An update on nanoparticle-based contrast agents in medical imaging

Abstract

Despite the great value of current exogenous contrast agents for providing main diagnostic information, they still have certain drawbacks such as short blood half life, nonspecific biodistribution, fast clearance, slight renal toxicity and poor contrast in fat patients. Nanoparticles (NPs) are used as novel contrast agents that represent a promising strategy for the non invasive diagnosis. As a platform, nanoparticulates are compatible for developing targeted contrast agents. Advances in nanotechnology will provide enhanced sensitivity and specificity for tumor imaging enabling earlier detection of metastases. This article focuses on fundamental issue such as biological interactions, clearance routes, coating of NPs and presents a wide discussion about most recent category of NPs that are used as contrast agents and thebenefits/concerns issues associated with their use in clinical procedures.

Keywords:

• Contrast agents
• nanoparticles
• biological interactions
• clearance routes
• coating

Introduction

Recently imaging has been widely used in both bio- and medical imaging due to its visual and intuitional interface with the goal of enabling early detection and diagnosis of diseases. In economical and practical terms, it is more feasible to develop supplements that can maximize the ability of the current devices in the detection, diagnosis and treatment of variety of illnesses, such as cancer and other diseases. There is a large intrinsic contrast under normal conditions between bone and its surrounding tissues that differentiate them. However, it is not efficient to distinguish normal organ/tumors or soft tissues such as fat/muscle [1,2].

Current exogenous contrast agents applied as enhancer are based on iodine, barium sulfate, Gadolinium ions (Gd3+) complexes, etc. Despite the great value of present medical imaging techniques for providing main diagnostic information, they still have certain drawbacks challenging important part of their clinical applications [3,4].

Clinical procedures fail to yield accurate results because contrast agents applied for enhancing of the image sensitivity have many shortcomings such as short blood half life, nonspecific biodistribution, fast clearance, slight renal toxicity and poor contrast in fat patients [5].

Nanoparticles (NPs) are used as novel contrast agents that represent a promising strategy for the non invasive diagnosis. As a platform, nanoparticulates are compatible for developing targeted contrast agents, because: (a) they have a surface, which can be functionalized with one or more targeting molecules at a wide range of densities; (b) their plasma circulation time can be turned over several orders of magnitude based on their physico-chemico properties and (c) contrast agents and drugs can be included at predetermined ratios either in the interior or on the surfaces [6,7]. Advances in nanotechnology may lead to a NP-based tumor-targeting contrast agent that will provide enhanced sensitivity and specificity for tumor imaging enabling earlier detection of metastases [8].

In this review, we will first address the fundamental issues such as biological interactions, clearance routes, Coating of NPs and we will also provide an overview of the two major technologies currently applied for diagnostic imaging. In the latter part of the study we will focus mainly on the most recent categories of NPs that are used as contrast agents and the benefits/concerns issues associated with their use in clinical procedures.

Biological interactions and clearance routes

Biological interactions and accumulation/interference of nanomaterials employed for contrast agent are fundamentally important. Many nanomaterials designed for the use as contrast agent in medical imaging, are still limited by their slow renal clearance and non-specific accumulation in the mononuclear phagocyte system (MPS) found in the liver, spleen and lymph nodes [9,10]. The main parameters governing how NPs interact with biological systems are their size, shape and surface properties [11]. It has been found that larger particles experience more rapid clearance than smaller particles. NPs with hydrodynamic diameters larger than 200 nm are sequestered by MPS found in the spleen while NPs smaller than 10 nm are usually stealthy to the reticuloendothelial system (RES) organs, these NPs are still found in the liver [12,13]. Majority of clearance for NPs smaller than 5.5 nm are through renal routes thus one must ensure that the NPs are not too small which have a tendency to be removed rapidly by the kidneys [14,15]. In addition to size, surface properties of particles play an important role in RES uptake. It has been found that hydrophilic and neutral surfaces generally are not prone to adsorption or opsonization and are thus more “stealthy” for complement system [16,17]. The long-term fate, minimal non-specific binding and uptake, selective binding to desired cell surface receptors, effective elimination from the body and little or no toxicity of NPs in body are major concerns in the design of these NPs platforms as contrast agent in medical imaging. Improper biodistribution and partial clearance can cause toxicities such as developmental and reproductive risks, acute/chronic toxicity, immunotoxicity and carcinogenicity through biological interactions in the body. Certain materials break down into highly toxic components during degradation in vivo and thus can not be considered safe [18–20].

