies affect worldwide population with an incidence of 18.1 million new cancer cases and 9.6 million cancer deaths (GLOBOCAN 2018). Usually, the most used treatment scheme is surgery, radiotherapy and chemotherapy. These strategies are not very efficient because it does not only affect the disease site, but healthy tissues too, and in many cases, cancer can develop therapy resistance [2].

Nanotechnology tools have potential to overcome the side effects and the inefficiency of some therapies. Due to its small size, nanoparticles (NPs) can be used for molecular characterization of the disease, and based on this, it can contribute to discover new therapies. Moreover, various oncological chemotherapeutics are nanoformulated and now are involved in clinical trials [3].

Besides drug encapsulation, NPs can be used for the delivery of growth factors and other compounds applied in tissue engineering. On the other hand, NPs’ properties are advantageous for new sensing and molecular imaging tools development (Figure 1).

Figure 1.

Nanotechnology applications in medicine.

For each of these applications, NPs’ formulations involve various encapsulation procedures, which need to meet specific characteristics. Firstly, the NPs should not interfere with the encapsulated compound pharmacological activity, and it has to prevent its premature degradation and to become biodegradable at the tumor site, thus decreasing its toxicity [4]. Secondly, for sensing applications, the nanosystem needs to have some unique chemical, electrical, and catalytical properties to provide accuracy of the measurements [5]. On the other hand, for molecular imaging applications, the NPs benefit from their optical properties like fluorescence in various spectra. Also, the features such as biocompatibility, stability and long circulation time are very important [6, 7, 8].

Theranostic side of the nano-oncology field focuses on developing new structures that able to perform efficient target therapy. Therefore, this type of NPs disposes of unique physical and chemical properties for active targeting of the desired cells providing imaging and therapeutic action against the disease [8].

Advertisement

2. Nanoparticles

The term “nanoparticles” is intensively used in the nanomedicine field in order to describe a particle with a size in the range of 1–100 nm. NPs are designed from a wide class of materials, including metals, silicates, metal oxides, polymers, organics, non-oxide ceramics, carbon and biomolecules. For biomedical applications, NPs are presented in different morphological states such as spheres, tubes, cylinders, platelets [9].

NPs have surface modifications that can facilitate the internalization/uptake of therapeutic agents and also their capability to travel through the bloodstream to the target sites. Generally, the structure of NPs is composed of three different layers, including the surface layer (can be functionalized with a wide range of small molecules, surfactants, metal ions and polymers), the shell layer (consists of different chemical material according to the core of the NPs) and the core (represents the central portion of the NP) [10]. Therefore, NPs have exceptional characteristics due to their structure and design and gained an enormous interest in multidisciplinary fields such as drug delivery [11], cancer therapy, tissue engineering, protein detection, multicolor optical coding for biological assays, manipulation of cells and biomolecules [12], imaging, biosensors, hyperthermia, photoablation therapy and gene delivery [13]. They exhibit special physical and chemical properties like a high surface area-to-volume ratio and also a unique quantum size effect superior to their corresponding bulk materials. Moreover, NPs’ controllable size and shape play an important role in medical applications [14]. Moreover, there are some nanomaterials that can exhibit intrinsic therapeutic properties such as gold nanoshells, which have the potential to deliver photothermal therapy [15].

Currently, the term “theranostics” starts to gain attention in the medical and research field, and it describes single biocompatible and biodegradable nanoparticle, which can contain both therapeutic and diagnostic compounds (Figure 2) [16]. Specifically, theranostic nanoparticles (TNPs) have been designed in order to be applied for multiple imaging approaches including optical imaging, ultrasound (US), magnetic resonance imaging (MRI), computed tomography (CT), single-photon computed tomography (SPECT) and positron emission tomography (PET) [17]. Moreover, TNPs are able to improve the accumulation and delivery of the active compounds at the tumor site, enhancing therapeutic efficacy and reducing the intensity of side effects on healthy tissues [18], and they can be eliminated from the body in a short period of time and degrade into nontoxic bioproducts [19].

Figure 2.

Theranostic nanoparticles used in the medical field in order to improve the diagnosis and therapeutic approaches.

2.1 Synthesis of NPs

Synthesis of NPs can be performed using various methods, which are divided into two main classes such as bottom-up (chemical synthesis) and top-down (mechanical attrition) approaches (Figure 3) [20]. Bottom-up method is based on larger nanostructures design beginning from smaller building blocks including atoms and molecules. Meanwhile, the top-down approach refers to larger molecules, which are decomposed into smaller building blocks and then converted into suitable NPs [10]. Traditional chemical and physical methods present some main drawback due to the presence of reducing and stabilizing agents, which carry a risk of toxicity to the environment and also to the cell [21].

Figure 3.

Common methods used to synthesis NPs via top-down and bottom-up approaches.

Currently, green chemistry has been suggested as a valuable alternative for metal nanoparticles synthesis that employs biological entities including microorganisms and plant extracts [22]. The main role of microorganisms (bacteria and fungi) is involved in the remediation of toxic materials by reducing metal ions [23]. The most often used metal for green synthesis is silver, gold, iron, and copper [24]. Therefore, the size distribution of NPs is strongly depended on the presence of the biocompounds, which are found in the extract. These biocompounds (phenolic compounds, alkaloids, enzymes, terpenoids, proteins, co-enzymes, sugar and others) are mainly involved in reducing the oxidative state of the metal salts from positive to zero oxidative state [25]. Few bacteria have been shown the potential to synthesize silver nanoparticles intracellularly where intracellular components have the ability to act as reducing and stabilizing agents, respectively [26]. Thus, the green synthesis of nanoparticles could be a promising approach to replace many complex physiochemical syntheses due to their advantages such as no need to use toxic chemicals, free from hazardous by-products and also the use of natural capping agents [27].

In their study, Mirtaheri et al. had succeeded in synthesis of mesoporous tungsten oxide using a template-assisted sol-gel method, which relies on the photocatalytic degradation of Rhodamine B [28]. Mesoporous TiO2-SiO2 were synthesized by Haghighatzadeh et al. using an ultrasonic impregnation method. In addition, under 800°, they synthesized the anatase crystals with higher photocatalytic efficiency for degradation of methylene blue [29]. Deshmukh et al. synthesized various nanoparticles using plant extracts in order to evaluate their antibacterial and antioxidant activity for targeted applications [30]. Another study on this topic is showed by Baltazar-Encarnacion et al., which described the green synthesis of Ag nanoparticles using an E. coli for the production of NPs with antimicrobial properties against bacteria [31]. Green biosynthesis methods are more reliable and safer than chemical synthesis [32].

Structural DNA nanotechnology is a precise method, which is used to control the NPs shape. In particular, the DNA-origami method allows the controlled self-assembly of 2D and 3D nanostructures with nanometer precision [33]. Such nanoparticles can be used to detect short oligonucleotides in a microbead-based assay [34] and can be applied in the biological field, nanoelectronics and nanophotonics [35]. Therefore, these designs provide comprehensive understanding of cellular interactions regarding tumor detection strategies [36, 37].

Specifically, TNPs can be engineered in several ways. For example, TNPs can be obtained by conjugating therapeutic agents (chemotherapy and photosensitizers) to existing imaging NPs (quantum dots, gold nanocages and iron oxide NPs). On the other hand, NPs can encapsulate both imaging and therapeutic agents in biocompatible nanosystems such as ferritin nanocages, polymeric and porous silica NPs. Other unique NPs such as porphycenes, [64Cu] CuS, gold nanoshells or cages have inherent imaging and therapeutic characteristics [19].

2.2 Characterization of NPs

Physicochemical properties of NPs (shape, size, composition, optics) can be analyzed through different techniques.

The morphology of NPs is characterized through microscopic techniques including polarized optical microscopy (POM), transmission electron microscopy (TEM) and scanning electron microscopy (SEM), which are the most relevant techniques in this area. SEM technique provides relevant information regarding the nanoscale level of the NPs [38]. Moreover, TEM provides features about the bulk material used for NPs synthesis at very low to higher magnification [39]. The morphological features of the NPs exhibit a relevant interest since their morphology influences the NP’s properties [10].

Structural characterization is based on the study of the composition and nature of bonding materials. The common techniques used to study the bulk properties are X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), infrared spectroscopy (IR), Raman, Brunauer-Emmett-Teller (BET), energy dispersive X-ray (EDX) and Zeta size analyzer. Through XRD technique, the crystalline structure and the phase of the NPs are identified. The most sensitive technique used to characterize NPs is XPS, which determines the exact element ratio and bonding nature of the elements used for NPs synthesis [10].

Optical characterizations are widely used to obtain information about the absorption, reflectance, phosphorescence and luminescence of NPs. This method is based on the Beer-Lambert law and basic light principles. These properties are highlighted through several techniques, including diffuse reflectance spectroscopy (DRS), UV and UV-Vis, which reveal good knowledge about the mechanism of their photochemical processes [10].

2.3 Physicochemical properties of NPs

For cancer research, NPs can be modified respecting the size, shape and surface to improve their ability to reach tumors. Smaller NPs have the ability to accumulate more easily in the leaky blood vessels of tumor sites compared to larger NPs, which can remain at the injection site [40].

Nowadays, ultrasmall nanoparticles (1–3 nm cores) are widely used for medical applications because of their advantages regarding biodistribution, targeting features, adsorption, easy surface modifications and pharmacokinetics [18, 41, 42, 43]. Gadolinium ultrasmall nanoparticles achieved theranostic potential without considerable toxicity in vivo in the case of brain cancers [44]. Another example is represented by ultrasmall silica nanoparticles functionalized with antibody fragments used to target HER2-overexpressed breast cancer as imaging agents [42].

Metallic nanoparticles can be designed as ultrasmall constructs too. In this regard, it is important to mention D-peptide p53 activator gold nanoparticle conjugates used for cancer target therapy [45], bimetallic nanoparticles for triggered ultrasound cancer therapy [46] and Cu ultrasmall nanoparticles’ valuable ability for photothermal cancer therapy [47].

On the other hand, NP shape influences the fluid dynamics and uptake into tumor sites. Non-spherical NPs present excellent optical properties due to surface plasmon resonances and are strongly recommended for cancer phototherapy applications [48, 49, 50]. Furthermore, rod-like shape nanoparticles are better accepted and tolerated by the organism [51, 52].

Specifically, spherical NPs started to be more common than non-spherical NPs due to challenges in synthesis approaches and testing [53]. Spherical silver nanoparticles ensure anti-inflammatory potential [54] and promote camptothecin apoptotic activity in cervical cancer [55]. Despite the advantages offered by silver nanoparticles, progress in spherical gold nanoparticles makes possible their use for combined therapies like drug delivery and photothermy [56].

There are other significant factors that contribute to a successful therapy development. Stability and distribution are affected by NPs charge. A positive charge is most effective according to tumor vessels targeting, but a switch to a neutral charge allows NPs to diffuse to the tumor sites [57]. In order to prolong blood circulation of NPs, their surface can also be modified with specific molecules (hydrophilic polymers/surfactants, biodegradable copolymers such as polyethylene glycol, poloxamine, polyethylene oxide and polysorbate 80), which facilitate cellular uptake into tumor tissue [58, 59].

2.4 Classification of NPs

Modern nanosystems can enhance drug diagnosis, delivery and also monitor therapeutic responses to the provided drugs [60]. In order to improve clinical outcomes, researchers tried to synthesize a theranostic platform consisting of multifunctional NPs, which exhibit valuable imaging properties. Therefore, TNPs can be composed of lipids, polymers, metals, carbon and ceramics [61].

Lipid nanoparticles are widely used in medical field due to their biodegradability, biocompatibility, low toxicity and high loading capacity for both hydrophobic and hydrophilic drug molecules [62, 63]. Moreover, they can improve the pharmacodynamics and the pharmacokinetics of therapeutic agents based on controlled release profile [64]. Another important characteristic of lipid NPs is their availability for functionalization with antibodies, peptides, small molecules or aptamers in order to perform target therapy [65, 66, 67].

Polymeric NPs are normally organic-based NPs with a diameter lower than 1 μm. They can be called nanospheres or nanocapsules depending on their composition [68, 69, 70]. These nanoparticles have the ability to improve both the solubility and the bioavailability of hydrophobic drugs [71] and are intensively used as delivery systems [72, 73].

Metallic NPs are designed from metal precursors, including noble metals (Cu, Ag, and Au). The most researched area in biomedical field is represented by gold NPs, which possess unique optical and electronic characteristics as well as chemical inertness. Also, their availability for surface functionalization [74, 75, 76] makes them very useful for a lot of medical applications such as biosensing [77], bioimaging [78] and photothermal therapy [79]. Silver nanoparticles exhibit unique properties such as thermal conductivity, high electrical conductivity, catalytic activity, chemical stability, antibacterial and improved optical properties [80]. These NPs are suitable for photonic [81], electronic [82], antimicrobial and disinfectant applications [83, 84], biosensors [85], drug delivery, photothermal therapy [26] and cellular imaging [86].

