Cell Biochem Biophys DOI 10.1007/s12013-015-0529-4

ORIGINAL PAPER

Gold Nanoparticles: Recent Advances in the Biomedical Applications Xiaoying Zhang

Ó Springer Science+Business Media New York 2015

Abstract Among the multiple branches of nanotechnology applications in the area of medicine and biology, Nanoparticle technology is the fastest growing and shows significant future promise. Nanoscale structures, with size similar to many biological molecules, show different physical and chemical properties compared to either small molecules or bulk materials, find many applications in the fields of biomedical imaging and therapy. Gold nanoparticles (AuNPs) are relatively inert in biological environment, and have a number of physical properties that are suitable for several biomedical applications. For example, AuNPs have been successfully employed in inducing localized hyperthermia for the destruction of tumors or radiotherapy for cancer, photodynamic therapy, computed tomography imaging, as drug carriers to tumors, bio-labeling through single particle detection by electron microscopy and in photothermal microscopy. Recent advances in synthetic chemistry makes it possible to make gold nanoparticles with precise control over physicochemical and optical properties that are desired for specific clinical or biological applications. Because of the availability of several methods for easy modification of the surface of gold nanoparticles for attaching a ligand, drug or other targeting molecules, AuNPs are useful in a wide variety of applications. Even though gold is biologically inert and thus shows much less toxicity, the relatively low rate of clearance from circulation and tissues can lead to health problems and therefore, specific targeting of diseased cells and tissues must be achieved before AuNPs find their application for routine human use.

X. Zhang (&) National Hepatobiliary and Enteric Surgery Research Center, Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, Hunan, People’s Republic of China e-mail: [email protected]

Keywords Gold nanoparticles  Photodynamic therapy  Nanomaterials  Nanomedicine  Photothermal therapy  Drug carriers

Introduction Nanoscale structures, because of their very small size, on a molecular scale, show different physical and chemical properties compared to either small molecules or bulk materials, and find multiple applications in the fields of biomedical imaging and therapy. Engineering Nanoparticle technology is one of the fastest growing areas of biomedical research. Nanoparticles have been successfully employed in hyperthermia or radiotherapy cancer treatments, photodynamic therapy, as drug carriers to tumors, bio-labeling through single particle detection by electron microscopy, and in photothermal microscopy. Interaction of nanomaterials or nanoparticles with the surrounding biological environment has an impact on their biological activity and a thorough understanding of the nature of these interactions is essential for proper designing of the nanoparticles for diagnostic and therapeutic purposes [1]. Because of the increased surface area, nanoparticles possess specific intrinsic reactivity and because of this, it is very important to make appropriate choice of materials for manufacturing the nanoparticle-based therapeutics [2]. Nanomaterials, using their surface functionalities and depending on the particle size and shape, and state of aggregation, can interact with biological systems in many ways depending on the cell type, employing different uptake routes or targeting different organelles. So far, only a few types of nanoparticles, e.g., liposomes and albumin nanoparticles have been approved as nanoparticle-based therapeutics in clinical practice [3]. Recent advances in nanotechnology led to the development

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of gold nanoparticles (Fig. 1), which have been employed in diverse biomedical applications, including diagnostic assays [4], drug and gene delivery to target tissues or tumors [5] and as enhancers/sensitizers of radiotherapy [6].

Interactions Between Nanoparticle and Biological Surface: The Bio-Nano Interface The interface at which the nanoparticles interact with biological systems, such as a cell surface, surface receptors, cytoplasmic proteins, nucleic acids, or cell organelles, at the nanoscale level is termed as ‘bio-nano interface.’ These interactions are dependent on the colloidal forces, dynamic biophysicochemical interplays, and thermodynamic exchanges between nanoparticle surface and the biological surface [7]. These interactions eventually govern the efficacy and impact of the nanoparticles, and therefore, complete understanding of these interactions is imperative when designing the nanoparticles to be used for a specific diagnostic/therapeutic activity. The ability of a nanoparticle to cross the cell membrane determines its potential toxicity. The plasma membrane or cell surface is entirely different from the surface of nanoparticles and presents a biological barrier to nanoparticles and displays a heterogeneous distribution of various membrane components. Nanoparticles derivatized with ligands such as antibodies, proteins, or organic chemicals specific to a given cell membrane-bound

Fig. 1 Diagrammatic representation of the gold nanoparticles (AuNPs), highlighting their main properties and their dependence with particle size and shape. Surface chemistry enables attachment with different ligands, drugs, and etc. Photoactivation of AuNPs is dependent on their size and shape and useful in radiosensitization and hyperthermia therapy of cancers. Z, atomic number of gold (Au); e, electrons in the gold atoms of the nanoparticle; S, sulfur atoms in thiols

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receptor are capable of targeting specific cells [8]. In fact, receptor patch interaction have been shown to play a major role in the uptake of nanoparticles, after the electrostatic, steric and Van der Waal’s forces that resist and prevent particle–cell membrane interactions are overcome [9]. Hydrophobicity of the nanoparticles also plays a role in membrane adhesion and penetration into cell and nanoparticles with hydrophobic character higher than the cell membrane itself can gain easily access to the cell interior. Thus, a nanoparticle with a many characteristics such as hydrophobicity, cationic nature, and surface protrusions is ideal for cell membrane interaction and uptake [10].