Rapid biodistribution and complete clearance are therefore essential for the design of biocompatible, biodegradable and targeted contrast agents and thus can seriously be considered for clinical use [21].

Coating and targeting

As discussed previously, the surface of NPs can greatly determine fate and their interaction with the body in clinical application. Coating can efficiently protect NPs from MPS and protein adsorption [22].

Coatings are also effective at creating a neutral and hydrophilic surface that can resist aggregation and agglomeration through contact with proteins. One of the major challenges is to develop a surface coating material that can provide colloidal stability and biocompatibility of functional groups under physiological conditions. The stability and biocompatibility of NPs are not only dependent on the choice of the coating agent but how it interacts with the biological environment [8,11,20]. Some of NPs provide functional groups for coating and targeting and have also proved to be safe and biocompatible. Studies have shown that synthetic and natural hydrophilic polymeric coating agents have least impact on the immunologic response. For in vivo applications, there are common classes of polymeric coating materials such as poly ethylene glycol (PEG), poly L-lysine (PLL), poly vinyl alcohol (PVA), poly acrylic acid (PAA), alginate, dextran, chitosan and starch [11,23].

PEG, one of the most common coating agents, is a coiled polymer of repeating ethylene ether units. Currently a large number of US FDA-approved NPs often are coated by it. PEG is inexpensive, versatile and FDA approved, thus it used in many preclinical studies for medical imaging. The addition of PEG to the NP surface reduces the contact typical of proteins and small-molecule interactions and increases the enhanced permeability and retention (EPR) effect and solubility in buffer and serum. Nevertheless, addition of coating materials also comes with the disadvantage of increasing the NPs hydrodynamic diameter. For the controllable bioconjugation of other molecules such as antibodies, small peptides or molecules, lectins, aptamersand engineered proteins, proper selection of surface coating agent will be an important and considerable issue [8,24].

Computed tomography scanning

NP-based contrast agents, as valuable and potentially transformative tools, have been used for a wide range of imaging modalities such as positron emission tomography (PET), magnetic resonance imaging (MRI), ultrasound (US), computed tomography (CT) and single-photon emission computed tomography (SPECT) for enhancing medical diagnostics (Figure 1). In addition to the online resource http://www.mi-central.org, data on numerous and emerging imaging technologies can be found in reviews by Ryvolova et al. [25] and Michael Farle [26], the latter focused on molecular imaging applying NPs. This part was added to the revised manuscript. Among the imaging modalities, MRI and CT are the the two major technologies currently used for diagnostic imaging.

Figure 1. Concept of contrast agent based on NPs in varius modality of imaging [101].

CT is one of the most important diagnostic tools in medical imaging today in terms of cost, efficiency and availability and has become an important part of modern medicine. This technique can construct detailed cross-sectional images of many various tissues in human body. Since atomic number, electron density and consequently X-ray attenuation coefficient of different tissue in body is different, based on this fact, the CT is able to distinguish between different tissues to produce images for body structures and tissues. Mass attenuation coefficient determines the loss of X-ray photon intensity via interactions with matter. Generally, tissues that are denser and consist of large quantities of electron rich elements absorb higher amounts of X-rays beam, while less dense materials absorb lesser amounts [27].

CT images naturally appear in grayscale, which is based on the coefficient attenuation of the different tissues in body. More strongly X-ray attenuating matter such as bone display a light gray or white image, because attenuation in bone is very efficient while soft tissues appear dark gray or black in the image [28,29]. There is a large intrinsic contrast under normal conditions between bone and its surrounding tissues that differentiate them. However, it is not efficient to distinguish normal organ/tumors or soft tissues such as fat/muscle owing to their similar mass attenuation coefficients [1]. Many CT scans that are used currently involve intravenously injected iodine-based or oral barium sulfate suspensions as contrast agents in clinical use, in order to enhance the sensitivity of the scan. However, clinical procedures indicate that these agents are not optimal because they have many shortcomings such as short blood half life, nonspecific biodistribution, fast clearance, slight renal toxicity and poor contrast in fat patients [1,30,31].

