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Nanotechnology is the science of materials of sizes in the range of 1 - 100 nm (1-100 Ã- 10 âˆ’9 m). For instance, the sizes of some familiar matter are DNA, 1-2 nm; virus, 3 - 50 nm; and red blood cells, âˆ¼ 300 nm. At the nano scales, materials behave quite differently than it do at the macro sizes. Properties of material are different in both physical and chemical ones. Physical properties such as conductivity, magnetism, stability, and chemical reactivity might be different at the nano and macro scales due to the quantum mechanical physics properties of small structures at molecular dimensions. Nanotechnology provides a tool to produce particles with a high surface area to mass ratio and, together with their unique properties, may provide opportunities for more surface interactions and biochemical reactions [NG, et al 2009].
The role of nanosized material in medicine
Nanotechnology as a new technology became important recently. Researchers started finding new applications for nanotechnology in various fields of medicine investigation. One of the high interest nanotechnology applications in the field of medicine currently being developed involves using nanoparticles for drug delivery, heat delivery, light delivery, or other moieties to specific cell types (such as cancer cells). Particles are designed and engineered so that they are attracted by cancer cells selectively, which helpÂ direct treatment of those cells. The advantage of this technique is reduction of the damage to normal cells in the body and allows for earlier detection of disease. For example, nanoparticles that deliver chemotherapy drugs directly to cancer cells are under development. Tests are in progress for targeted delivery of chemotherapy drugs and their final approval for their use with cancer patients is pending [CytImmune Science's website]. CytImmune has published the preliminary results of a Phase 1 clinical trial of their first targeted chemotherapy drug. Researchers are trying to facilitate the delivery process using nanoparticles as carriers. The nanoparticle encapsulates the drug and helps the drug to pass through the stomach in order to carry the drug into the bloodstream. The size scale is the key point in this process. Recently, researchers are working on developing the methods for oral administration of various drugs by employing nanoparticles as tool.Â Clinical test stages of nanoparticles have been recently started using a drug for treating fungal infections. They used a special type of nanoparticle which is called cochleate. Oral drug delivery of drugs encapsulated in a nanocrystalline structure called a nanocochleate is another area which attracts new interest [BioDelivery Sciences].
The use of nanoparticles in "Therapy Techniques" is another recent field of interest. Nanoshells can be applied to focus the heat using infrared (IR) to demolish cancer cells with the advantage of minimal damage to near normal cells and tissues.Â A nanoshell is a type of spherical nanoparticle consisting of a dielectric core which is covered by a thin metallic shell (usually gold) (Loo, et al 2004). X-ray is another way of activation of nanoparticles which leads to the killing of cancer cells. This method could be an appropriate substitute instead of radiation therapy. The incorporated advantage of this method is much less damage and side effect to healthy cells and tissue. Imaging Techniques using Quantum Dots (qdots) can be employed in later works to locate cancer tumors in patients. Qdots are applicable for diagnostic tests and treatments application. However, up to this time the application in "in vivo" systems is not considerable with animals. Iron oxide nanoparticles can be employed to improve Magnetic Resonance Imagining (MRI) images for the cancer tumors. Designed nanoparticle is covered by s aquence of amino acids in a peptide that can specifically bind to a cancer tumor. Once the nanoparticles are attached to the tumor the magnetic property of the iron oxide enhances the images from the Magnetic Resonance Imagining scan. Nanoparticles modified with proteins or other biological substances are able to detect the disease at a very early stage.Â "Anti-Microbial Techniques" is another topic for nanotechnology applications. Nanocrystalline silver was one of the nanoparticle pioneers which used as an antimicrobial agent in the case of wounds healing [Nucryst Pharmaceuticals Corporation website]. Nanocrystal is any nanomaterial with at least one dimension â‰¤ 100nm and that is singlecrystalline (Fahlman, et al 2007). The nanoparticles contain nitric oxide gas, is known to kill bacteria. Nanoparticle cream is a cream consisting of drugs encapsulated in nanoparticles. The "in vivo" use of nanoparticle cream to generate nitric oxide gas at the site of staph abscesses significantly decreased the infection.
The application of nanotechnology in the field of medicine could revolutionize the way we detect and treat damage to the human body and disease in the future, and many techniques only imagined a few years ago are making remarkable progress towards becoming realities. Therefore, a growing interest in the field of nanotechnology can be
Synthesis of gold nanoparticles
Different types of gold nanoparticles have been synthesized based on various properties such as size, shape, and physical properties. Gold nanospheres (although not exactly spherical) are the first type of gold nanoparticles. Nanorods, nanoshells, and nanocages have all been reported after gold nanospheres. The term "gold nanoparticle(s)" refers to all types of gold nanoparticles including: nanospheres, nanorods, nanoshells, and nanocages. There is an increasing development in the case of synthesis methods in recent years. Recently, the methods have become sufficiently developed to synthesize gold nanoparticles with well-defined size, shape, and functionality.