Gold Nanoparticles Gold nanoparticles are made in different sizes, shapes, and structures, depending on the application at hand (Fig. 2). Gold nanospheres (AuNPs) are solid balls of gold and are made by the reduction of chloroauric acid, and their diameter varies from 5 to [100 nm. AuNPs are useful for biomedical imaging and also for radiation dose enhancement. Another type of gold nanomaterials is Gold nanoshells (AuNSs) which are spherical structures. These are 50–150 nm in size and are comprised of a silica core with thin surrounding layer of gold. AuNSs find many applications in microscopy and imaging as their optical properties can be tuned by adjusting the core diameter and shell thickness [11]. Gold nanorods (AuNRs) are made using a gold seed and cetyltrimethylammonium bromide (CTAB) as a stabilizing agent, from chloroauric acid [12]. Other forms of gold nanoparticles include nanocages and hollow gold nanospheres and these structures have excellent plasmonic photothermal activities. The differences in size, shape, and surface properties of gold nanoparticles are manipulated for specific therapeutic purposes, depending on the nature of preclinical or clinical application. Gold nanoparticles are ideal for drug targeting and also for imaging-based detection of diseases at an early stage [13], because their sizes are smaller than the biological targets, which gives them interacting capability to specifically bind with biomolecules located either on the cell surface or inside the cell cytoplasm and cell organelles. Gold nanoparticles are not only easy to prepare but also highly versatile. They can be made in a range of sizes (Fig. 2) and shapes [14, 15]. Employing thiol ligands with hydrophilic functional groups, it has become possible to make gold nanoparticles that are capable of forming self-assembling monolayer (SAM) at the surface [16]. Such ligand molecule containing SAM formation on the surface of gold nanoparticles provides better advantages over using polymers, in terms of minimal changes in hydrodynamic particle diameter, avoidance of steric

Cell Biochem Biophys Fig. 2 Biomedical applications of gold nanoparticles. AuNPs, depending on their size and shape, can be used in a wide variety of biomedical applications ranging from biomedical imaging to targeted cancer therapy and vaccines. More recently applications in gene therapy are being tested

hindrance as well as the access of the nanoparticle to constrained biological spaces, which are critical for many biomedical applications. There are four critical physical and chemical properties, on the basis of which the AuNPs have been tested in many clinical studies: (i) chemical inertness; (ii) surface properties; (iii) electronic structure; and (iv) optical properties [17] (Fig. 1). The chemical inertness of AuNPs facilitates obtaining them in a wide range of shapes, without compromising the high stability and low toxicity and immunogenicity which are essential aspects in medical applications [18]. The high surface curvature and relatively low number of ligands capped on smaller AuNPs cause reduced flocculation, whereas the larger particles form insoluble aggregates.

The Structure of Gold Nanoparticles and Their Medical Application The electronic structure of AuNPs is central for their clinical applications, specifically in the areas of radiography and radiotherapy (Fig. 1). Considering that Au has higher number of electrons per atom (Z = 79), AuNPs are capable of absorbing the X-ray radiation energy at *1,000-fold higher probability as compared to any soft tissue. This property of AuNPs is useful in labeling cancer cells [19] and in enhanced radiotherapy [20]. Exposure of AuNPs with light causes in a collective oscillation of their conduction electrons, in resonance with the frequency of the absorbed light. AuNRs or AuNSs have optical properties of light absorbance and scattering in near-infrared wavelengths (650–900 nm) [21]. This phenomenon is called localized surface plasmon resonance (LSPR), which causes strong absorption and scattering bands in the visible near-infrared region of the electromagnetic spectrum. This process is also dependent on the size and shape of the AuNPs and LSPR forms an enhanced electric field at the gold nanoparticle

surface, which can be transformed into heat [22]. LSPRs render AuNPs as excellent sensitizers for light-related medical applications, including light-triggered drug delivery and photothermal therapies (PTT).