Over the recent decades, the nanoparticulte contrast agents for CT have been introduced to overcome this limitation. They carry a much higher payload of contrast generating material and increase absorption of X-ray compared to iodine-based contrast agents, meaning that patients can be exposed to lesser doses of X-ray. Furthermore, pharmacokinetic properties of these are different to other available agents that may provide imaging over a wide range time window and exhibit better perfusion imaging [32,33].

Various type of NPs have been studied as novel contrast enhancing agents including emulsions, liposomes, micelles, lipoproteins, polymeric NPsand gold NPs for several types of soft tissue. In this formulation, the material used to generate contrast is usually encapsulated by NPs. Various compounds can be used for modification and coating of NPs as contrast agents that yield solubility in biological media and biocompatibility [28,34,35].

The iodinated molecules are used as CT contrast agents in the clinic but these molecules demonstrate adverse effect and have short circulation times in vivo. For these reasons, researchers have used nanomaterial for unique properties such as long circulating half-life, simple surface modification and ability of passive targeting. Recently in many studies, researchers have designed nanoparticulate CT contrast agents and assessed the in vivo applications of these nanomaterials. A novel Yb-based nanoparticulate agent has better contrast efficacy compared to usual CT contrast agents. In the study conducted by Yanlan et al. they integrated both Ba and Yb [30]. They demonstrated that the Ba and Yb have much higher contrast than iodinated agents and alsohave prolonged in vivo circulation time and very low toxicity. Hence these agents are good candidates for use in angiography.

In another study, Myoung et al. have used bioinert tantalum oxide NPs as contrast agents [31]. The results of studies showed that these NPs have remarkable performances in the in vivo X-ray CT angiography and bimodal image-guided lymph node mapping. When the in vivo toxicity of tantalum oxide NPs was assessed the results did not show toxicity in normal functioning of organs.

Magnetic resonance imaging (MRI)

MRI has evolved as a most powerful noninvasive imaging technique in clinical medicine. Clinical applications of MRI developed in the beginning of the 1980 s. The advent of improved gradient coils, high magnetic fields and pulse sequences has provided means to obtain 3 D images of body. A strong magnetic field (B0) is applied to certain atoms in body, such as hydrogen protons, which are excited and aligned for producing high resolution and high-contrast images of tissue structure and function. Upon application of a radiofrequency (RF) pulse, these protons are perturbed from B0. Subsequently protons return to their original state that is called as the relaxation phenomenon [16,36]. The principal tissue signal of all clinical image in MRI arises from water protons and this intrinsic contrast is known as “proton density contrast”. Another type of MRI contrast is related to spatial differences in the relaxation properties of the MR signal, which includes two principal relaxation processes longitudinal and transverse relaxation time constants, T1 and T2, respectively. Although intrinsic contrast is sufficient for most MRI applications, intensity of contrast in tissue is enhanced by administration of exogenous contrast agents in 40% of all clinical MRI studies. Typically MRI contrast agents are categorized into paramagnetic and superparamagnetic materials. Toxicity of metal ion is an unfavorable effect of physiologic administration of contrast agents, but can be reduced by complexation of the metals with organic molecules or magnetic NPs [37,38].

Depending on the magnetic property of the core of particles there are two different relaxation pathways and consequently contrast agents are classified as T1 (longitudinal) and T2 (transverse) contrast agents. Depending on the application, both types of technique can be carried out using any MRI system. The first, are those that reduce the longitudinal (T1) relaxation time and cause positive contrast enhancement based on the paramagnetic ions including Gd3+ complexes. Due to toxicity issues related to metal ion, the second, called negative contrast agents, are presented which are based on magnetic iron oxide NPs (SPIONs) and cause darker state in the T2-weighted image, thus are the most representative nanoparticulate agents [39–41].

In the recent years, the potential types of superparamagnetic particles (SMP) has been evaluated based on size in many preclinical and clinical trials, including: (I) micrometer-sized paramagnetic iron oxide (MPIO, micron size), (II) superparamagnetic iron oxide (SPIO, nanometeric size) that mainly is used for diagnosis of hepatic diseases and tomur detection and (III) ultrasmall superparamagnetic iron oxide (USPIO, <50 nm) that generally are highly useful for blood pool imaging and angiography. As compared to Gd, SPIONs show the advantages including tunable size and shape, possibility of surface modification, high sensitivity and effectiveness at low concentrations due to their superparamagnetic property. It is clear that it is possible to provide significant enhancment in magnetic resonance activity by proper selection of special coatings on SPIONs [18,41,42].