Another class of metallic nanoparticles is represented by semiconductor nanocrystals, which are well known as quantum dots. Many studies report their potential use in biomedical imaging [87], drug and gene delivery [88] and also in diagnosis [89] based on their unique chemical and optical properties.

Magnetic NPs represented by iron oxide NPs possess unique chemical, biological and magnetic characteristics including non-toxicity, chemical stability, biocompatibility, high magnetic susceptibility and high saturation magnetization [90, 91]. The main drawback of iron nanoparticle is that it has a tendency to oxidize [13]. To eliminate this unwanted process, coating with a biocompatible shell, such as a polymer [92], ceramics [93] or metals [13], is needed in order to prevent conglomeration. In addition, iron oxide NPs can be functionalized with proteins, antibodies, enzymes and anticancer drugs [13] and are investigated for different applications including magnetic hyperthermia [94], contrast agents in MRI (magnetic resonance imaging) [95], targeted drug delivery [96], multimodal imaging and gene therapy [61].

In the term of carbon-based NPs, fullerenes and carbon nanotubes exhibit promising biomedical applications. Fullerenes are suitable for multiple functionalization steps according to their particular globular network structure [97]. They are widely used as excellent antioxidants [98], antiviral agents [99, 100], drug and gene delivery systems [101, 102, 103] and photosensitizers for photodynamic therapy [104, 105]. On the other hand, elongated design of carbon nanotubes diagnostic imaging strategies [106, 107, 108, 109, 110], drug delivery [111, 112, 113] and also photothermal therapy [114, 115].

Ceramics NPs are inorganic non-metallic solids, which are synthesized by heating and successive cooling [116]. Therefore, these ceramics NPs are intensively used in the research field as photocatalysis, catalysis, agents for photodegradation of dyes and imaging agents [117].

There are significant challenges in engineering and designing new nanosystems. The “nanoparticle loaded nanoparticle” concept is described as an innovative strategy composed of at least two different nanoparticles. For example, porous nanoparticles made by silica can encapsulate DNA-conjugated small gold nanoparticles in their pores with great applicability in penetrating tumors [118].

Hybrid constructs gained increased interest in obtaining programmed nanoparticles. DNA nanorobots built of a DNA robot and a DNA aptamer that confers molecular recognition of nucleolin are used for target therapy in cancer [119].

Advertisement

3. Cellular internalization and endosomal escape

Once the delivery system comes in the proximity of its target site, the drug must be internalized in order to fulfill its biological effect. While free drugs usually have the ability to pass through cellular membranes and accumulate inside the cell unless they are externalized by efflux pump mechanisms, NPs are internalized differently, mainly through various types of endocytosis [120], as presented in Figure 4.

Figure 4.

Cellular internalization through endocytosis.

Phagocytosis is a mechanism by which specialized cells known as phagocytes recognize and engulf large particles (≥0.5 μm) into vesicles called phagosomes [121]. This process involves actin polymerization and the extension of pseudopods, which surround the opsonized target object [122] leading to its internalization (Figure 4(5)). Phagosomes fuse with early endosomes, followed by late endosomes and then lysosomes, becoming highly acidic and possessing hydrolytic enzymes leading to the degradation of the engulfed object [122].

Macropinocytosis is a process by which nonselective molecules suspended in extracellular fluid are internalized into the cell, giving rise to endocytic vesicles. Like phagocytosis, it involves cytoskeleton rearrangement beneath the plasma membrane. This leads to a plasma membrane circular ruffle formation that extends and entraps extracellular material, producing a so-called macropinosome [123]. The maturation of these vesicles involves shrinking while concentrating their contents, migration and digestion or recycling of their contents [124]. Depending on the cell line, macropinosomes can fuse with lysosomes or directly to the plasma membrane expelling their content to the extracellular space (Figure 4(4)) [124, 125].

Caveolae are small (60–80 nm) plasma membrane invaginations, important in processes such as endocytosis, transcytosis, potocytosis and certain signaling pathways [126]. Caveolin-dependent endocytosis is a triggered, energy-dependent event involved in the uptake of extracellular molecules and membrane components [127]. It is dependent on actin and dynamin, a GTPase, which is present at the neck of caveolae and is responsible for the release of the caveolar vesicle inside the cytoplasm [128]. These vesicles deliver the internalized molecules to caveosomes or to early endosomes (Figure 4(2)). Caveosomes bypass lysosomes, thus being an important approach for administering easily degradable therapeutic agents [129].

Clathrin-mediated endocytosis involves the uptake of extracellular molecules through invagination of the plasma membrane. The vesicles are formed when ligands interact with receptors on the plasma membrane, thus recruiting clathrin triskelions and adaptor proteins, which form a multifaceted cage structure [130] that is released inside the cell with the help of dynamin. These vesicles are known as clathrin-coated vesicles and can lose their clathrin coat and fuse with early endosomes (Figure 4(1)). They are directed towards degradation in lysosomes or recycled to the plasma membrane [131].

Extracellular cargo can also be internalized via clathrin- and caveolin-independent pathways (Figure 4(3)) [132].

Depending on the internalization mechanism, NPs have different fates. They can face lysosomal degradation when internalized through clathrin-mediated endocytosis while skipping this process when taken up through a caveolin-mediated mechanism [133].

Many nanomaterials are degraded in endocytic vesicles leading to new approaches of carrier designs that are able to escape the endosomal or lysosomal degradation. Three main strategies, presented in Table 1, are commonly used to bypass this cellular barrier for drug administration. They rely on molecules, which possess the ability to destabilize the endosomal membrane in a pH-dependent or independent way or to fuse with the endosomal membrane, leading to the release of previously internalized cargo. Another approach involves the photochemical membrane rupture via photothermal nanomaterials.

StrategyMechanismExamplesRef.
Endosomal membrane destabilizationpH dependentpH buffering (proton sponge effect)Polyamines (PEI, PEAAc, Mglu-HPG)[134]
Pore-formationListeriolysin O (LLO)
GALA peptide
[135]
pH independentPore formationAmphotericin B
Melittin
[136, 137]
Fusion with endosomal membraneFlip-flop mechanismGALA peptide[138, 139]
Via viral fusion proteins/peptidesHA2 fusion peptide/hemagglutinin[140]
Photochemical membrane ruptureLight-induced ROS and/or heat generationTatU1A-photosensitizer conjugates
M-PLL (melanin-poly-L-lysine)
[141, 142]

Table 1.

Approaches for endosomal escape.

Advertisement

4. Diagnosis through molecular imaging mechanisms

Molecular imaging is a medical discipline related to medical imaging and is representing the evolution of imaging techniques for diagnosis and therapy monitoring. It involves cell biology and molecular biology [143].

Current clinical applications of molecular imaging are CT, SPECT, PET, MRI, US and also hybrid imaging techniques SPECT/CT, PET/CT or PET/MRI. CT, MRI and US provide anatomical information, while PET/CT, and SPECT/CT offer functional and molecular information [144]. All these techniques are based on the accumulation of a contrast agent at the target site [145].

Even if they provide high-resolution images from anatomical [146] to molecular level for further clinical investigations [147, 148, 149, 150, 151, 152, 153], there are some disadvantages regarding the use of them. High doses of radiation and exposure can cause DNA damage in some tissues [154, 155]. Also, radiopharmaceutical biodistribution and effectiveness may cause image artifacts and also side effects for the patient [156, 157, 158, 159]. Moreover, the patient care quality is not granted in most of the cases [156].

4.1 NPs involved in diagnosis imaging strategies

Diagnostic imaging using NPs refers to the detection of specific disease sites through molecular recognition of tumor cell particularities like the overexpression of several genes and the presence of different cell surface molecules or media excreted compounds/molecules that are involved in various disease processes, microenvironment particularities and also cell development stages [160, 161].

Physical properties of nanoparticle systems are very important for molecular imaging applications. Nanoparticle accepted diameters for this application are between 30 and 150 nm. Usually, the nanoparticle surface is modified using a ligand in order to target specific tumor cell molecules. As more ligands are attached on the nanoparticle surface, there are more chances to bind the target cell. The amount of signaling groups influence the sensitivity of the detection method [145].

Some NPs have innate optical properties like QDs [162] and metallic NPs due to surface plasmon resonance [48, 163, 164, 165]. QDs nanoparticles labeled with 18F-Fluoropropionate and functionalized with RGD peptides demonstrate proper optical characteristics for PET imaging of prostate cancer [166].

Gold nanoparticles proved long circulation time and useful optical properties like high spatial resolution and high sensitivity for CT imaging. By functionalization with chitosan polymers, they were used for colorectal adenocarcinoma imaging [167]. Also, they were conjugated with antibodies for lymph nodes and metastases imaging in squamous cell carcinoma, head and neck cancer [168]. Moreover, gold nanoparticles radiolabeled with 111In and 125I can be used in SPECT imaging of epidermoid carcinoma [169].

Iron oxide nanoparticles are widely used in MRI imaging because they can improve and enhance the contrast [170]. In glioblastoma, iron oxide nanoparticles functionalized with peptides and polymers accumulate within tumor microenvironment by forming self-assembly structures [171].

Furthermore, polymeric materials such as mesoporous silica nanoparticles carry tumor targeting properties and are proposed for PET imaging in breast cancer. Besides this, they are able to perform drug delivery applications [172].

Regarding US imaging, perfluorocarbon nanoparticles can be used for a real-time and non-invasive analysis of thyroid carcinoma [173].

Considering the other nanoparticle formulations (nanoliposomes, micelles, polymersomes, dendrimers and aptamers), these ones need to be functionalized with specific contrast agents and fluorophores. The advantages to implement NPs such as molecular imaging tools are biocompatibility and biodegradability [174], encapsulation properties [175], water solubility in some cases [176] and targeting ligands accessibility [177].

Fluorophores are widely used in diagnosis applications and imaging of cellular processes. One drawback of conventional fluorophores is represented by the loss of fluorescence after a long exposure to light, known as photobleaching.

Various processes are known to induce the molecular relaxation without the emission of light, which depends on different chemical or physical factors like temperature, pressure, the presence of organic molecules or polymers and ionic strength, resulting in a decrease in the fluorescence intensity, referred to as quenching [178]. Quantifying this decrease in fluorescence emission can give information about the concentration of a specific compound in the proximity of the nano-objects. Lately, numerous diagnostic techniques based on this phenomenon have been introduced [179, 180].

On the other hand, another luminogen system based on a process called aggregation-induced emission (AIE), developed by Ben Zhong Tang’s group in 2001 [181], gathered increased interest for imaging and theranostic applications. Most luminescent systems have a lower efficiency in an aggregated state, thus limiting the concentration that can be used for imaging purposes and at the same time the achievable intensity of the emitted light. However, in the case of AIEgens, aggregation works constructively becoming highly luminescent in concentrated solutions or in an aggregated state. The utilization of AIEgens in theranostics has lately become a reliable approach, because of several advantages that include good biocompatibility, excellent optical properties and simple preparation and conjugation [182]. One example implies the conjugation of an AIEgen (TPS) with a short peptide (DEVD) that is susceptible to caspase-3 cleavage and that is bound to a prodrug that induces apoptosis [183].

Advertisement

5. Targeted therapy

Targeted therapy is a form of treatment, which implies the ability of a drug to accumulate at a target site in the body and thus decrease the side effects in healthy cells and tissues. Nanocarriers are often used to improve the bioavailability of the active compounds at the target site and allow the use of significantly reduced concentrations, therefore limiting the exposure of normal cells to the toxic effects of the drugs [184].

The most common strategies for drug delivery include local drug delivery, passive targeting, physical targeting, magnetic targeting and active targeting [185].

Local drug delivery is a promising strategy for the treatment of metabolic disorders (diabetes and obesity) [186], periodontitis [187] and bone disorders [188] due to its potential to keep drug availability in the target site for a prolonged period of time.

Passive targeting is based on enhanced permeability and retention effect (EPR effect) present in many tissues [189, 190]. Macromolecules and NPs from the bloodstream accumulate preferentially in tumors and inflamed sites, where the permeability of the vasculature is often enhanced. Moreover, the lymphatic drainage system is damaged in tumors, leading to a prolonged retention of the macromolecules and NPs in the tumor interstitium [191].

Physical targeting depends on the optical, thermal and electrical properties of the carriers [192], which can disintegrate at lower pH values or higher temperature and release the free drug. The tumor microenvironment is more acidic compared to the normal surrounding tissues, due to the accumulation of lactate, and therefore provides an opportunity for the use of pH-sensitive nanocarriers in cancer therapy [193].

Another approach for drug targeting refers to the accumulation of superparamagnetic carriers in target sites under the action of external magnetic field. Thus, a larger dose of the drug can be released at the tumor site for an increased period of time and side effects of chemotherapy can be diminished [194]. Once systemically administered, besides the type and intensity of the magnetic field and size of the NPs, many biological factors influence the infiltration of the superparamagnetic carriers to the target site, including the effect of Brownian motion, blood viscosity, interaction of the particles with the red blood cells and blood matrix [195].