Gold Nanoparticles in Cancer Therapy Since the spaces in tumor vessels range from 100 nm to 2 lm and are larger than those in the endothelial lining of normal capillaries, AuNPs can easily gain access to the tumor vasculature and remain in tumors because of their disordered extracellular matrix and absence of lymphatic system. Gold nanoparticles were shown to cross the blood– brain barrier and accumulate in brain tumors in contrast to normal brain tissue [23]. However, in vivo, AuNP uptake by tumors is significantly curtailed because of the opsonization of the AuNPs with plasma proteins followed by phagocytosis by monocytes and macrophages. Because of this most of the injected AuNPs are retained in the liver and spleen. PEGylation of AuNPs can effectively minimize this uptake by macrophages and monocytes, by providing a ‘‘stealth’’ cloak to the nanoparticles [24] thereby prolonging their availability and concentration in tumor tissue. Experiments in mice showed that injection of AuNPs (1.9 nm; 2.7 g Au/kg body weight) could significantly enhance the radiotherapy of epithelial mesenchymal transition-mammary carcinomas. At this dosage, a tumor-tonormal-tissue gold concentration ratio of 8:1 could be achieved with nearly fourfold increase in survival by only one 6-min session of 256 kVp X-ray therapy (5 Gy/min) as compared to radiotherapy alone [25]. PTT functions by delivering local cytotoxic hyperthermia on cancer cells. In this approach, a photothermal contrast agent is employed for transferring the radiation energy to the tumor tissue. AuNPs, because of their optical properties, are currently used as photothermal contrast agents in clinical and preclinical trials for cancer treatment [26]. Localized AuNPs-mediated hyperthermia induced

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during a mild PTT, can induce apoptosis in cancer cells via denaturation of proteins and enzymes, metabolic signaling disruption, endothelial swelling, and etc. [27]. A combination of AuNP-based radiotherapy when combined with PTT can be more effective in reducing cancer burden and also lower the dosage of X-ray radiation required for the tumor destruction with much less exposure and damage to the surrounding normal tissue [28]. Gold nanoparticles are useful not only for imaging but also for treatment of breast cancer (Fig. 2). Use of AuNPs can be beneficial both for the therapy of early stage breast cancer disease and for the palliative control of more advanced breast tumors, because majority of the breast tumors occur relatively near the surface of the skin, where they can be easily accessed. Because of the cosmetic reasons and for lowering the risk of axillary lymph node dissection-associated lymphedema, there is a great demand and need for minimally invasive procedures to treat breast cancers. AuNPs-based hyperthermic therapy, while still experimental, can prove to be highly effective in the treatment of breast cancer and also the AuNP-dependent noninvasive imaging can be helpful in making decisions about axillary lymph node dissection for breast cancer cases involving positive sentinel lymph nodes [29].

Pharmacokinetics and Toxicology of Gold Nanoparticles Gut absorption of gold nanoparticles is very limited and thus their oral administration is not an efficient way for the particles to reach internal organs. On the other hand, C90 % of the intravenously administered gold nanoparticles may remain in the blood circulation for nearly 7 days or more, and eventually accumulating in the liver. The larger surface area-to-mass ratio of the nanoparticles, which makes them biologically more active, is an important property to keep in mind in terms of toxicity, as these particles show higher persistence in the body as compared to other pharmacological agents [30]. More recent studies showed the existence of clearing mechanisms that do not allow a build up of AuNPs, in spite of their repeated administration [31]. AuNPs (30-nm size) were shown to cause concentration dependent hemolysis, in vitro, without any platelet aggregation or altered ROS generation [32]. There was no evidence of overt acute toxicity in rabbits within 24 h after administration of AuNPs, and no organ specific changes were observed [33]. Chronic toxicity studies in dogs using AuNSs revealed transient weight loss with a complete recovery within 37 days, without any significant abnormalities in blood chemistry or hematology. Pathological examination of these dogs after 10 months showed some black pigmentation,

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possibly gold accumulation, in the Kupffer cells in the liver, in the red pulp of the spleen, and in the lymph nodes [34].

Gold Nanoparticles and Their Use in Vaccines AuNPs conjugated with carbohydrates and proteins have been employed in novel approaches toward the development of vaccines, as the glyco-conjugated AuNPs act as a scaffold for carrying a large amount of carbohydrate derivatives. Glyco-conjugated AuNPs (1–5 nm) capped with carbohydrate-based antigens that are present in cancer cells, such as Thomsen-Friedenreich disaccharide [35], sialyl-Tn and Lewis-Y [36], and Tn [37] have been tested for their immune response and were found to exhibit significantly higher immune response than the corresponding free carbohydrate.

Conclusions Gold nanoparticles, because of their different sizes and shapes offer a multitude of opportunities for their use in biomedical applications. The variety of synthetic methods for obtaining particles provides a versatile toolbox for producing conjugates with Gold nanoparticles with appropriate ligand conjugation with higher affinity for cell receptors, efficient cell and tumor internalization, and long circulation half-life. The physicochemical properties of AuNPs pave ways for better imaging and enhanced radiotherapy and PTT for cancer, development of novel vaccines, efficient methods for gene therapy, and enhanced LTDD-based chemotherapies. Even though gold is less toxic, health problems may arise from the relatively low rate of clearance from circulation and tissues and because of this approaches that increase the specific targeting of diseased cells must be standardized before AuNPs find their application for routine human use.

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Gold Nanoparticles: Recent Advances in the Biomedical Applications.

Among the multiple branches of nanotechnology applications in the area of medicine and biology, Nanoparticle technology is the fastest growing and sho...
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