Multifunctional superparamagnetic iron oxide

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Cancer Letters 336 (2013) 8–17

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Multifunctional superparamagnetic iron oxide nanoparticles: Promising tools in cancer theranostics Poornima Budime Santhosh a, Nataša Poklar Ulrih a,b,⇑ a b

Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, 1000 Ljubljana, Slovenia Centre of Excellence for Integrated Approaches in Chemistry and Biology of Proteins (CipKeBiP), Jamova 39, 1000 Ljubljana, Slovenia

a r t i c l e

i n f o

Article history: Received 22 January 2013 Received in revised form 23 April 2013 Accepted 29 April 2013

Keywords: Cancer Superparamagnetic nanoparticles Targeting Imaging Anticancer drugs

a b s t r a c t Iron-oxide nanoparticles of small dimensions that have superparamagnetic properties show immense potential to revolutionize the future of cancer theranostics, the combinatorial diagnosis and therapeutic approach towards cancer. Superparamagnetic iron-oxide nanoparticles (SPIONs) have unique magnetic properties, due to which they show excellent tumor-targeting efficiency, and this paves the way for effective personalized cancer treatment. The aim of this review is to focus on the ability of SPIONs to perform multiple roles in the field of cancer biology, such as in diagnosis, monitoring, targeting and therapy. Also, other topics are discussed, including the synthesis of SPIONs, the challenges and recent advances. Ó 2013 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Cancer includes a range of diseases that arise as a result of unregulated growth and spread of malignant cells. Cancer-related deaths are projected to increase in the future, with the World Health Organization (WHO) estimating about 13.1 million cancer-related deaths by the year 2030 [1]. To control this growing burden and to improve the quality of life of cancer patients, novel technologies with high tumor targeting and drug delivery efficacies are being conceptualized. Research and development in the areas of nanoscience and nanotechnology provide more innovative and effective approaches in various areas of cancer research, like diagnosis [2,3], monitoring [4,5] and therapy [6–8]. An emerging trend in this direction is ‘cancer nanotheranostics’, which includes the simultaneous imaging and effective treatment of cancer cells through the application of nanoparticles [9]. This is a very efficient method that aims to eliminate the multi-step procedures, reduce the delays in treatment, and pave the way for personalized medicine. Among the different types of nanoparticles, superparamagnetic iron-oxide nanoparticles (SPIONs) are considered to be promising candidates in cancer theranostics due to their superparamagnetic behavior and surface-modification properties. When the size of

⇑ Corresponding author at: Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, 1000 Ljubljana, Slovenia. Tel.: +386 1 3230780; fax: +386 1 2566296. E-mail address: [email protected] (N.P. Ulrih). 0304-3835/$ - see front matter Ó 2013 Elsevier Ireland Ltd. All rights reserved.

iron-oxide nanoparticles is reduced to a few nanometers (1– 20 nm), they are forced to have a single domain and become superparamagnetic [10]. In contrast to multiple-domain ferromagnetic materials that retain their magnetism even after the removal of the magnetic field, SPIONs lose their magnetization and become highly dispersed when the magnetic field is switched off [11]. This feature is very important in clinical applications, because if the nanoparticles tend to aggregate, they can be easily recognized and engulfed by macrophages, thereby rendering them unavailable for disease treatment. The multifunctional abilities of engineered SPIONs have profound impact on various fields of cancer therapeutics. They have the potential to improve contrasting features in magnetic resonance imaging (MRI) [3], drug delivery [7], and hyperthermia [8]. Due to their smaller size and hence greater surface to volume ratio, and flexible surface-modification properties, they have improved binding kinetics to a variety of substances. As SPIONs are biodegradable and biocompatible, they find applications in various biomedical fields, such as magnetofection [12], gene therapy [13], cell and biological material separation [14]. SPIONs are mostly magnetite (Fe3O4), and when they are exposed to oxygen, they are converted to maghemite (c-Fe2O3). They can be metabolized easily and transported by proteins like ferritin, transferritin and hemosiderin, and they can be stored in endogenous iron reserves of the body for later use. The benefit of applying a magnetic field to guide the nanoparticles for their targeting is to reduce drug wastage, to lower the frequency of drug administration, and to avoid unwanted side-effects