Nowadays, the most commonly available contrast agents for MRI are paramagnetic and low molecular weight Gd3 + complexes that enhance contrast by non-specific improvment of water proton relaxation rates within the blood stream. Amongst them, Gd-DTPA has been currently used under the routine and commercial name Magnevist® that is excreted renally. However, anatomical abnormalities, such as gliomas and lesions within the brain can be visualised when they are administrated in clinical MRI [23,39,43,44]. Gadolinium can be incorporated into a variety of NP for enhancing MRI contrast agents, because these formulations can concentrate a large number of metal ion in the tissue of interest, they show greater sensitivity at magnetic fields [45].

Recent categories of NPs used as contrast agents

Gold NPs

X-ray contrast agents were introduced to increase the contrast between tissues and the sinal-to-noise ratio without increasing the radiation dose to the patients. The most practical CT contrast agents are iodine-based compounds which work by blocking X-rays, provide contrast and enhance a part of the body. Some of the iodine-based contrast agents side effects are vomiting, itching and anaphylactic shock [46–48]. Therefore, over the last decade, gold NPs (AuNPs) have gained attention as an X-ray contrast agent as they are biocompatible, are competent to target the tumor by the EPR effect and have a very high X-ray absorption coefficient, which makes them proper agents for replacing iodine in CT imaging. As gold is a metal with a high atomic number it provides better X-ray attenuation and hence is considered as a suitable candidate for CT imaging [49–51].

Simple surface modification for achieving colloidal stability and enabling active targeting is an advantage of AuNPs in a comparison with other NPs. Some of materials which is used to form linkages with AuNP surfaces are carboxylate, amine, disulfide, thiol, alkanthiol and phosphine ligands [52].

Another approach for linking molecules to gold is utilization of dendrimers. Dendrimer-entrapped AuNPs can be modified through the dendrimer molecules to improve cytocompatibility, colloidal stability [53] and active targeting [54,55] for using as an imaging agents.

Different types of molecules can be attached to the surface of AuNPs through the linkages for surface functionalization to improve colloidal stability and enable active targeting in imaging agents. For instance PEG [56], gum arabic [57], polysaccharides [58] and polyvinyl alcohol [59] have been used to improve colloidal stability while peptides [60], antibodies [56,61–63], saccharides [58,64], lipoproteins [65] and numerous small molecules [54,55,66–69] are used for active targeting or for promoting both colloidal stability and active targeting capabilities. Molecular ligands can lead AuNPs to a site of intrest for target-specific binding, including cancerous cells or tumors [54,58,60,70,71], the liver [72], lymph nodes [61], atherosclerotic plaque [73], bone or mineral deposits [67,69,74,75] and myocardial scar.

Leaky vasculature of tumors and enhanced permeability and retention effect can result in accumulating of AuNPs in tumor sites which is principle of passive targeting. Surface-functionalized AuNPs can enhance the blood circulation time, which leads to accumulate the AuNPs within a tumor [76]. Approximately two-fold increase in the X-ray attenuation of the tumor was seen as a result of passive targeting of surface-functionalized AuNPs to tumor xenografts when compared with before the delivery of AuNPs [77,78]. On the other hands, active targeting of AuNPs have also showed site-specific accumulation and resulted in contrast-enhanced radiographic imaging in vivo. Table 1 exhibits the examples of actively targeted AuNPs [79–87].

Table 1. Examples of actively targeted AuNPs.

Sorting by	Type	Example
Molecular structure	1. Lipid [79]	a. Lipid such as phospholipids [80]
	2. Polymeric [81]	b. Polymer such as synthetic polymer (PLGA) [82]
Phase	1. Typical phase	a. Oil in water micelle
	2. Inverse phase [83]	b. Water in oil micelle
Shape and size	1. Spherical [84]
	2. Oval [85]
	3. Cylindrical [86]
	4. Lamellar [87]

Iron oxide NPs

Currently, many clinically used contrast agents are gadolinium-based compounds due to their unpaired electrons and large magnetic moment. Ions are highly toxic so to overcome this obstacle proper ligands can be used to produce gadolinium chelates which are nontoxic and well stable during the period of administration [45,88]. Gadolinium chelates have also been used in targeted drug delivery. For example, Park et al. conjugated the peptide RGD to Gd-DOTA (tetraazacyclododecane tetraacetic acid) to obtain an MRI contrast agent with tumor targeting capability [89].