While in the case of passive targeting the physicochemical properties of the nanocarrier system play the major role, active targeting relies on the interaction between the surface of the carrier and antigens expressed on target cells. NPs are functionalized by adsorption or chemical conjugation with a large variety of ligand types such as peptides, small molecules, proteins, and aptamers, which present a high specificity for epitopes or receptors that are uniquely expressed or overexpressed on the target sites [196]. Examples of commonly used ligands and their targets are presented in Table 2.

ClassLigandTargeted biomarkerDisease (clinical trials = *)Ref.
AntibodiesTrastuzumab, cetuximab, Anti-CD20 mAbs (Rituximab)HER2 receptor, EGFR, CD20Breast cancer*, esophageal carcinoma*, pancreatic adenocarcinoma*, head and neck cancer*, non-Hodgkin’s lymphoma*, rheumatoid arthritis*[197, 198, 199, 200, 201, 202, 203]
PeptidesTransferrinTransferrin receptorCancer[204, 205]
Small moleculesFolic acidFolate receptorRheumatoid arthritis*, ovarian cancer, lung cancer*[206, 207]
AptamersA10RNA, AS1411, Anti-MUC1Extracellular domain of the PSMA, nucleolin, MUC1Prostate cancer, breast cancer[208, 209, 210]

Table 2.

Commonly used molecules for active targeting.

*Refers to clinical studies.

Advertisement

6. Theranostic NPs recently developed

Theranostics refers to the use of the nanoparticle for molecular imaging and therapy. Considering the biological barriers, the biocompatibility, easy surface modifications, controlled pharmacokinetics and biodistribution and accommodation in various microenvironment conditions are still necessary to be accomplished [211]. Polymers are widely used for NP formulations because of biocompatibility and biodegradability properties in vivo [212, 213, 214, 215]. Besides coating the nanoparticle surface with polymers, the fluorophores and other contrast probes are widely used to achieve high-sensitivity molecular imaging.

There are three main theranostic directions that involve the use of nanoparticles. The first strategy refers to treatment effect evaluation through molecular imaging with NPs as contrast agents. The aim of the second one is to assess a nanoparticle therapeutic strategy with molecular imaging probes. The third one describes nanoparticles as target therapy agents and molecular imaging tools at the same time. In this regard, for the first two procedures, the NP system is either the evaluator or the evaluated component, and for the last strategy, these roles are overlapping. Each one of these roles makes possible the development of future therapies (Figure 5).

Figure 5.

Theranostic NPs action strategies.

The nanoparticles’ evaluator role (Figure 5(1)) can be emphasized in the next study. Zhang et al. developed Annexin A5-conjugated polymeric micelles with dual role: detection of apoptosis via SPECT and optical imaging and also therapy outcomes investigation. In this study, the apoptosis was induced by drugs like cyclophosphamide, etoposide, poly (L-glutamic acid)-paclitaxel and cetuximab (IMC-C225) anti-EGFR antibody. The NPs were used to observe the apoptosis-induced processes in lymphoma and breast cancer in vivo. Therefore, SPECT and fluorescence molecular tomography allowed cellular death visualization in tumors [216].

NP effect evaluation (Figure 5(2)) can be performed based on probes that are currently used in clinical molecular imaging. For example, 2-deoxy-2-[F-18]fluoro-D-glucose (18F-FDG) probe is used for metabolic activity measurements via PET/CT imaging. This radiolabeled probe can act as prognostic biomarker for nanoparticle-assisted photothermal therapy monitoring in neuroendocrine lung cancer in vivo [217].

Another strategy is to ensure both imaging and therapy at the same time (Figure 5(3)). In this situation, the nanosystem can be composed of two different components bonded together in order to perform a theranostic action.

The easiest way is to make use of the optical properties developed by some materials at nanoscale. Therefore, metallic nanoparticles can scatter and absorb the light in the NIR wavelength domain and are promising tools for cancer photothermal therapy [218].

In a different way, nanoparticles can be associated with molecular imaging techniques in order to enhance their efficiency. For example, doxorubicin-loaded polymeric micelles and perfluoropentane stabilized by the same block copolymer can perform US imaging and target therapy for breast and ovarian cancer [219, 220].

Some designs suggest the use of two different nanoparticles, which by conjugation with targeting ligands and drug molecules provide tumor visualization and target therapy. For example, quantum dot-mucin 1 aptamer-doxorubicin conjugates were used for ovarian cancer targeting and proved suitable optical properties for imaging and controlled release of the drug [221].

In addition to the molecular imaging techniques previously described, some nanoparticles can be used for photodynamic and photothermal therapy in order to perform targeting therapy.

Photodynamic therapy (PDT) implies the use of photosensitizer agents that under laser irradiation exert cytotoxic activity by generating reactive oxygen species [222, 223]. This therapy is very appreciated regarding multidrug resistance cancers and is suppose that it can replace the conventional chemotherapy [224]. PDT-specific nanoparticles are used as photosensitizer carriers [225, 226]. Moreover, these nanocarriers can be functionalized with targeting ligands for better tumor selectivity and also with drug molecules for therapeutic effectiveness [227, 228, 229]. Gold nanoparticles loaded with a fluorescent drug Pc4 targeting PSMA-1 membrane antigen in prostate cancer are promising tools for surgical guidance and further therapeutic intervention [228]. EGFR-targeted liposomal nanohybrid cerasomes are proposed for PDT and immunotherapy in colorectal cancer due to their sensitive detection properties and anti-tumor efficacy [229].

By a theranostic point of view, photothermal therapy (PTT), also known as hyperthermia or thermal ablation therapy, acts as a diagnosis and a treatment strategy. It uses electromagnetic radiation in infrared (IR) region and provides high specificity analysis and minimal invasiveness [230]. The nanocarriers used for PTT need to have the capacity to target the tumor site after heat generation under laser irradiation [231]. For this purpose, various drug molecules and targeting ligands are encapsulated into nanoparticles. Gold nanoshells targeting HER2 positive breast cancer proved optical contrast and high tissue penetration under NIR irradiation [218]. Polymer nanoparticles functionalized with IR820 and doxorubicin were used in ovarian cancer and showed prolonged circulation time and drug accumulation at the target site [232]. It is important to mention that the generated temperature is usually between 42 and 45°C and sometimes higher depending on tumor tissue [233, 234].

6.1 Theranostic nanoparticles used in the clinic

There are various types of theranostic NPs that can be designed and used for cancer diagnosis and therapy. Their applicability is highlighted by liposomes, which are intensively used in clinical trials due to their specific features. In Table 3, several theranostic nanoparticles used in clinical (clinical trials) and pre-clinical work for cancer diagnosis and therapy are shown.

StageNanoparticle typeTherapeutic agentDiagnostic agentPathologyTargetRef.
Pre-clinicalLiposomes (100–200 nm)PaclitaxelpH-sensitive poly(ethylene oxide) (PEO)-modified poly(beta-amino ester) (PbAE) nanoparticlesOvarian adenocarcinomaEPR[235]
Silica (100–200 nm)Paclitaxel and camptothecinSuperparamagnetic iron oxide nanocrystalsPancreatic cancerFolic acid[236]
Iron oxide (10–25 nm)Anti-EGFRIgGIron oxide nanoparticlesGlioblastomaEGFR[237]
Gold nanorod (10 x 40 nm)HeatThermal/CTBreast cancerEPR[238]
Quantum dots (30–50 nm)Paclitaxel, doxorubicin, 5-fluorouracilQuantum dotsMany cancersCD44, folic acid[239]
Clinical trialsSilica (6–7 nm)cRGDYUltrasmall inorganic hybrid nanoparticlesMelanoma and malignant brain tumorsανβ3 integrin[240]
Cyclodextrin (70 nm)RNAiTransferrinSolid tumorsTransferrin receptor[241]
Silica-gold nanoshellPhotothermal ablationNanoshell (MR and optical)Head/neck cancer, primary and/or metastatic lung tumorsEPR[242]
Gold (27 nm)Tumor necrosis factor alphaGold nanoparticlesSolid tumorsEPR (passive mechanism)
rhTNF (active mechanism)
[243]
Iron oxideEndorem (superparamagnetic particles of iron oxide)Iron oxideHealthy volunteersnone[244]

Table 3.

Nanoparticles used in clinical (according to clinicaltrials.gov) and pre-clinical work.

Abbreviations: EPR, enhanced permeability and retention effect; EGFR, epidermal growth factor receptor; cRGDY, peptide cyclo-(Arg-Gly-Asp-Tyr); rhTNF, recombinant human tumor necrosis factor alpha; RNAi, ribonucleic acid interference; MR, magnetic resolution.

Theranostics has the potential to predict and evaluate therapy response, offering advantageous opportunities to modify the ongoing treatments and to develop new ones even in a personalized manner [245]. Nanoparticles have gained a lot of confidence in becoming important tools for a lot of medical applications due to their properties [17, 19].

The newest designs focus on hybrid nanostructures for better sensitivity and accuracy. These nanohybrids are currently studied and they proved effectiveness in cancer targeting by combining different imaging techniques with drug delivery strategies [246, 247, 248].

Advertisement

Acknowledgments

This research was funded by the research grants “Clinical and economic impact of personalized targeted anti-microRNA therapies in reconverting lung cancer chemoresistance”-CANTEMIR, POC-P-37-796/2016, “Innovative advanced approaches for predictive regenerative medicine”—REGMED, no. 65PCCDI/2018, PN-III-P1-1.2-PCCDI-2017-0782, “Increasing the performance of scientific research and technology transfer in translational medicine through the formation of a new generation of young researchers”—ECHITAS, no. 29PFE/18.10.2018, PNCDI III 2015-2020.

Advertisement

Conflict of interest

The authors declare no conflict of interest.