The synthesis of gold nanospheres, (also introduced as gold colloids) with the diameter size of 2 nm to100 nm carried out by the reduction of aqueous HAuCl4 solution in the presence of various reducing agents such as natural or chemical under varying conditions. Citrate derivatives are used as the most common reducing agent which is able to produce monodisperse gold nanospheres (Turkevich et al 1951). The ratio of citrate to gold is a factor to control the size of the nanospheres. Basically, in the presence of a lesser amount of reducing agent, larger sized nanospheres will be obtained. The main drawback for this procedure is the low yield. Using the aqueous media for the synthesis of gold nanospheres is another disadvantage of this method. This method was further modified using a phase-transfer reagent such as tetraoctylammonium bromide (Brust et al 1994). Basically, phase transfer reagents are able to shift from aqueous phase to non-aqueous and opposite. The sizes of gold nanospheres are determined by the ratio of the amount of the thiol group to gold. Small-sized gold nanospheres are obtained when synthesized using a higher ratio of thiol/gold. An adsorption peak in the range visible from 510nm to 550 nm is the characteristic peak for the identification of gold nanospheres. In the formation of larger range of particles the peak is shifted to a longer wavelength. Also there is a relationship between the absorption spectra width and the size distribution range.
There are a wide range of reports for the synthesis of gold nanorods available in the literature. Typically, gold nanorods are synthesized using the template method. This method is based on the electrochemical deposition of gold within the pores of nanoporous polycarbonate or alumina template membranes (Martin et al 1994). There is a direct relationship between the diameter of the gold nanorod and pore diameter of the template membrane, but the nanorod length is dependent on the amount of gold deposited within the pores of the membrane. A major drawback of this protocol is the moderate/low yield of gold nanorod because only one monolayer of nanorods is prepared. Also, the synthesis of gold nanorods using electrochemical method has been reported (Reetz and Helbig 1994). In this approach, many experimental parameters can determine the length of the nanorod, thereby controlling its aspect ratio (defined as the length divided by the width).
The general method for synthesis of gold nanoshells includes the formation of the dielectric core moiety, which are silica or polystyrene and then chemical functionalization of their surface with amine groups to improve binding of small colloidal gold. Most of the times colloidal gold particles are synthesized by a separate method, on the amine terminated core to prepare a precursor particle for later growth of the polycrystalline gold shell in a well-defined procedure.
Up to now there are not many applications for gold nanoparticles as contrast agents for optical imaging in human studies. However, basic studies showed the absorbance of biomolecules in the near-infrared spectroscopic region (NIR; 700-900 nm) reaches a minimum which supports a promising future work for optical imaging (Frangioni 2003). Gold nanoshells can be synthesized with surface plasmon resonance (SPR) peaks in the range of visible to the NIR region (Oldenburg et al 1999). This modification is performed by a change in composition and dimensions of the layers. The SPR peak can be tuned by changing the ratio of the size of core to the shell width. By covering silica or polymer beads with gold shells in different thickness gold nanoshells with different SPR peaks in the NIR region can be prepared (Caruso et al 2001; Oldenburg et al 1998). In order to cover the nano sized silica with gold a seeded growth technique is employed. Gold nanospheres in the range size of (2-4 nm in diameter) can be introduced to the silica core by an amine-terminated silane. The advantage of this method is that additional gold can be reduced as long as the seed particles integrate into a full shell (Oldenburg et al 1999). The thickness of the gold nanoshell is relatively dependent on the diameter of the silica core. Shell diameter can be optimized by controlling the amount of the deposited gold on the core surface. Another route to synthesis of gold nanoshells is the "in-situ" gold nanoparticle method. In this method, thermo-sensitive core-shell particles used as the template (Suzuki and Kawaguchi 2005). Using a microgel as the core for the synthesis of nano shells has several advantages, such as decreasing the aggregation of particles, as well as diameter optimization of the gold nanoshells using electroless gold plating.
SERS is a new optical technique. This technique includes several advantages as compare to old methodologies, such as fluorescence and luminescence, higher sensitivity, multiplexing, power, stability, and efficiency in biological matrices like blood (Shah et al 2007). The silica coating improves the physical stability and makes them inert to different conditions. This modification is carried out by simple modification on the surface via silica chemistry.