To create enhanced MRI contrast agents, gadolinium has also been employed in various NP formulations. As these formulations can hold and deliver a large number of gadolinium ions to the tissue of interestand show better sensitivity at high magnetic fields [45]. Gadolinium ions can be incorporated into different types of NPs like polymers [90,91], liposomes [92,93], carbon nanotubes [94–96] and silica NPs [97–99]. Gadolinium oxide NPs are also good candidates for prospective paramagnetic contrast agent formulations usage [39].

Another commonly used contrast agent for MRI is the superparamagnetic iron oxide NP (SPION). SPIONs improve imaging by dipping the T2 relaxation time of water protons. T2 relaxivity of a SPION-based agent is much higher than that of gadolinium agents [100].

Charge, surface decoration and size, can influence stability, biodistribution and metabolism. Surface charge is one of the important factor in determining the colloidal nature of NPs and can also influence plasma protein binding which directly influences NP in vivo biodistribution and its clearance from the body [101]. By biocompatible and biodegradable surface coating, SPIONs can escape from immune system and serum protein adsorption [102]. When the particles size are below 20 nm, the superparamagnetic property of SPIONs have been occured which is one of the most important characteristics for in vivo imaging applications [103]. As bulk iron oxide is a ferromagnetic (permanently magnetized) material, it cannot exhibit this property. Superparamagnetism is similar to the paramagnetism showed by materials like gadolinium which can only exhibits a net magnetization when placed in an external magnetic field [104]. Thus, the lack of magnetization decreases the magnetic dipole-dipole interactions between SPIONs and helps to keep them from agglomeration [16]. Even though iron oxide is deemed non-toxic and is finally metabolized into haemoglobin [105,106], large amount of iron augment the probability of toxicity [107]. Thus, it is essential to use SPIONs with high saturation magnetization values to lessen iron loading for in vivo work.

Various biocompatible materials, coated or conjugated with targeting moieties such as glycosaminoglycan [108], proteins like heat shock protein 70 [109], chitosan [110], folic acid [111] and antibodies [112] have been attached to SPIONs surface to provide tissue specificity to hepatocytes, myocardium, tumor regions, macrophages, endothelial cells in order to reduce non-specific uptake and improve biocompatibility.

SPIONs also were attached to gadolinium complexes to increase MRI contrast [110,113]. NPs are also used for dual imaging [114,115].