References

  1. 1. Singh NA. Nanotechnology innovations, industrial applications and patents. Environmental Chemistry Letters. 2017;15:185-191. DOI: 10.1007/s10311-017-0612-8
  2. 2. Nikolaou M, Pavlopoulou A, Georgakilas AG, Kyrodimos E. The challenge of drug resistance in cancer treatment: A current overview. Clinical & Experimental Metastasis. 2018;35:309-318. DOI: 10.1007/s10585-018-9903-0
  3. 3. Ventola CL. Progress in nanomedicine: Approved and investigational nanodrugs. P T. 2017;42:742-755
  4. 4. Riggio C, Pagni E, Raffa V, Cuschieri A. Nano-oncology: Clinical application for cancer therapy and future perspectives. Journal of Nanomaterials. 2011;2011:1-10. DOI: 10.1155/2011/164506
  5. 5. Luo X, Morrin A, Killard AJ, Smyth MR. Application of nanoparticles in electrochemical sensors and biosensors. Electroanalysis. 2006;18:319-326. DOI: 10.1002/elan.200503415
  6. 6. Kim J, Lee N, Hyeon T. Recent development of nanoparticles for molecular imaging. Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences. 2017;375:20170022. DOI: 10.1098/rsta.2017.0022
  7. 7. Hasan A, Morshed M, Memic A, Hassan S, Webster T, Marei H. Nanoparticles in tissue engineering: Applications, challenges and prospects. International Journal of Nanomedicine. 2018;13:5637-5655. DOI: 10.2147/IJN.S153758
  8. 8. Lymperopoulos G, Lymperopoulos P, Alikari V, Dafogianni C, Zyga S, Margari N. Application of Theranostics in Oncology. Cham: Springer; 2017. pp. 119-128
  9. 9. Mudshinge SR, Deore AB, Patil S, Bhalgat CM. Nanoparticles: Emerging carriers for drug delivery. Saudi Pharmaceutical Journal. 2011;19:129-141. DOI: 10.1016/j.jsps.2011.04.001
  10. 10. Khan I, Saeed K, Khan I. Nanoparticles: Properties, applications and toxicities. Arabian Journal of Chemistry. 2017;10(4). DOI: 10.1016/J.ARABJC.2017.05.011
  11. 11. Bahrami B, Hojjat-Farsangi M, Mohammadi H, Anvari E, Ghalamfarsa G, Yousefi M, et al. Nanoparticles and targeted drug delivery in cancer therapy. Immunology Letters. 2017;190:64-83. DOI: 10.1016/j.imlet.2017.07.015
  12. 12. Salata O. Applications of nanoparticles in biology and medicine. Journal of Nanobiotechnology. 2004;2:3. DOI: 10.1186/1477-3155-2-3
  13. 13. McNamara K, Tofail SAM. Nanoparticles in biomedical applications. Advances in Physics: X. 2017;2:54-88. DOI: 10.1080/23746149.2016.1254570
  14. 14. Mauricio MD, Guerra-Ojeda S, Marchio P, Valles SL, Aldasoro M, Escribano-Lopez I, et al. Nanoparticles in medicine: A focus on vascular oxidative stress. Oxidative Medicine and Cellular Longevity. 2018;2018:1-20. DOI: 10.1155/2018/6231482
  15. 15. Roy Chowdhury M, Schumann C, Bhakta-Guha D, Guha G. Cancer nanotheranostics: Strategies, promises and impediments. Biomedicine & Pharmacotherapy. 2016;84:291-304. DOI: 10.1016/j.biopha.2016.09.035
  16. 16. Janib SM, Moses AS, MacKay JA. Imaging and drug delivery using theranostic nanoparticles. Advanced Drug Delivery Reviews. 2010;62:1052-1063. DOI: 10.1016/j.addr.2010.08.004
  17. 17. Zavaleta C, Ho D, Chung EJ. Theranostic nanoparticles for tracking and monitoring disease state. SLAS Technology (Translating Life Sciences Innovation). 2018;23:281-293. DOI: 10.1177/2472630317738699
  18. 18. Jurj A, Braicu C, Pop L-A, Tomuleasa C, Gherman C, Berindan-Neagoe I. The new era of nanotechnology, an alternative to change cancer treatment. Drug Design, Development and Therapy. 2017;11:2871-2890. DOI: 10.2147/DDDT.S142337
  19. 19. Chen F, Ehlerding EB, Cai W. Theranostic nanoparticles. Journal of Nuclear Medicine. 2014;55:1919-1922. DOI: 10.2967/jnumed.114.146019
  20. 20. Wang Y, Xia Y. Bottom-up and top-down approaches to the synthesis of monodispersed spherical colloids of low melting-point metals. Nano Letters. 2004;4(10):2047-2050. DOI: 10.1021/NL048689J
  21. 21. Iravani S, Korbekandi H, Mirmohammadi SV, Zolfaghari B. Synthesis of silver nanoparticles: Chemical, physical and biological methods. Research in Pharmaceutical Sciences. 2014;9:385-406
  22. 22. Saiqa Ikram SA. Silver nanoparticles: One pot green synthesis using Terminalia arjuna extract for biological application. Journal of Nanomedicine & Nanotechnology. 2015;6:4. DOI: 10.4172/2157-7439.1000309
  23. 23. Arokiyaraj S, Vincent S, Saravanan M, Lee Y, Oh YK, Kim KH. Green synthesis of silver nanoparticles using Rheum palmatum root extract and their antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. Artificial Cells, Nanomedicine, and Biotechnology. 2017;45:372-379. DOI: 10.3109/21691401.2016.1160403
  24. 24. Han C, Pelaez M, Nadagouda MN, Obare SO, Falaras P, Dunlop PSM, et al. Chapter 5. The green synthesis and Environmental Applications of nanomaterials. In: Sustainable Preparation of Metal Nanoparticles: Methods and Applications. London: Royal Society of Chemistry; 2012. pp. 106-143. DOI: 10.1039/9781849735469-00106
  25. 25. Roy A, Bulut O, Some S, Mandal AK, Yilmaz MD. Green synthesis of silver nanoparticles: Biomolecule-nanoparticle organizations targeting antimicrobial activity. RSC Advances. 2019;9:2673-2702. DOI: 10.1039/C8RA08982E
  26. 26. Patra S, Mukherjee S, Barui AK, Ganguly A, Sreedhar B, Patra CR. Green synthesis, characterization of gold and silver nanoparticles and their potential application for cancer therapeutics. Materials Science and Engineering: C. 2015;53:298-309. DOI: 10.1016/j.msec.2015.04.048
  27. 27. Lee S, Jun B-H. Silver nanoparticles: Synthesis and application for nanomedicine. International Journal of Molecular Sciences. 2019;20:865. DOI: 10.3390/ijms20040865
  28. 28. Mirtaheri B, Shokouhimehr M, Beitollahi A. Synthesis of mesoporous tungsten oxide by template-assisted sol-gel method and its photocatalytic degradation activity. Journal of Sol-Gel Science and Technology. 2017;82:148-156. DOI: 10.1007/s10971-016-4289-4
  29. 29. Haghighatzadeh A, Mazinani B, Shokouhimehr M, Samiee L. Preparation of mesoporous TiO2-SiO2 by ultrasonic impregnation method and effect of its calcination temperature on photocatalytic activity. Desalination and Water Treatment. 2017;92:145. DOI: 10.5004/dwt.2017.21481
  30. 30. Deshmukh AR, Gupta A, Kim BS. Ultrasound assisted green synthesis of silver and iron oxide nanoparticles using fenugreek seed extract and their enhanced antibacterial and antioxidant activities. BioMed Research International. 2019;2019:1-14. DOI: 10.1155/2019/1714358
  31. 31. Baltazar-Encarnación E, Escárcega-González CE, Vasto-Anzaldo XG, Cantú-Cárdenas ME, Morones-Ramírez JR. Silver nanoparticles synthesized through green methods using Escherichia coli top 10 (Ec-Ts) growth culture medium exhibit antimicrobial properties against nongrowing bacterial strains. Journal of Nanomaterials. 2019;2019:1-8. DOI: 10.1155/2019/4637325
  32. 32. Yu C, Tang J, Liu X, Ren X, Zhen M, Wang L. Green biosynthesis of silver nanoparticles using Eriobotrya japonica (Thunb.) leaf extract for reductive catalysis. Materials. 2019;12:189. DOI: 10.3390/ma12010189
  33. 33. Bastings MMC, Anastassacos FM, Ponnuswamy N, Leifer FG, Cuneo G, Lin C, et al. Modulation of the cellular uptake of DNA origami through control over mass and shape. Nano Letters. 2018;18:3557-3564. DOI: 10.1021/acs.nanolett.8b00660
  34. 34. Choi Y, Schmidt C, Tinnefeld P, Bald I, Rödiger S. A new reporter design based on DNA origami nanostructures for quantification of short oligonucleotides using microbeads. Scientific Reports. 2019;9:4769. DOI: 10.1038/s41598-019-41136-x
  35. 35. Kasyanenko N, Varshavskii M, Ikonnikov E, Tolstyko E, Belykh R, Sokolov P, et al. DNA modified with metal nanoparticles: Preparation and characterization of ordered metal-DNA nanostructures in a solution and on a substrate. Journal of Nanomaterials. 2016;2016:1-12. DOI: 10.1155/2016/3237250
  36. 36. Arora AA, de Silva C. Beyond the smiley face: Applications of structural DNA nanotechnology. Nano Reviews & Experiments. 2018;9:1430976. DOI: 10.1080/20022727.2018.1430976
  37. 37. Perrault SD, Shih WM. Virus-inspired membrane encapsulation of DNA nanostructures to achieve in vivo stability. ACS Nano. 2014;8:5132-5140. DOI: 10.1021/nn5011914
  38. 38. Saeed K, Khan I. Preparation and properties of single-walled carbon nanotubes/poly(butylene terephthalate) nanocomposites. Iranian Polymer Journal. 2014;23:53-58. DOI: 10.1007/s13726-013-0199-2
  39. 39. Khlebtsov N, Dykman L. Biodistribution and toxicity of engineered gold nanoparticles: A review of in vitro and in vivo studies. Chemical Society Reviews. 2011;40:1647-1671. DOI: 10.1039/c0cs00018c
  40. 40. Bregoli L, Movia D, Gavigan-Imedio JD, Lysaght J, Reynolds J, Prina-Mello A. Nanomedicine applied to translational oncology: A future perspective on cancer treatment. Nanomedicine: Nanotechnology, Biology and Medicine. 2016;12:81-103. DOI: 10.1016/j.nano.2015.08.006
  41. 41. Park W, Heo Y-J, Han DK. New opportunities for nanoparticles in cancer immunotherapy. Biomaterials Research. 2018;22:24. DOI: 10.1186/s40824-018-0133-y
  42. 42. Chen F, Ma K, Madajewski B, Zhuang L, Zhang L, Rickert K, et al. Ultrasmall targeted nanoparticles with engineered antibody fragments for imaging detection of HER2-overexpressing breast cancer. Nature Communications. 2018;9:4141. DOI: 10.1038/s41467-018-06271-5
  43. 43. Zarschler K, Rocks L, Licciardello N, Boselli L, Polo E, Garcia KP, et al. Ultrasmall inorganic nanoparticles: State-of-the-art and perspectives for biomedical applications. Nanomedicine: Nanotechnology, Biology and Medicine. 2016;12:1663-1701. DOI: 10.1016/j.nano.2016.02.019
  44. 44. Verry C, Sancey L, Dufort S, Le Duc G, Mendoza C, Lux F, et al. Treatment of multiple brain metastases using gadolinium nanoparticles and radiotherapy: NANO-RAD, a phase I study protocol. BMJ Open. 2019;9:e023591. DOI: 10.1136/bmjopen-2018-023591
  45. 45. Bian Z, Yan J, Wang S, Li Y, Guo Y, Ma B, et al. Awakening p53 in vivo by D-peptides-functionalized ultra-small nanoparticles: Overcoming biological barriers to D-peptide drug delivery. Theranostics. 2018;8:5320-5335. DOI: 10.7150/thno.27165
  46. 46. Gong F, Cheng L, Yang N, Betzer O, Feng L, Zhou Q , et al. Ultrasmall oxygen-deficient bimetallic oxide MnWO X nanoparticles for depletion of endogenous GSH and enhanced sonodynamic cancer therapy. Advanced Materials. 2019;31:1900730. DOI: 10.1002/adma.201900730
  47. 47. Wan X, Liu M, Ma M, Chen D, Wu N, Li L, et al. The ultrasmall biocompatible CuS@BSA nanoparticle and its photothermal effects. Frontiers in Pharmacology. 2019;10:141. DOI: 10.3389/fphar.2019.00141
  48. 48. Onaciu A, Braicu C, Zimta A-A, Moldovan A, Stiufiuc R, Buse M, et al. Gold nanorods: From anisotropy to opportunity. An evolution update. Nanomedicine. 2019;14(9):1203-1226. DOI: 10.2217/nnm-2018-0409
  49. 49. Brzobohatý O, Šiler M, Chvátal L, Karásek V, Zemánek P. Optical trapping of non-spherical plasmonic nanoparticles. In: Andrews DL, Galvez EJ, Glückstad J, editors. Proceedings of SPIE - The International Society for Optical Engineering. Bellingham, Washington USA; 2014. p. 899909. DOI: 10.1117/12.2041199