P.B. Santhosh, N.P. Ulrih / Cancer Letters 336 (2013) 8–17

to the regions surrounding a tumor [15]. SPIONs have been recognized as being very promising materials for biomedical applications due to the following factors. The extensive surface area of SPIONs enables the possibility of increased covalent attachment with various receptors, peptides, antibodies or ligands, to bind to specific targets and to release their drug at an appropriate dose, termed as ‘controlled drug release’ [16]. This technique has many advantages over traditional chemotherapeutic drugs, which are relatively nonspecific and need larger doses for treatment. Drugloaded multifunctional SPIONs can be selectively targeted to an organ, tissue or cell type, thereby minimizing drug exposure to the surrounding region [17]. SPIONs grafted to high-affinity ligands and molecular markers have important roles in ‘molecular imaging’, a technique that enables to visualize and follow the changes in metabolic pathways and functions of cells in a detailed manner [18]. The success of SPIONs in cancer biology depends on their ability to overcome the hurdles in this field, and to bring innovative and beneficial studies, such as the development of novel anticancer vaccines, extended nanoparticle half-life inside biological systems, and development of cell-based delivery systems. This article aims to provide a broad overview of SPIONs, along with their properties and widespread applications in biomedical fields. Our growing knowledge of magnetic nanoparticles enables specialized studies to be carried out in a multi-disciplinary environment. 1.1. Desirable features of SPIONs For any biological application, the nanoparticles need to be biocompatible, non-toxic and stable at physiological pH. The ideal features of SPIONs for cancer management should have: (1) High magnetization and narrow size distribution. (2) Contrast enhancement properties for imaging and tracking of malignant cells/tissues. (3) Surface coating with biodegradable material, to minimize nanoparticle aggregation. (4) Ability to conjugate with a range of receptors, functional groups and drugs. (5) High targeting and drug-delivery efficiencies [7]. (6) Optimized zeta-potential values. (7) Increased half-life. (8) Ability to respond to stimuli (e.g., magnetic field, heat, pH).


which increases the temperature of the surrounding region. This property is exploited in magnetic hyperthermia, to destroy cancer cells [8]. 2. Synthesis of SPIONs Depending upon the specific requirements, SPIONs can be synthesized by various techniques. Co-precipitation is by far the simplest and universally used method to prepare SPIONs. The synthesis of magnetic nanomaterials occurs when ferrous and ferric salts are co-precipitated in aqueous solutions [21]. The overall reaction is depicted in the following:

2Fe3þ þ Fe2þ þ 8OH ! Fe3 O4 þ 4H2 O Maghemite (cFe2O3) is formed instantaneously on exposure to oxygen:

4Fe3 O4 þ O2 ! 6cFe2 O3 The advantages of the co-precipitation method are rapid synthesis, versatility, and high yield of nanoparticles with the desired morphology and characteristics. On the other hand, the disadvantages include large particles of varying diameters, polydispersion, and poor crystallization, which can result in low saturation magnetization levels [7]. Microemulsions are formed when the dispersions of colloidal substances (e.g., water in oil, or oil in water) are stabilized with the help of surfactants. These emulsions can then be conveniently used as nano-devices, to carry out the chemical reactions [22]. This method has the advantage of yielding very small nanoparticles with uniform morphology. The poor yield of the nanoparticles and the large amounts of solvent requirements are the major drawbacks of this method. Thermal decomposition of iron precursors in the presence of hot organic surfactants is another widely used method for SPION production [23]. SPIONs produced by this method have high monodispersion rate, good crystallinity, and a narrow size range. The hydrothermal method, which is considered to be one of the oldest methods, produces SPIONs by heating the precursors of iron in aqueous solutions under controlled temperature and pressure conditions [24]. A new approach uses microwaves to synthesize SPIONs of uniform size, and this can be used for large-scale processes [25]. Another recent approach to produce monodispersed nanoparticles is by the application of sonochemical routes [26].

1.2. Superparamagnetism 2.1. Surface modification of SPIONs In general, molecular imaging probes consist of nanoparticles that have been functionalized with a targeting agent. Magnetism is a property of the response of a material in a magnetic arena. A few elements are strongly magnetic (e.g., Fe, Ni, Co), whereas others are weakly magnetic (e.g., Mg, Li, Mo). Bulk iron oxide materials contain multiple domains and express strong ferromagnetic behavior. Interestingly when their size is reduced (

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