Dendrimers

Dendrimers are macromolecules which has a regular three-dimensional architecture, uniform sizeand are highly branched. They have three parts: core, branch and end groups [116]. Dendrimers are nano-structures which are considered in many areas of biomedical. This structure consists of a central core that many branch step by step, like a tree that has been split. Each group of these particles in terms of size, shape, length, particle density and particle surface functional groups as well as the overall structure of the particle (whether internal or external building) are very similar [117,118]. These particles have the ability to accommodate different molecules in between the branches. However, due to the presence of multiple functional groups on the surface, they can carry a variety of molecules attached to their surfaceand can also enable this feature for a tissue-specific targeting. To date, two groups of family dendrimers are available commercially: Poly amidoamines dendrimers (PAMAM) and polypropylene imine (PPI) [119–121]. The unique properties of dendrimers are multifunctional nature of these particles. So that at the same time it contains drug molecules and targeting parts [122,123]. This unique structure allows particles conjugated molecules on the surface and provides encapsulation of them. PEGylated dendrimers (dendrimers coated with polyethylene glycol) are one of the best classes that attract many researchers due to its low levels of toxicity in the blood, prolonged circulation time and relatively less accumulation in different organs [124,125]. As mentioned earlier, due to multiple functional groups on the surface of dendrimers, many materials can be attached to their surface. Multifunctional nature of the NPs has attracted the attention of many researchers. Using dendrimers, can be done targeted drug delivery and imaging of tissue can be done at the same time [94]. One of the applications of dendrimers, is imaging [126,127]. Many studies have been done in this area, which continues to be mentioned. In a recent study conducted by Zhu et al. dendrimers has been used for imaging and drug delivery to tumor cells. This team synthesized the multifunctional dendrimer-entrapped gold NPs (Au DENPs) modified with alpha-tocopheryl succinate and arginine–glycine–aspartic acid (RGD) peptide for targeted chemotherapy and CT imaging of cancer cells. The results showed that the existence of AuNPs, enabled the multifunctional Au DENPs to have a better X-ray attenuation property than clinically used iodinated CT contrast agents (e.g. Omnipaque) and they could be used as a nanoprobe for targeted CT imaging of cancer cells in vitro [128]. The next study on the use of dendrimers in medical imaging was conducted by Markowicz-Piasecka et al. In this research PAMAM dendrimer was used as delivery vehicles of MRI contrast agents. Here G4 PAMAM dendrimers were used as carriers of gadolinium complexes of iminodiacetic acid derivatives and also was used to determine imaging properties of synthesized compounds in the in vivo studies. The results demonstrated that the compounds composed of PAMAM G4 dendrimers and gadolinium complexes of iminodiacetic acid derivatives increase signal intensity in MRI studies which corresponds with the greatest accumulation of gadolinium after administration of the compounds [129], but to prove this claim the results of research and testing need to be studied in more detail.. Another study which was conducted on the application of dendrimers in medical imaging was by Zhou et al. They prepared PEGylated polyethylenimine-entrapped gold NPs modified with folic acid for targeted tumor CT imaging. Here folic acid targeted multifunctional gold NPs wereused with cost-effective branched polyethylenimine dendrimers modified with polyethylene glycol as a template for tumor CT imaging applications. The results showed that this complex may hold great promise to be used as a nanoprobe for CT imaging tumors [130].

Quantum dots

Quantum dots are nanoscale semiconductor crystals (1–10 nm) [131]. Quantum dots normally are shell-core structures. The core is usually composed of II–VI or III–V group elements of the periodic table which is covered by a shell made of semiconductor compounds [132]. Shell and core are both are semiconductors. The energy difference between the valence and conduction layeris called the band gap. The band gap is different depending on the type of compound semiconductor. Quantum dots of different sizes have different band gap. Whenever the size of the quantum dots becomes smaller, the band gap is larger. As a result, more energy is needed to excite the smaller particles (light with shorter wavelength) [133,134]. Quantum dots have many advantages over conventional fluorophore, such as organic dyes, fluorescent proteins and lanthanide chelates. There is wide excitation spectrum in quantum dots. Therefore, the exitation process occurs in a wide range of wavelengths. The width of the emission spectrum of the quantum dots is narrow. The wavelength of the emission spectrum in quantum dots with NPs size, composition and surface coating of the NP can be controlled. In fact, the emission wavelength with these control parameters in a wide range of wavelengths (UV to infrared) is adjustable [135,136]. The most important application of quantum dots is now in the field of medical imaging. The main reasons for its usage is the high brightness and stability. The use of quantum dots in cellular imaging is one of the most important advances in recent decades. Because of the high stability of quantum dots, optical trackingof cell or biological molecules can be used in a long time [137]. In a study that was done by Ding et al. thay synthesized a new type of Mn-doped Cd-free QDs with Zn gradient CuInS2 core and ZnS outer shell as dual-modality probes for fluorescence/magnetic resonance imaging of tumors. The results indicated that the fluorescence and MR imaging of tumors have shown that the both subcutaneous and intraperitoneal tumor xenografts can be visualized in vivo. Figure 2 shows a schematic representation of imaging tumors in mice [138]. In the other study conducted by Zhang et al., they synthesised a GdS coated CdTe NPs(CdTe@GdSNPs) as multimodal agents for fluorescence (FL) and T1 weighted magnetic resonance (MR) imaging. The results of this study showed that the probe can obtain good capability for tumor-targeting imaging and can be effectively used in live cell and animal model for tumor-targeting FL and MR dual-modality imaging [114].

Figure 2. In vivo fluorescence imaging of the nude mouse bearing a subcutaneous tumor [138].