  50. 50. Eremin YA, Wriedt T, Hergert W. Analysis of the scattering properties of 3D non-spherical plasmonic nanoparticles accounting for non-local effects. Journal of Modern Optics. 2018;65:1778-1786. DOI: 10.1080/09500340.2018.1459911
  51. 51. Kolhar P, Anselmo AC, Gupta V, Pant K, Prabhakarpandian B, Ruoslahti E, et al. Using shape effects to target antibody-coated nanoparticles to lung and brain endothelium. Proceedings of the National Academy of Sciences. 2013;110:10753-10758. DOI: 10.1073/pnas.1308345110
  52. 52. Zhao Y, Wang Y, Ran F, Cui Y, Liu C, Zhao Q , et al. A comparison between sphere and rod nanoparticles regarding their in vivo biological behavior and pharmacokinetics. Scientific Reports. 2017;7:4131. DOI: 10.1038/s41598-017-03834-2
  53. 53. Truong NP, Whittaker MR, Mak CW, Davis TP. The importance of nanoparticle shape in cancer drug delivery. Expert Opinion on Drug Delivery. 2015;12:129-142. DOI: 10.1517/17425247.2014.950564
  54. 54. Singh P, Ahn S, Kang J-P, Veronika S, Huo Y, Singh H, et al. In vitro anti-inflammatory activity of spherical silver nanoparticles and monodisperse hexagonal gold nanoparticles by fruit extract of Prunus serrulata: A green synthetic approach. Artificial Cells, Nanomedicine, and Biotechnology. 2017;46(8):2022-2032. DOI: 10.1080/21691401.2017.1408117
  55. 55. Yuan Y-G, Zhang S, Hwang J-Y, Kong I-K. Silver nanoparticles potentiates cytotoxicity and apoptotic potential of camptothecin in human cervical cancer cells. Oxidative Medicine and Cellular Longevity. 2018;2018:1-21. DOI: 10.1155/2018/6121328
  56. 56. Pedrosa P, Mendes R, Cabral R, Martins LMDRS, Baptista PV, Fernandes AR. Combination of chemotherapy and Au-nanoparticle photothermy in the visible light to tackle doxorubicin resistance in cancer cells. Scientific Reports. 2018;8:11429. DOI: 10.1038/s41598-018-29870-0
  57. 57. Stylianopoulos T, Poh M-Z, Insin N, Bawendi MG, Fukumura D, Munn LL, et al. Diffusion of particles in the extracellular matrix: The effect of repulsive electrostatic interactions. Biophysical Journal. 2010;99:1342-1349. DOI: 10.1016/j.bpj.2010.06.016
  58. 58. Tran S, DeGiovanni P-J, Piel B, Rai P. Cancer nanomedicine: A review of recent success in drug delivery. Clinical and Translational Medicine. 2017;6:44. DOI: 10.1186/s40169-017-0175-0
  59. 59. Guerrini L, Alvarez-Puebla R, Pazos-Perez N, Guerrini L, Alvarez-Puebla RA, Pazos-Perez N. Surface modifications of nanoparticles for stability in biological fluids. Materials. 2018;11:1154. DOI: 10.3390/ma11071154
  60. 60. Chen J, Wang D, Xi J, Au L, Siekkinen A, Warsen A, et al. Immuno gold nanocages with tailored optical properties for targeted photothermal destruction of cancer cells. Nano Letters. 2007;7:1318-1322. DOI: 10.1021/nl070345g
  61. 61. Vats S, Singh M, Siraj S, Singh H, Tandon S. Role of nanotechnology in theranostics and personalized medicines. Journal of Health Research and Reviews. 2017;4:1. DOI: 10.4103/2394-2010.199328
  62. 62. Deshpande PP, Biswas S, Torchilin VP. Current trends in the use of liposomes for tumor targeting. Nanomedicine. 2013;8:1509-1528. DOI: 10.2217/nnm.13.118
  63. 63. Voinea M, Simionescu M. Designing of ?Intelligent? Liposomes for efficient delivery of drugs. Journal of Cellular and Molecular Medicine. 2002;6:465-474. DOI: 10.1111/j.1582-4934.2002.tb00450.x
  64. 64. Strebhardt K, Ullrich A. Paul Ehrlich’s magic bullet concept: 100 years of progress. Nature Reviews Cancer. 2008;8:473-480. DOI: 10.1038/nrc2394
  65. 65. Huwyler J, Drewe J, Krähenbuhl S. Tumor targeting using liposomal antineoplastic drugs. International Journal of Nanomedicine. 2008;3:21-29
  66. 66. Riaz M, Riaz M, Zhang X, Lin C, Wong K, Chen X, et al. Surface functionalization and targeting strategies of liposomes in solid tumor therapy: A review. International Journal of Molecular Sciences. 2018;19:195. DOI: 10.3390/ijms19010195
  67. 67. Puri A, Loomis K, Smith B, Lee J-H, Yavlovich A, Heldman E, et al. Lipid-based nanoparticles as pharmaceutical drug carriers: From concepts to clinic. Critical Reviews in Therapeutic Drug Carrier Systems. 2009;26:523-580
  68. 68. Guterres SS, Alves MP, Pohlmann AR. Polymeric nanoparticles, nanospheres and nanocapsules, for cutaneous applications. Drug Target Insights. 2007;2:147-157
  69. 69. Mansha M, Khan I, Ullah N, Qurashi A. Synthesis, characterization and visible-light-driven photoelectrochemical hydrogen evolution reaction of carbazole-containing conjugated polymers. International Journal of Hydrogen Energy. 2017;42:10952-10961. DOI: 10.1016/J.IJHYDENE.2017.02.053
  70. 70. Hickey JW, Santos JL, Williford J-M, Mao H-Q. Control of polymeric nanoparticle size to improve therapeutic delivery. Journal of Controlled Release. 2015;219:536-547. DOI: 10.1016/j.jconrel.2015.10.006
  71. 71. Palmerston Mendes L, Pan J, Torchilin V. Dendrimers as nanocarriers for nucleic acid and drug delivery in cancer therapy. Molecules. 2017;22:1401. DOI: 10.3390/molecules22091401
  72. 72. Chaniotakis N, Thermos K, Kalomiraki M. Dendrimers as tunable vectors of drug delivery systems and biomedical and ocular applications. International Journal of Nanomedicine. 2015;11:1. DOI: 10.2147/IJN.S93069
  73. 73. Yang J, Zhang Q , Chang H, Cheng Y. Surface-engineered dendrimers in gene delivery. Chemical Reviews. 2015;115:5274-5300. DOI: 10.1021/cr500542t
  74. 74. Muddineti OS, Ghosh B, Biswas S. Current trends in using polymer coated gold nanoparticles for cancer therapy. International Journal of Pharmaceutics. 2015;484:252-267. DOI: 10.1016/j.ijpharm.2015.02.038
  75. 75. Lee J, Chatterjee DK, Lee MH, Krishnan S. Gold nanoparticles in breast cancer treatment: Promise and potential pitfalls. Cancer Letters. 2014;347:46-53. DOI: 10.1016/j.canlet.2014.02.006
  76. 76. Nagy-Simon T, Tatar A-S, Craciun A-M, Vulpoi A, Jurj M-A, Florea A, et al. Antibody conjugated, Raman tagged hollow gold–silver nanospheres for specific targeting and multimodal dark-field/SERS/two photon-FLIM imaging of CD19(+) B lymphoblasts. ACS Applied Materials & Interfaces. 2017;9:21155-21168. DOI: 10.1021/acsami.7b05145
  77. 77. Azzouzi S, Rotariu L, Benito AM, Maser WK, Ben Ali M, Bala C. A novel amperometric biosensor based on gold nanoparticles anchored on reduced graphene oxide for sensitive detection of l-lactate tumor biomarker. Biosensors & Bioelectronics. 2015;69:280-286. DOI: 10.1016/j.bios.2015.03.012
  78. 78. Sun I-C, Na JH, Jeong SY, Kim D-E, Kwon IC, Choi K, et al. Biocompatible glycol chitosan-coated gold nanoparticles for tumor-targeting CT imaging. Pharmaceutical Research. 2014;31:1418-1425. DOI: 10.1007/s11095-013-1142-0
  79. 79. Rengan AK, Bukhari AB, Pradhan A, Malhotra R, Banerjee R, Srivastava R, et al. In vivo analysis of biodegradable liposome gold nanoparticles as efficient agents for photothermal therapy of cancer. Nano Letters. 2015;15:842-848. DOI: 10.1021/nl5045378
  80. 80. Wei L, Lu J, Xu H, Patel A, Chen Z-S, Chen G. Silver nanoparticles: Synthesis, properties, and therapeutic applications. Drug Discovery Today. 2015;20:595-601. DOI: 10.1016/j.drudis.2014.11.014
  81. 81. Biswas A, Wang T, Biris AS. Single metal nanoparticle spectroscopy: Optical characterization of individual nanosystems for biomedical applications. Nanoscale. 2010;2:1560. DOI: 10.1039/c0nr00133c
  82. 82. Zhang Y, Huang R, Zhu X, Wang L, Wu C. Synthesis, properties, and optical applications of noble metal nanoparticle-biomolecule conjugates. Chinese Science Bulletin. 2012;57:238-246. DOI: 10.1007/s11434-011-4747-x
  83. 83. Abou El-Nour KMM, Eftaiha A, Al-Warthan A, Ammar RAA. Synthesis and applications of silver nanoparticles. Arabian Journal of Chemistry. 2010;3:135-140. DOI: 10.1016/J.ARABJC.2010.04.008
  84. 84. Fernando S, Gunasekara T, Holton J. Antimicrobial nanoparticles: Applications and mechanisms of action. Sri Lankan Journal of Infectious Diseases. 2018;8:2. DOI: 10.4038/sljid.v8i1.8167
  85. 85. Numnuam A, Thavarungkul P, Kanatharana P. An amperometric uric acid biosensor based on chitosan-carbon nanotubes electrospun nanofiber on silver nanoparticles. Analytical and Bioanalytical Chemistry. 2014;406:3763-3772. DOI: 10.1007/s00216-014-7770-3
  86. 86. Plackal Adimuriyil George B, Kumar N, Abrahamse H, Ray SS. Apoptotic efficacy of multifaceted biosynthesized silver nanoparticles on human adenocarcinoma cells. Scientific Reports. 2018;8:14368. DOI: 10.1038/s41598-018-32480-5
  87. 87. He X, Gao J, Gambhir SS, Cheng Z. Near-infrared fluorescent nanoprobes for cancer molecular imaging: Status and challenges. Trends in Molecular Medicine. 2010;16:574-583. DOI: 10.1016/j.molmed.2010.08.006
  88. 88. Medarova Z, Pham W, Farrar C, Petkova V, Moore A. In vivo imaging of siRNA delivery and silencing in tumors. Nature Medicine. 2007;13:372-377. DOI: 10.1038/nm1486
  89. 89. Rhyner MN, Smith AM, Gao X, Mao H, Yang L, Nie S. Quantum dots and multifunctional nanoparticles: New contrast agents for tumor imaging. Nanomedicine. 2006;1:209-217. DOI: 10.2217/17435889.1.2.209
  90. 90. Karimi Z, Karimi L, Shokrollahi H. Nano-magnetic particles used in biomedicine: Core and coating materials. Materials Science and Engineering: C. 2013;33:2465-2475. DOI: 10.1016/j.msec.2013.01.045
  91. 91. Tural B, Özkan N, Volkan M. Preparation and characterization of polymer coated superparamagnetic magnetite nanoparticle agglomerates. Journal of Physics and Chemistry of Solids. 2009;70:860-866. DOI: 10.1016/J.JPCS.2009.04.007
  92. 92. Sahu NK, Gupta J, Bahadur D. PEGylated FePt–Fe3O4 composite nanoassemblies (CNAs): in vitro hyperthermia, drug delivery and generation of reactive oxygen species (ROS). Dalton Transactions. 2015;44:9103-9113. DOI: 10.1039/C4DT03470H
  93. 93. Ye F, Laurent S, Fornara A, Astolfi L, Qin J, Roch A, et al. Uniform mesoporous silica coated iron oxide nanoparticles as a highly efficient, nontoxic MRI T2 contrast agent with tunable proton relaxivities. Contrast Media & Molecular Imaging. 2012;7:460-468. DOI: 10.1002/cmmi.1473
  94. 94. Barick KC, Singh S, Bahadur D, Lawande MA, Patkar DP, Hassan PA. Carboxyl decorated Fe3O4 nanoparticles for MRI diagnosis and localized hyperthermia. Journal of Colloid and Interface Science. 2014;418:120-125. DOI: 10.1016/j.jcis.2013.11.076
  95. 95. Topel SD, Topel Ö, Bostancıoğlu RB, Koparal AT. Synthesis and characterization of Bodipy functionalized magnetic iron oxide nanoparticles for potential bioimaging applications. Colloids and Surfaces. B, Biointerfaces. 2015;128:245-253. DOI: 10.1016/j.colsurfb.2015.01.043
  96. 96. Zhao G, Wang J, Peng X, Li Y, Yuan X, Ma Y. Facile solvothermal synthesis of mesostructured Fe3O4/chitosan nanoparticles as delivery vehicles for pH-responsive drug delivery and magnetic resonance imaging contrast agents. Chemistry—An Asian Journal. 2014;9:546-553. DOI: 10.1002/asia.201301072
  97. 97. Astefanei A, Núñez O, Galceran MT. Characterisation and determination of fullerenes: A critical review. Analytica Chimica Acta. 2015;882:1-21. DOI: 10.1016/j.aca.2015.03.025