The role of nanosized material in medicine
Gold nanoparticles have became an important research topic over the last couple of years. A simple search of the term "gold nanoparticle" in scientific websites returned more than hundreds of publications. Synthesis of gold nanoparticles was the first topic in this field which investigated by numerous researchers from various parts of the world. Recently, the major consideration of researchers is shifting to find some application for gold nanoparticles in different fields. Two main areas of gold nanoparticle use are "material science" and "biomedicine". Considerable achievements have been obtained in the material science arena. The use of gold nanoparticles as a catalyst for different reactions and the synthesis of new generations of material with specific properties are part of this recent progress. However, applications of gold nanoparticles in the field of biomedical have not accomplished the expectations. Gold nanoparticle-based agents are not commercialized for different treatment in clinical trial step so far. There is still a long way to go for gold nanparticle technology to be able to improve patient care as many have hoped it would. Gold nanoparticles have been studied in different areas including in vitro assays, in vitro and in vivo imaging, cancer therapy, and drug delivery.
In vitro assays
Oligonucleotide-capped gold nanoparticles have been used for the detection of polynucleotide or protein (such as p53, a tumor suppressor gene). Different methods to detect and characterize such as atomic force microscopy (AFM) (Han et al 2000; Jin et al 2007), gel electrophoresis (Qin and Yung 2007), chronocoulometry (Zhang et al 2007), amplified voltammetric detection (Wang et al 2008), SPR imaging (Li et al 2006), and Raman spectroscopy (Cao et al 2002) have been used. Bi-functional DNA-based adsorbate molecules have been evaluated as molecular rulers, based on the SERS signals that vary independently in intensity as a function of the distance from the gold nanoshell surface (Lal et al 2006). There are a number of other applications of gold nanoparticles such as immunoassay (Hirsch et al 2003), protein assay (Tang et al 2007), time of flight secondary ion mass spectrometry (Kim et al 2006), capillary electrophoresis (Tseng et al 2005), and detection of cancer cells. Basically, dynamic light scattering (DLS) used to measure the size of nanoparticles, the size distribution, and the charge on their surface. Recently, (DLS) was used as a tool to quantify the amount of intravenously injected gold nanoshells in the mouse blood stream (Xie et al 2007). This technique can also be useful for estimation of the half life time of other solid nanoparticles. Another modification on gold nanoshells is their functionalization with a pH-sensitive SERS reporter moiety, 4-mercaptopyridine, which made the nanoshell pH responsive to the environment in media between the ranges of 3 to 7 (Jensen et al 2007). One of the recent studies has introduced the application of gold nanoshells as optical biosensors for real-time detection of streptavidinbiotinm interactions in diluted human blood (Wang et al 2008). In order to increase the efficiency in several studies findings have been mixed. For the same model system different assays can be performed and concluded which can significantly help the candidates for potential clinical testing. Selection of an appropriate candidate in the early development stage not only conserves time, but also can significantly reduce the cost for new assay trials.
Cell and phantom imaging
Cell culture is the media that most of the imaging studies using gold nanoparticles were carried out in. Flexible gold nanoparticles optical properties have allowed optical imaging of cells and phantoms with a wide range of contrast mechanisms. The functional cellular imaging around single molecules is another application which used facilitated second harmonic signal by the conjugation of antibody and gold nanospheres (Peleg et al 1999). Many recent studies have been have been employed photothermal interference contrast (Cognet et al 2003), AFM (Yang et al 2005), dark-field imaging (Loo et al 2005a; Dunn and Spudich 2007), reflectance imaging (Sokolov et al 2003; Nitin et al 2007), as well as fluorescence and scanning electron microscopy. Gold nanorods have been employed for two-photon luminescence imaging of cancer cells in a 3D tissue phantom down to the 75 Î¼m depth (Durr et al 2007). There is a significant signal intensity difference between gold nanorod-labeled cancer cells and two-photon auto fluorescence emission from unlabeled cancer cells under 760 nm excitation. Because of this difference the fluorescent dyes conjugated gold nanoparticles have been used for fluorescence imaging of cells, using modification with certain targeting ligands (Nitin et al 2007). The main advantage of using gold nanoparticles in imaging is the absence of photo-bleaching or blinking, which is innate to several fluorophores. The major drawback of using of gold nanoparticles is their intensity. They are not as intense as known fluorescent dyes. Dark field light SPR scattering (Oyelere et al 2007) and photoacoustic imaging are other examples of use of gold nanorods for cell imaging techniques. Photoacoustic tomography (PAT) as a new technique of imaging employs light to heat elements within the tissue very fast. PAT uses photo-acoustic waves which produced from thermoelastic expansion and they can be detected by ultrasonic transducers. Recently, it was observed that near-IR gold nanoparticles absorption improves the image contrast, because of more significant differences in the case of optical absorption. This significant optical absorption is based on the fact that they can produce a strong photo-acoustic wave compared to the endogenous tissue chromophores. Photoacoustic imaging offers several advantages, such as various molecular targets that can be identified at the same time by various monoclonal antibodies conjugated with gold nanorod species. These gold nanorod species have dissimilar aspect ratios and, as such, they have different peak optical absorption at different wavelengths.