Micelles

A micelle is an aggregate of surfactant molecules dispersed in a colloidal liquid. Micelles are two types: (a) typical micelle (b) inverse micelle. A typical micelle is known as a normal-phase micelle (oil in water micelle). In this type of micelle it forms an aggregate in aqueous solution with the hydrophilic head regions in contact with surrounding solvent, sequestering the hydrophobic single-tail regions in the micelle centre. Inverse micelle is known as water in oil micelle. This type of micelle has the head groups at the centre with the tails extending out. Micelles are classified according to the molecular structure, phase, shape and size of the micelle. Table 1 shows the categories based on these factors. Micelles have variety of applications in drug delivery [139], imaging agents, therapeutic agents [140] and in particularly anti-cancer drugs. One of the micelles applications, is their use as a carrier to deliver differentiation agents for imaging to identify the target cells [141]. Many studies have been done in this area . In one study performed by Kim et al. they designed a cancer-recognizable MRI contrast agents (CR-CAs) by using pH-responsive polymeric micelles. The results demonstrated the effectiveness of CR-CAsfor cancer diagnosis [142].

Core-shell NPs

Core-shell NPs are hybrid systems. They have a core and a coating or shell. Core and shell can be any features such as metallic conductivity, semiconductivity, magnetic properties and so on [143]. The core and shell can also be of a similar kind, for example, a metal core with a shell made of metal, such as Au-Ag [144]. An interesting aspect of these systems makes it possible to protect the core of the chemical environment around. Core-shell NPs in drug delivery and imaging are widely used [145,146]. Much research in the field of application core-shell NPs in imaging is done. One of these studies was conducted by Ho et al., their goal was to design a system with novel platform, termed unibody core-shell. Unibody core-shell is contained of two covalent-bonded polymers differed only by the functional groups at the core and the shell. Core-shell system was designed so that conjugating Gd3+ at the stable core and encapsulating doxorubicin (Dox) at the shell. Study of them demonstrated that the anti-cancer effect of UCS-Gd- Dox is notably better than free Dox in tumor-bearing mouse models [147].

Ratanajanchai et al. [148] introduced amine-functionalized core–shell NPs (Polymethyl methacrylate/Polyethyleneimine; PMMA/PEI) as a useful imaging agent. Previous studies have demonstrated core-shell structured agents are promising delivery system as a superior MRI contrast agent for targeted MR imaging [149,150] especially for hepatic lesion [148], brain [151], tumor [147]. In Zhou et al. work mesoporous core-shell structured up-conversion NPs (mUCNPs), could also be used as the contrast agents for X-ray CT and MR imaging [152].

Limitations of currently studied NP-based contrast agents and outlook of the future

Although NPs are frequently recommended as diagnostic agents, just iron oxide NPs have been incorporated into clinical use so far [153]. This is chiefly due to difficulties in achieving desirable pharmacokinetic properties and particle homogeneity as well as to concerns about elimination, toxicity and biodegradation. Moreover, the clinical utilization of most approved contrast agents shows immunological reactivity as a common toxicity. Binding to plasma proteins (opsonization) and taken up by phagocytic cells in the blood, liver, spleen, lymph nodes, inflammatory lesions and bone marrow are other concern. Although this effect can be used to provide contrast in this lesions, may leads to two challenges that includes increase of NPs removal from circulation and long retention times of potentially toxic NP components or metabolites [154]. To mitigate these limitations, a mostly commonly used approach is steric stabilization of NP by polyethylene glycol (PEG) coating [24]. To sum up, a significant effort is required to design particles with optimal characteristics associated with both body clearance and tumor specific accumulation.

Conclusion

Although small molecules such as organic dyes have been usually used as contrast agents in medical imaging, NPs are receiving increasing interest as a ompatible platform for developing targeted contrast agents that represent a future strategy for the non invasive diagnosis but most of them are still being tested in vitro or in vivo with small animals and will need to solve the possible toxicity concern. It is expected that nanoparticulate contrast agents offer a broad range of opportunities, including diagnosis and effective treatment of diseases which is in early stage and will eventually move into the clinical phase.

Acknowledgements

Authors would like to thank Department of Medical Nanotechnology, School of Advanced Technologies in Medicine (SATiM), Tehran University of Medical Sciences and Stem Cell and Regenerative Medicine Institute, Tabriz University of Medical Sciences for supporting this project.

Disclosure statement

No potential conflict of interest was reported by the authors.