  98. 98. Chistyakov VA, Smirnova YO, Prazdnova EV, Soldatov AV. Possible mechanisms of fullerene C 60 antioxidant action. BioMed Research International. 2013;2013:1-4. DOI: 10.1155/2013/821498
  99. 99. Martinez ZS, Castro E, Seong C-S, Cerón MR, Echegoyen L, Llano M. Fullerene derivatives strongly inhibit HIV-1 replication by affecting virus maturation without impairing protease activity. Antimicrobial Agents and Chemotherapy. 2016;60:5731-5741. DOI: 10.1128/AAC.00341-16
  100. 100. Shetti NP, Malode SJ, Nandibewoor ST. Electrochemical behavior of an antiviral drug acyclovir at fullerene-C60-modified glassy carbon electrode. Bioelectrochemistry. 2012;88:76-83. DOI: 10.1016/j.bioelechem.2012.06.004
  101. 101. Bolskar RD. Fullerenes for Drug Delivery. In: Encyclopedia of Nanotechnology. Dordrecht: Springer Netherlands; 2016. pp. 1267-1281
  102. 102. Kumar M, Raza K. C60-fullerenes as drug delivery carriers for anticancer agents: Promises and hurdles. Pharmaceutical Nanotechnology. 2018;5:169-179. DOI: 10.2174/2211738505666170301142232
  103. 103. Maeda-Mamiya R, Noiri E, Isobe H, Nakanishi W, Okamoto K, Doi K, et al. In vivo gene delivery by cationic tetraamino fullerene. Proceedings of the National Academy of Sciences. 2010;107:5339-5344. DOI: 10.1073/pnas.0909223107
  104. 104. Hamblin MR. Fullerenes as photosensitizers in photodynamic therapy: Pros and cons. Photochemical & Photobiological Sciences. 2018;17:1515-1533. DOI: 10.1039/C8PP00195B
  105. 105. Grebinyk A, Grebinyk S, Prylutska S, Ritter U, Matyshevska O, Dandekar T, et al. C60 fullerene accumulation in human leukemic cells and perspectives of LED-mediated photodynamic therapy. Free Radical Biology & Medicine. 2018;124:319-327. DOI: 10.1016/j.freeradbiomed.2018.06.022
  106. 106. Ibrahim KS. Carbon nanotubes-properties and applications: A review. Carbon Letters. 2013;14:131-144. DOI: 10.5714/CL.2013.14.3.131
  107. 107. Chen Z, Zhang A, Wang X, Zhu J, Fan Y, Yu H, et al. The advances of carbon nanotubes in cancer diagnostics and therapeutics. Journal of Nanomaterials. 2017;2017:1-13. DOI: 10.1155/2017/3418932
  108. 108. Sanginario A, Miccoli B, Demarchi D. Carbon nanotubes as an effective opportunity for cancer diagnosis and treatment. Biosensors. 2017;7:9. DOI: 10.3390/bios7010009
  109. 109. Hong H, Gao T, Cai W. Molecular imaging with single-walled carbon nanotubes. Nano Today. 2009;4:252-261. DOI: 10.1016/j.nantod.2009.04.002
  110. 110. Liu Z, Tabakman S, Sherlock S, Li X, Chen Z, Jiang K, et al. Multiplexed five-color molecular imaging of cancer cells and tumor tissues with carbon nanotube Raman tags in the near-infrared. Nano Research. 2010;3:222-233. DOI: 10.1007/s12274-010-1025-1
  111. 111. Guo Q , Shen X, Li Y, Xu S. Carbon nanotubes-based drug delivery to cancer and brain. Current Medical Science. 2017;37:635-641. DOI: 10.1007/s11596-017-1783-z
  112. 112. Madani S Y, Naderi N, Dissanayake O, Tan A, Seifalian A M. A new era of cancer treatment: Carbon nanotubes as drug delivery tools. International Journal of Nanomedicine. 2011;6:2963-2979. DOI: 10.2147/IJN.S16923
  113. 113. Son KH, Hong JH, Lee JW. Carbon nanotubes as cancer therapeutic carriers and mediators. International Journal of Nanomedicine. 2016;11:5163-5185. DOI: 10.2147/IJN.S112660
  114. 114. Sobhani Z, Behnam MA, Emami F, Dehghanian A, Jamhiri I. Photothermal therapy of melanoma tumor using multiwalled carbon nanotubes. International Journal of Nanomedicine. 2017;12:4509-4517. DOI: 10.2147/IJN.S134661
  115. 115. Eldridge BN, Bernish BW, Fahrenholtz CD, Singh R. Photothermal therapy of glioblastoma multiforme using multiwalled carbon nanotubes optimized for diffusion in extracellular space. ACS Biomaterials Science & Engineering. 2016;2:963-976. DOI: 10.1021/acsbiomaterials.6b00052
  116. 116. Sigmund W, Yuh J, Park H, Maneeratana V, Pyrgiotakis G, Daga A, et al. Processing and structure relationships in electrospinning of ceramic fiber systems. Journal of the American Ceramic Society. 2006;89:395-407. DOI: 10.1111/j.1551-2916.2005.00807.x
  117. 117. Thomas SC, Harshita, Mishra PK, Talegaonkar S. Ceramic nanoparticles: Fabrication methods and applications in drug delivery. Current Pharmaceutical Design. 2015;21:6165-6188
  118. 118. Kim J, Jo C, Lim W-G, Jung S, Lee YM, Lim J, et al. Programmed nanoparticle-loaded nanoparticles for deep-penetrating 3D cancer therapy. Advanced Materials. 2018;30:1707557. DOI: 10.1002/adma.201707557
  119. 119. Li S, Jiang Q , Liu S, Zhang Y, Tian Y, Song C, et al. A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo. Nature Biotechnology. 2018;36:258-264. DOI: 10.1038/nbt.4071
  120. 120. Ahn S, Seo E, Kim K, Lee SJ. Controlled cellular uptake and drug efficacy of nanotherapeutics. Scientific Reports. 2013;3:1997. DOI: 10.1038/srep01997
  121. 121. Richards DM, Endres RG. The mechanism of phagocytosis: Two stages of engulfment. Biophysical Journal. 2014;107:1542-1553. DOI: 10.1016/j.bpj.2014.07.070
  122. 122. Rosales C, Uribe-Querol E. Phagocytosis: A fundamental process in immunity. BioMed Research International. 2017;2017:9042851. DOI: 10.1155/2017/9042851
  123. 123. Bloomfield G, Kay RR. Uses and abuses of macropinocytosis. Journal of Cell Science. 2016;129:2697-2705. DOI: 10.1242/jcs.176149
  124. 124. Buckley CM, King JS. Drinking problems: Mechanisms of macropinosome formation and maturation. The FEBS Journal. 2017;284:3778-3790. DOI: 10.1111/febs.14115
  125. 125. Lim JP, Gleeson PA. Macropinocytosis: An endocytic pathway for internalising large gulps. Immunology and Cell Biology. 2011;89:836-843. DOI: 10.1038/icb.2011.20
  126. 126. Lajoie P, Nabi IR. Lipid rafts, caveolae, and their endocytosis. International Review of Cell and Molecular Biology. 2010;282:135-163
  127. 127. Pelkmans L, Helenius A. Endocytosis via caveolae. Traffic. 2002;3:311-320
  128. 128. Kirkham M, Parton RG. Clathrin-independent endocytosis: New insights into caveolae and non-caveolar lipid raft carriers. Biochimica et Biophysica Acta, Molecular Cell Research. 2005;1745:273-286. DOI: 10.1016/j.bbamcr.2005.06.002
  129. 129. Chen K, Li X, Zhu H, Gong Q , Luo K. Endocytosis of nanoscale systems for cancer treatments. Current Medicinal Chemistry. 2018;25:3017-3035. DOI: 10.2174/0929867324666170428153056
  130. 130. Ferguson JP, Huber SD, Willy NM, Aygün E, Goker S, Atabey T, et al. Mechanoregulation of clathrin-mediated endocytosis. Journal of Cell Science. 2017;130:3631-3636. DOI: 10.1242/jcs.205930
  131. 131. O’Kelly I. Endocytosis as a mode to regulate functional expression of two-pore domain potassium (K2P) channels. Pflügers Archiv—European Journal of Physiology. 2015;467:1133-1142. DOI: 10.1007/s00424-014-1641-9
  132. 132. Mayor S, Pagano RE. Pathways of clathrin-independent endocytosis. Nature Reviews Molecular Cell Biology. 2007;8:603-612. DOI: 10.1038/nrm2216
  133. 133. Petros RA, DeSimone JM. Strategies in the design of nanoparticles for therapeutic applications. Nature Reviews Drug Discovery. 2010;9:615-627. DOI: 10.1038/nrd2591
  134. 134. Sharma A, Vaghasiya K, Ray E, Verma RK. Lysosomal targeting strategies for design and delivery of bioactive for therapeutic interventions. Journal of Drug Targeting. 2018;26:208-221. DOI: 10.1080/1061186X.2017.1374390
  135. 135. Seveau S. Multifaceted Activity of Listeriolysin O, the Cholesterol-Dependent Cytolysin of Listeria monocytogenes. Dordrecht: Springer; 2014. pp. 161-195
  136. 136. Yu H, Zou Y, Wang Y, Huang X, Huang G, Sumer BD, et al. Overcoming endosomal barrier by amphotericin B-loaded dual pH-responsive PDMA-b-PDPA micelleplexes for siRNA delivery. ACS Nano. 2011;5:9246-9255. DOI: 10.1021/nn203503h
  137. 137. Hou KK, Pan H, Schlesinger PH, Wickline SA. A role for peptides in overcoming endosomal entrapment in siRNA delivery—A focus on melittin. Biotechnology Advances. 2015;33:931-940. DOI: 10.1016/j.biotechadv.2015.05.005
  138. 138. Nishimura Y, Takeda K, Ezawa R, Ishii J, Ogino C, Kondo A. A display of pH-sensitive fusogenic GALA peptide facilitates endosomal escape from a bio-nanocapsule via an endocytic uptake pathway. Journal of Nanobiotechnology. 2014;12:11. DOI: 10.1186/1477-3155-12-11
  139. 139. Nakase I, Futaki S. Combined treatment with a pH-sensitive fusogenic peptide and cationic lipids achieves enhanced cytosolic delivery of exosomes. Scientific Reports. 2015;5:10112. DOI: 10.1038/srep10112
  140. 140. Erazo-Oliveras A, Muthukrishnan N, Baker R, Wang T-Y, Pellois J-P. Improving the endosomal escape of cell-penetrating peptides and their cargos: Strategies and challenges. Pharmaceuticals (Basel). 2012;5:1177-1209. DOI: 10.3390/ph5111177
  141. 141. Ohtsuki T, Miki S, Kobayashi S, Haraguchi T, Nakata E, Hirakawa K, et al. The molecular mechanism of photochemical internalization of cell penetrating peptide-cargo-photosensitizer conjugates. Scientific Reports. 2016;5:18577. DOI: 10.1038/srep18577
  142. 142. Yang X, Fan B, Gao W, Li L, Li T, Sun J, et al. Enhanced endosomal escape by photothermal activation for improved small interfering RNA delivery and antitumor effect. International Journal of Nanomedicine. 2018;13:4333-4344. DOI: 10.2147/IJN.S161908
  143. 143. Rollo FD. Molecular imaging: An overview and clinical applications. Radiology Management. 2003;25:28-32; quiz 33-35
  144. 144. Jokerst JV, Gambhir SS. Molecular imaging with theranostic nanoparticles. Accounts of Chemical Research. 2011;44:1050-1060. DOI: 10.1021/ar200106e
  145. 145. Debbage P, Jaschke W. Molecular imaging with nanoparticles: Giant roles for dwarf actors. Histochemistry and Cell Biology. 2008;130:845-875. DOI: 10.1007/s00418-008-0511-y
  146. 146. Kircher MF, Willmann JK. Molecular body imaging: MR imaging, CT, and US. Part I. Principles. Radiology. 2012;263:633-643. DOI: 10.1148/radiol.12102394
  147. 147. van Beek EJR, Hoffman EA. Functional imaging: CT and MRI. Clinics in Chest Medicine. 2008;29:195-216. DOI: 10.1016/j.ccm.2007.12.003
  148. 148. Kiessling F, Huppert J, Palmowski M. Functional and molecular ultrasound imaging: Concepts and contrast agents. Current Medicinal Chemistry. 2009;16:627-642. DOI: 10.2174/092986709787458470
  149. 149. Gambhir SS, Czernin J, Schwimmer J, Silverman DH, Coleman RE, Phelps ME. A tabulated summary of the FDG PET literature. Journal of Nuclear Medicine. 2001;42:1S-93S
  150. 150. Griffeth LK. Use of PET/CT scanning in cancer patients: Technical and practical considerations. Proceedings (Baylor University Medical Center). 2005;18:321-330
  151. 151. Jadvar H, Colletti PM. Competitive advantage of PET/MRI. European Journal of Radiology. 2014;83:84-94. DOI: 10.1016/j.ejrad.2013.05.028
  152. 152. Khalil MM, Tremoleda JL, Bayomy TB, Gsell W. Molecular SPECT imaging: An overview. International Journal of Molecular Imaging. 2011;2011:796025. DOI: 10.1155/2011/796025
  153. 153. Gnanasegaran G, Ballinger JR. Molecular imaging agents for SPECT (and SPECT/CT). European Journal of Nuclear Medicine and Molecular Imaging. 2014;41:26-35. DOI: 10.1007/s00259-013-2643-0