In vivo imaging
Different kinds of paramagnetic nano-sized particles have been employed for magnetic resonance (MR) imaging, in clinical test and preclinical test (Thorek et al 2006). Nanoshells were employed to improve the contrast of blood vessels in vivo condition. This study offered that nanoshells can be used in MR angiography as blood-pool agents (Su et al 2007). Activities of proteases and protease inhibitors in vitro media and in vivo condition were monitored by using protease sensitive self-quenched and gold nanosphere quenched probes (Lee et al 2008). Further development can be performed by using the same method to other proteases employing a certain peptide substrate as a spacer, and use of self-quenching properties of organic fluorescent dyes (Weissleder et al 1999). Gold nanoparticles as contrast agents have the best performance in Raman spectroscopy. Basically, Raman spectroscopy studies different low frequency modes in the system such as: vibational, rotational, and etc. The Raman spectra and Raman images of methylene blue molecules adsorbed as a single layer on gold nanospheres were found useful for studying the plasmon properties (Laurent et al 2005). Recently, all antibody combined with gold nanorods was employed to obtain a Raman spectrum which is improved, distincted, and polarized (Huang et al 2007). These studies used Raman imaging in "in vitro" conditions not in animals (in vivo).
Surgery, chemotherapy, and radiation therapy are traditional ways for cancer therapy. Gold nanoparticle as a new candidate for cancer therapy has been recently investigated. Because of gold nanoparticle unique properties, researchers used them for destruction of cancer cells or tumor tissues through photothermal therapy which looks promising to be tested in clinical studies. Similar studies have been investigated using gold nanospheres, nanorods, nanoshells, and nanocages for killing bacteria under the irradiation of a laser (Zharov et al 2006). Also, laser has been employed to irradiate to gold nanoparticles for destruction of cancer cells (Loo et al 2005). Light absorption increases the temperature of cells up to 70-80 Â°C and this is why cancer cells died. Several antibodies can be combined with nanoparticles using a PEG linker (Lowery et al 2006). One intriguing observation is that most of these studies targeted either EGFR or human epidermal growth factor receptor 2 (HER2), obviously due to the ready availability of monoclonal antibodies (already approved by the Food and Drug Administration [FDA] for cancer therapy) that recognize these two proteins. The assembly of gold nanoparticles on the cell membrane was studied to simulate the in vivo environment, since the absorbance wavelength which is in the visible range of certain size gold nanospheres is not optimized for in vivo applications. This assembly helps the researchers to track the place of the gold nanoparticles in the body of animals (Zharov et al 2005). Up to now, NIR laser is the most efficient tool for killing the cancer cells using gold nanoparticles. Due to the size of gold nanoshells which is in the range of 100nm to 300nm, they have a surface plasmon resonance peaks in the near-IR spectroscopic region.
Drug delivery is another field of application of gold nanoparticles. They are able to transport drugs into the cells efficiently. One of the applications of gold nanopaticles in drug delivery is PEG covered gold nanoparticle conjugated with Tumor necrosis factor-alpha (TNF-Î±). TNF-Î± is a cytokine which has a good anticancer activity, but the problem is that this agent is basically toxic which restricts its therapeutic use. PEG covered gold nanoparticle conjugated with TNF-Î± was designed to increase the tumor damage and decrease the toxicity (Visaria et al 2006). Local heat was combined with nanoparticle-based delivery of TNF-Î± and the therapeutic index was increased significantly. Nanoparticles were found to be efficient to postpone the proliferation of tumor using heat induced methods. The efficacy is determined by the dosage and timing which administered intravenously. The observations include:tumor blood flow restraint and perfusion flaw. Interestingly, no indication of aggregation in healthy organs was found in this vivo study (Paciotti et al 2004). Nanoparticles have also been employed to demolish the tumor. The advantage of this nano particles was that the toxicity was significantly low (Goel et al 2007). This compound is in Phase I clinical trials currently (termed "CYT-6091") to obtain safety, pharmacokinetics, pharmacodynamics, and efficacy.