  154. 154. Schmidt CW. CT scans: Balancing health risks and medical benefits. Environmental Health Perspectives. 2012;120:A118-A121. DOI: 10.1289/ehp.120-a118
  155. 155. Hill MA, O’Neill P, McKenna WG. Comments on potential health effects of MRI-induced DNA lesions: Quality is more important to consider than quantity. European Heart Journal Cardiovascular Imaging. 2016;17:1230-1238. DOI: 10.1093/ehjci/jew163
  156. 156. Hladik WB, Norenberg JP. Problems associated with the clinical use of radiopharmaceuticals: A proposed classification system and troubleshooting guide. European Journal of Nuclear Medicine. 1996;23:997-1002
  157. 157. Shukla A, Kumar U. Positron emission tomography: An overview. Journal of Medical Physics. 2006;31:13. DOI: 10.4103/0971-6203.25665
  158. 158. Huang Y-Y. An Overview of PET radiopharmaceuticals in clinical use: Regulatory, quality and pharmacopeia monographs of the United States and Europe. In: Nuclear Medicine Physics. Rijeka, Croatia: IntechOpen; 2018
  159. 159. Shankar H, Pagel PS. Potential adverse ultrasound-related biological effects. Anesthesiology. 2011;115:1109-1124. DOI: 10.1097/ALN.0b013e31822fd1f1
  160. 160. Anani T, Panizzi P, David AE. Nanoparticle-based probes to enable noninvasive imaging of proteolytic activity for cancer diagnosis. Nanomedicine. 2016;11:2007-2022. DOI: 10.2217/nnm-2016-0027
  161. 161. Heneweer C, Grimm J. Clinical applications in molecular imaging. Pediatric Radiology. 2011;41:199-207. DOI: 10.1007/s00247-010-1902-5
  162. 162. Boschi F, De Sanctis F. Overview of the optical properties of fluorescent nanoparticles for optical imaging. European Journal of Histochemistry. 2017;61:2830. DOI: 10.4081/ejh.2017.2830
  163. 163. Daniel M, Astruc D. Gold nanoparticles: Assembly, supramolecular chemistry, quantum-size-related properties, and applications toward biology, catalysis, and nanotechnology. Chemical Reviews. 2004;104:293-346. DOI: 10.1021/CR030698+
  164. 164. Choi J, Shin D-M, Song H, Lee D, Kim K. Current achievements of nanoparticle applications in developing optical sensing and imaging techniques. Nano Convergence. 2016;3:30. DOI: 10.1186/s40580-016-0090-x
  165. 165. Ștefan N, Moldovan AI, Toma V, Moldovan CS, Berindan-Neagoe I, Știufiuc G, et al. PEGylated gold nanoparticles with interesting plasmonic properties synthesized using an original, rapid, and easy-to-implement procedure. Journal of Nanomaterials. 2018;2018:1-7. DOI: 10.1155/2018/5954028
  166. 166. Hu K, Wang H, Tang G, Huang T, Tang X, Liang X, et al. In vivo cancer dual-targeting and dual-modality imaging with functionalized quantum dots. Journal of Nuclear Medicine. 2015;56:1278-1284. DOI: 10.2967/jnumed.115.158873
  167. 167. Sun I-C, Eun D-K, Koo H, Ko C-Y, Kim H-S, Yi DK, et al. Tumor-targeting gold particles for dual computed tomography/optical cancer imaging. Angewandte Chemie, International Edition. 2011;50:9348-9351. DOI: 10.1002/anie.201102892
  168. 168. Popovtzer R, Agrawal A, Kotov NA, Popovtzer A, Balter J, Carey TE, et al. Targeted gold nanoparticles enable molecular CT imaging of cancer. Nano Letters. 2008;8:4593-4596
  169. 169. Black KCL, Akers WJ, Sudlow G, Xu B, Laforest R, Achilefu S. Dual-radiolabeled nanoparticle SPECT probes for bioimaging. Nanoscale. 2015;7:440-444. DOI: 10.1039/C4NR05269B
  170. 170. Chen T-J, Cheng T-H, Chen C-Y, Hsu SCN, Cheng T-L, Liu G-C, et al. Targeted herceptin–dextran iron oxide nanoparticles for noninvasive imaging of HER2/neu receptors using MRI. JBIC, Journal of Biological Inorganic Chemistry. 2009;14:253-260. DOI: 10.1007/s00775-008-0445-9
  171. 171. Gallo J, Kamaly N, Lavdas I, Stevens E, Nguyen Q-D, Wylezinska-Arridge M, et al. CXCR4-targeted and MMP-responsive iron oxide nanoparticles for enhanced magnetic resonance imaging. Angewandte Chemie, International Edition. 2014;53:9550-9554. DOI: 10.1002/anie.201405442
  172. 172. Chen F, Hong H, Shi S, Goel S, Valdovinos HF, Hernandez R, et al. Engineering of hollow mesoporous silica nanoparticles for remarkably enhanced tumor active targeting efficacy. Scientific Reports. 2015;4:5080. DOI: 10.1038/srep05080
  173. 173. Hu Z, Yang B, Li T, Li J. Thyroid cancer detection by ultrasound molecular imaging with SHP2-targeted perfluorocarbon nanoparticles. Contrast Media & Molecular Imaging. 2018;2018:1-7. DOI: 10.1155/2018/8710862
  174. 174. Liu J, Li J, Rosol TJ, Pan X, Voorhees JL. Biodegradable nanoparticles for targeted ultrasound imaging of breast cancer cells in vitro. Physics in Medicine and Biology. 2007;52:4739-4747. DOI: 10.1088/0031-9155/52/16/002
  175. 175. Barrett T, Ravizzini G, Choyke P, Kobayashi H. Dendrimers in medical nanotechnology. IEEE Engineering in Medicine and Biology Magazine. 2009;28:12-22. DOI: 10.1109/MEMB.2008.931012
  176. 176. Zhu C, Liu L, Yang Q , Lv F, Wang S. Water-soluble conjugated polymers for imaging, diagnosis, and therapy. Chemical Reviews. 2012;112:4687-4735. DOI: 10.1021/cr200263w
  177. 177. Wang T, Ray J. Aptamer-based molecular imaging. Protein & Cell. 2012;3:739-754. DOI: 10.1007/s13238-012-2072-z
  178. 178. Chen S, Yu Y-L, Wang J-H. Inner filter effect-based fluorescent sensing systems: A review. Analytica Chimica Acta. 2018;999:13-26. DOI: 10.1016/J.ACA.2017.10.026
  179. 179. Zhang H, Zhang B, Di C, Ali MC, Chen J, Li Z, et al. Label-free fluorescence imaging of cytochrome c in living systems and anti-cancer drug screening with nitrogen doped carbon quantum dots. Nanoscale. 2018;10:5342-5349. DOI: 10.1039/c7nr08987b
  180. 180. Zhang F, He X, Ma P, Sun Y, Wang X, Song D. Rapid aqueous synthesis of CuInS/ZnS quantum dots as sensor probe for alkaline phosphatase detection and targeted imaging in cancer cells. Talanta. 2018;189:411-417. DOI: 10.1016/j.talanta.2018.07.031
  181. 181. Luo J, Xie Z, Lam JW, Cheng L, Chen H, Qiu C, et al. Aggregation-induced emission of 1-methyl-1,2,3,4,5-pentaphenylsilole. Chemical Communications. 2001;18:1740-1741
  182. 182. Wang D, Lee MMS, Xu W, Kwok RTK, Lam JWY, Tang BZ. Theranostics based on AIEgens. Theranostics. 2018;8:4925-4956. DOI: 10.7150/thno.27787
  183. 183. Yuan Y, Kwok RTK, Tang BZ, Liu B. Targeted theranostic platinum(IV) prodrug with a built-in aggregation-induced emission light-up apoptosis sensor for noninvasive early evaluation of its therapeutic responses in situ. Journal of the American Chemical Society. 2014;136:2546-2554. DOI: 10.1021/ja411811w
  184. 184. Din FU, Aman W, Ullah I, Qureshi OS, Mustapha O, Shafique S, et al. Effective use of nanocarriers as drug delivery systems for the treatment of selected tumors. International Journal of Nanomedicine. 2017;12:7291-7309. DOI: 10.2147/IJN.S146315
  185. 185. Prasad D, Chauhan H. Key targeting approaches for pharmaceutical drug delivery. American Pharmaceutical Review. 2013;16:6
  186. 186. Shi S, Kong N, Feng C, Shajii A, Bejgrowicz C, Tao W, et al. Drug delivery strategies for the treatment of metabolic diseases. Advanced Healthcare Materials. 2019;1801655:1801655. DOI: 10.1002/adhm.201801655
  187. 187. Joshi D, Garg T, Goyal AK, Rath G. Advanced drug delivery approaches against periodontitis. Drug Delivery. 2016;23:363-377. DOI: 10.3109/10717544.2014.935531
  188. 188. Sarigol-Calamak E, Hascicek C. Tissue scaffolds as a local drug delivery system for bone regeneration. Advances in Experimental Medicine and Biology. 2018;1078:475-493. DOI: 10.1007/978-981-13-0950-2_25
  189. 189. Maeda H, Matsumura Y. Tumoritropic and lymphotropic principles of macromolecular drugs. Critical Reviews in Therapeutic Drug Carrier Systems. 1989;6:193-210
  190. 190. Matsumura Y, Maeda H. A new concept for macromolecular therapeutics in cancer chemotherapy: Mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Research. 1986;46:6387-6392
  191. 191. Bazak R, Houri M, El AS, Hussein W, Refaat T. Passive targeting of nanoparticles to cancer: A comprehensive review of the literature. Molecular and Clinical Oncology. 2014;2:904-908. DOI: 10.3892/mco.2014.356
  192. 192. Yu X, Trase I, Ren M, Duval K, Guo X, Chen Z. Design of nanoparticle-based carriers for targeted drug delivery. Journal of Nanomaterials. 2016;2016:1-15. DOI: 10.1155/2016/1087250
  193. 193. Karimi M, Eslami M, Sahandi-Zangabad P, Mirab F, Farajisafiloo N, Shafaei Z, et al. pH-Sensitive stimulus-responsive nanocarriers for targeted delivery of therapeutic agents. Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology. 2016;8:696-716. DOI: 10.1002/wnan.1389
  194. 194. Polyak B, Friedman G. Magnetic targeting for site-specific drug delivery: Applications and clinical potential. Expert Opinion on Drug Delivery. 2009;6:53-70. DOI: 10.1517/17425240802662795
  195. 195. Rukshin I, Mohrenweiser J, Yue P, Afkhami S. Modeling superparamagnetic particles in blood flow for applications in magnetic drug targeting. Fluids. 2017;2:29. DOI: 10.3390/fluids2020029
  196. 196. Yoo J, Park C, Yi G, Lee D, Koo H, Yoo J, et al. Active targeting strategies using biological ligands for nanoparticle drug delivery systems. Cancers. 2019;11:640. DOI: 10.3390/cancers11050640
  197. 197. Tokunaga S, Takashima T, Kashiwagi S, Noda S, Kawajiri H, Tokumoto M, et al. Neoadjuvant chemotherapy with nab-paclitaxel plus trastuzumab followed by 5-fluorouracil/epirubicin/cyclophosphamide for HER2-positive operable breast cancer: A multicenter phase II trial. Anticancer Research. 2019;39:2053-2059. DOI: 10.21873/anticanres.13316
  198. 198. Safran H, DiPetrillo T, Akerman P, Ng T, Evans D, Steinhoff M, et al. Phase I/II study of trastuzumab, paclitaxel, cisplatin and radiation for locally advanced, HER2 overexpressing, esophageal adenocarcinoma. International Journal of Radiation Oncology. 2007;67:405-409. DOI: 10.1016/j.ijrobp.2006.08.076
  199. 199. Tummers WS, Miller SE, Teraphongphom NT, Gomez A, Steinberg I, Huland DM, et al. Intraoperative pancreatic cancer detection using tumor-specific multimodality molecular imaging. Annals of Surgical Oncology. 2018;25:1880-1888. DOI: 10.1245/s10434-018-6453-2
  200. 200. Rosenthal EL, Kulbersh BD, King T, Chaudhuri TR, Zinn KR. Use of fluorescent labeled anti-epidermal growth factor receptor antibody to image head and neck squamous cell carcinoma xenografts. Molecular Cancer Therapeutics. 2007;6:1230-1238. DOI: 10.1158/1535-7163.MCT-06-0741
  201. 201. Rosenthal EL, Kulbersh BD, Duncan RD, Zhang W, Magnuson JS, Carroll WR, et al. In vivo detection of head and neck cancer orthotopic xenografts by immunofluorescence. Laryngoscope. 2006;116:1636-1641. DOI: 10.1097/01.mlg.0000232513.19873.da
  202. 202. Jiang B, Qi JY, Sun MY, Li ZJ, Liu W, Liu LJ, et al. Tolerance and pharmacodynamics phase I clinical trial study of chimeric anti-CD20 monoclonal antibody IBI301 in Chinese patients with CD20-positive non-Hodgkin’s lymphoma. Zhonghua Xue Ye Xue Za Zhi. 2018;39:320-324. DOI: 10.3760/cma.j.issn.0253-2727.2018.04.013
  203. 203. Edwards JCW, Szczepański L, Szechiński J, Filipowicz-Sosnowska A, Emery P, Close DR, et al. Efficacy of B-cell–targeted therapy with rituximab in patients with rheumatoid arthritis. The New England Journal of Medicine. 2004;350:2572-2581. DOI: 10.1056/NEJMoa032534
  204. 204. Luria-Pérez R, Helguera G, Rodríguez JA. Antibody-mediated targeting of the transferrin receptor in cancer cells. Boletín Médico del Hospital Infantil de México. 2016;73:372-379. DOI: 10.1016/j.bmhimx.2016.11.004
  205. 205. Jhaveri A, Deshpande P, Pattni B, Torchilin V. Transferrin-targeted, resveratrol-loaded liposomes for the treatment of glioblastoma. Journal of Controlled Release. 2018;277:89-101. DOI: 10.1016/j.jconrel.2018.03.006
  206. 206. Dhir V, Sandhu A, Kaur J, Pinto B, Kumar P, Kaur P, et al. Comparison of two different folic acid doses with methotrexate—A randomized controlled trial (FOLVARI study). Arthritis Research & Therapy. 2015;17:156. DOI: 10.1186/s13075-015-0668-4
  207. 207. Ledermann JA, Canevari S, Thigpen T. Targeting the folate receptor: Diagnostic and therapeutic approaches to personalize cancer treatments. Annals of Oncology. 2015;26:2034-2043. DOI: 10.1093/annonc/mdv250
  208. 208. Fan X, Guo Y, Wang L, Xiong X, Zhu L, Fang K. Diagnosis of prostate cancer using anti-PSMA aptamer A10-3.2-oriented lipid nanobubbles. International Journal of Nanomedicine. 2016;11:3939-3950. DOI: 10.2147/IJN.S112951
  209. 209. Baneshi M, Dadfarnia S, Shabani AMH, Sabbagh SK, Haghgoo S, Bardania H. A novel theranostic system of AS1411 aptamer-functionalized albumin nanoparticles loaded on iron oxide and gold nanoparticles for doxorubicin delivery. International Journal of Pharmaceutics. 2019;564:145-152. DOI: 10.1016/j.ijpharm.2019.04.025
  210. 210. Mohammadinejad A, Taghdisi SM, Es’haghi Z, Abnous K, Mohajeri SA. Targeted imaging of breast cancer cells using two different kinds of aptamers -functionalized nanoparticles. European Journal of Pharmaceutical Sciences. 2019;134:60-68. DOI: 10.1016/j.ejps.2019.04.012
  211. 211. Andreou C, Pal S, Rotter L, Yang J, Kircher MF. Molecular imaging in nanotechnology and theranostics. Molecular Imaging and Biology. 2017;19:363-372. DOI: 10.1007/s11307-017-1056-z
  212. 212. Yildiz T, Gu R, Zauscher S, Betancourt T. Doxorubicin-loaded protease-activated near-infrared fluorescent polymeric nanoparticles for imaging and therapy of cancer. International Journal of Nanomedicine. 2018;13:6961-6986. DOI: 10.2147/IJN.S174068
  213. 213. Dobiasch S, Szanyi S, Kjaev A, Werner J, Strauss A, Weis C, et al. Synthesis and functionalization of protease-activated nanoparticles with tissue plasminogen activator peptides as targeting moiety and diagnostic tool for pancreatic cancer. Journal of Nanobiotechnology. 2016;14:81. DOI: 10.1186/s12951-016-0236-3
  214. 214. Yigit MV, Moore A, Medarova Z. Magnetic nanoparticles for cancer diagnosis and therapy. Pharmaceutical Research. 2012;29:1180-1188. DOI: 10.1007/s11095-012-0679-7
  215. 215. Lee S, Ryu JH, Park K, Lee A, Lee S-Y, Youn I-C, et al. Polymeric nanoparticle-based activatable near-infrared nanosensor for protease determination in vivo. Nano Letters. 2009;9:4412-4416. DOI: 10.1021/nl902709m
  216. 216. Zhang R, Lu W, Wen X, Huang M, Zhou M, Liang D, et al. Annexin A5-conjugated polymeric micelles for dual SPECT and optical detection of apoptosis. Journal of Nuclear Medicine. 2011;52:958-964. DOI: 10.2967/jnumed.110.083220
  217. 217. Norregaard K, Jørgensen JT, Simón M, Melander F, Kristensen LK, Bendix PM, et al. 18F-FDG PET/CT-based early treatment response evaluation of nanoparticle-assisted photothermal cancer therapy. PLoS One. 2017;12:e0177997. DOI: 10.1371/journal.pone.0177997
  218. 218. Loo C, Lowery A, Halas N, West J, Drezek R. Immunotargeted nanoshells for integrated cancer imaging and therapy. Nano Letters. 2005;5:709-711. DOI: 10.1021/nl050127s
  219. 219. Rapoport N, Gao Z, Kennedy A. Multifunctional nanoparticles for combining ultrasonic tumor imaging and targeted chemotherapy. Journal of the National Cancer Institute. 2007;99:1095-1106. DOI: 10.1093/jnci/djm043
  220. 220. Sorace AG, Warram JM, Umphrey H, Hoyt K. Microbubble-mediated ultrasonic techniques for improved chemotherapeutic delivery in cancer. Journal of Drug Targeting. 2012;20:43-54. DOI: 10.3109/1061186X.2011.622397
  221. 221. Savla R, Taratula O, Garbuzenko O, Minko T. Tumor targeted quantum dot-mucin 1 aptamer-doxorubicin conjugate for imaging and treatment of cancer. Journal of Controlled Release. 2011;153:16-22. DOI: 10.1016/j.jconrel.2011.02.015
  222. 222. Agostinis P, Berg K, Cengel KA, Foster TH, Girotti AW, Gollnick SO, et al. Photodynamic therapy of cancer: An update. CA: A Cancer Journal for Clinicians. 2011;61:250-281. DOI: 10.3322/caac.20114
  223. 223. Yi G, Hong SH, Son J, Yoo J, Park C, Choi Y, et al. Recent advances in nanoparticle carriers for photodynamic therapy. Quantitative Imaging in Medicine and Surgery. 2018;8:433-443. DOI: 10.21037/qims.2018.05.04
  224. 224. Sun Y, Campisi J, Higano C, Beer TM, Porter P, Coleman I, et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nature Medicine. 2012;18:1359-1368. DOI: 10.1038/nm.2890
  225. 225. Abrahamse H, Kruger CA, Kadanyo S, Mishra A. Nanoparticles for advanced photodynamic therapy of cancer. Photomedicine and Laser Surgery. 2017;35:581-588. DOI: 10.1089/pho.2017.4308
  226. 226. Li W-T. Nanoparticles for photodynamic therapy. In: Handbook of Biophotonics. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA; 2013. pp. 321-336
  227. 227. Calixto G, Bernegossi J, de Freitas L, Fontana C, Chorilli M. Nanotechnology-based drug delivery systems for photodynamic therapy of cancer: A review. Molecules. 2016;21:342. DOI: 10.3390/molecules21030342
  228. 228. Mangadlao JD, Wang X, McCleese C, Escamilla M, Ramamurthy G, Wang Z, et al. Prostate-specific membrane antigen targeted gold nanoparticles for theranostics of prostate cancer. ACS Nano. 2018;12:3714-3725. DOI: 10.1021/acsnano.8b00940
  229. 229. Li Y, Du Y, Liang X, Sun T, Xue H, Tian J, et al. EGFR-targeted liposomal nanohybrid cerasomes: Theranostic function and immune checkpoint inhibition in a mouse model of colorectal cancer. Nanoscale. 2018;10:16738-16749. DOI: 10.1039/c8nr05803b
  230. 230. Zou L, Wang H, He B, Zeng L, Tan T, Cao H, et al. Current approaches of photothermal therapy in treating cancer metastasis with nanotherapeutics. Theranostics. 2016;6:762-772. DOI: 10.7150/thno.14988
  231. 231. Jaque D, Martínez Maestro L, del Rosal B, Haro-Gonzalez P, Benayas A, Plaza JL, et al. Nanoparticles for photothermal therapies. Nanoscale. 2014;6:9494-9530. DOI: 10.1039/c4nr00708e
  232. 232. Lei T, Manchanda R, Fernandez-Fernandez A, Huang Y-C, Wright D, McGoron AJ. Thermal and pH sensitive multifunctional polymer nanoparticles for cancer imaging and therapy. RSC Advances. 2014;4:17959-17968. DOI: 10.1039/C4RA01112K
  233. 233. Zhu X, Feng W, Chang J, Tan Y-W, Li J, Chen M, et al. Temperature-feedback upconversion nanocomposite for accurate photothermal therapy at facile temperature. Nature Communications. 2016;7:10437. DOI: 10.1038/ncomms10437
  234. 234. Liu S, Doughty A, West C, Tang Z, Zhou F, Chen WR. Determination of temperature distribution in tissue for interstitial cancer photothermal therapy. International Journal of Hyperthermia. 2018;34:756-763. DOI: 10.1080/02656736.2017.1370136
  235. 235. Devalapally H, Shenoy D, Little S, Langer R, Amiji M. Poly(ethylene oxide)-modified poly(beta-amino ester) nanoparticles as a pH-sensitive system for tumor-targeted delivery of hydrophobic drugs: Part 3. Therapeutic efficacy and safety studies in ovarian cancer xenograft model. Cancer Chemotherapy and Pharmacology. 2007;59:477-484. DOI: 10.1007/s00280-006-0287-5
  236. 236. Liong M, Lu J, Kovochich M, Xia T, Ruehm SG, Nel AE, et al. Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery. ACS Nano. 2008;2:889-896. DOI: 10.1021/nn800072t
  237. 237. Hadjipanayis CG, Machaidze R, Kaluzova M, Wang L, Schuette AJ, Chen H, et al. EGFRvIII antibody-conjugated iron oxide nanoparticles for magnetic resonance imaging-guided convection-enhanced delivery and targeted therapy of glioblastoma. Cancer Research. 2010;70:6303-6312. DOI: 10.1158/0008-5472.CAN-10-1022
  238. 238. von Maltzahn G, Park J-H, Agrawal A, Bandaru NK, Das SK, Sailor MJ, et al. Computationally guided photothermal tumor therapy using Long-circulating gold nanorod antennas. Cancer Research. 2009;69:3892-3900. DOI: 10.1158/0008-5472.CAN-08-4242
  239. 239. Matea C, Mocan T, Tabaran F, Pop T, Mosteanu O, Puia C, et al. Quantum dots in imaging, drug delivery and sensor applications. International Journal of Nanomedicine. 2017;12:5421-5431. DOI: 10.2147/IJN.S138624
  240. 240. Phillips E, Penate-Medina O, Zanzonico PB, Carvajal RD, Mohan P, Ye Y, et al. Clinical translation of an ultrasmall inorganic optical-PET imaging nanoparticle probe. Science Translational Medicine. 2014;6:260ra149-260ra149. DOI: 10.1126/scitranslmed.3009524
  241. 241. Davis ME, Zuckerman JE, Choi CHJ, Seligson D, Tolcher A, Alabi CA, et al. Evidence of RNAi in humans from systemically administered siRNA via targeted nanoparticles. Nature. 2010;464:1067-1070. DOI: 10.1038/nature08956
  242. 242. Singh P, Pandit S, Mokkapati VRSS, Garg A, Ravikumar V, Mijakovic I, et al. Gold nanoparticles in diagnostics and therapeutics for human cancer. International Journal of Molecular Sciences. 2018;19:1979. DOI: 10.3390/ijms19071979
  243. 243. Libutti SK, Paciotti GF, Byrnes AA, Alexander HR, Gannon WE, Walker M, et al. Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine. Clinical Cancer Research. 2010;16:6139-6149. DOI: 10.1158/1078-0432.CCR-10-0978
  244. 244. Richards JMJ, Shaw CA, Lang NN, Williams MC, Semple SIK, MacGillivray TJ, et al. In vivo mononuclear cell tracking using superparamagnetic particles of iron oxide. Circulation. Cardiovascular Imaging. 2012;5:509-517. DOI: 10.1161/CIRCIMAGING.112.972596
  245. 245. Yaari Z, da Silva D, Zinger A, Goldman E, Kajal A, Tshuva R, et al. Theranostic barcoded nanoparticles for personalized cancer medicine. Nature Communications. 2016;7:13325. DOI: 10.1038/ncomms13325
  246. 246. Maniglio D, Benetti F, Minati L, Jovicich J, Valentini A, Speranza G, et al. Theranostic gold-magnetite hybrid nanoparticles for MRI-guided radiosensitization. Nanotechnology. 2018;29:315101. DOI: 10.1088/1361-6528/aac4ce
  247. 247. Saliev T, Akhmetova A, Kulsharova G. Multifunctional hybrid nanoparticles for theranostics. In: Core-Shell Nanostructures Drug delivery and Theranostics: Challenges, Strategies and Prospects for Novel Carrier Systems. Sawston, Cambridge: Elsevier; 2018. pp. 177-244. DOI: 10.1016/B978-0-08-102198-9.00007-7
  248. 248. Rajkumar S, Prabaharan M. Theranostic application of Fe3O4–Au hybrid nanoparticles. In: Noble Metal-Metal Oxide Hybrid Nanoparticles. Fundamentals and Applications. Sawston, Cambridge: Elsevier; 2019. pp. 607-623. DOI: 10.1016/B978-0-12-814134-2.00029-2

Written By

Anca Onaciu, Ancuta Jurj, Cristian Moldovan and Ioana Berindan-Neagoe

Submitted: 02 May 2019 Reviewed: 17 June 2019 Published: 12 October 2019