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Cite this article: Murali K, Neelakandan MS, Thomas S (2018) Biomedical Applications of Gold Nanoparticles. JSM Nanotechnol Nanomed 6(1): 1064.

*Corresponding author

Karthika Murali, International and Inter University Center for Nanoscience and Nanotechnology, Mahatma Gandhi University, Kottayam, Kerala, India, Email:

Submitted: 02 June 2018Accepted: 22 June 2018Published: 29 June 2018

ISSN: 2334-1815

Copyright© 2018 Murali et al.

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Keywords•Gold nanoparticle•Nano-medicine•Drug delivery•Photothermal therapy•Photodynamic therapy•Bioimaging

Research Article

Biomedical Applications of Gold NanoparticlesKarthika Murali*, Neelakandan MS, and Sabu ThomasInternational and Inter University Center for Nanoscience and Nanotechnology, Mahatma Gandhi University, India

Abstract

Research interest on biocompatible gold nanoparticles has been highly increased in recent years for potential applications in nanomedicine due to their fascinating size-dependent chemical, electronic and optical properties. Gold nanoparticles (AuNPs) with their biological inertness combined with various physical properties have accomplished an astonishing impact in the biomedical field within a short span. Some of its relevant applications like photothermal therapy, drug delivery, photodynamic therapy, gene therapy, biolabeling, biosensing, etc., are revolutionizing the field of biomedicine that attracts enormous research attention. In this chapter, we are mainly discussing the current applications of gold nanoparticles in biomedicine and the properties that enable them to be a prospective candidate in the same field.

INTRODUCTIONNanomedicine is one of the vital and rapidly developing

fields of nanotechnology that accounts for a variety of potential applications [1,2]. Nanoscale structures have a size almost like many biological molecules, show completely different physical and chemical properties compared to either tiny molecules or bulk materials that exhibit a wide range of uses within the fields of medicine, imaging and diagnosis and therapy [3-8]. The biological activities of these structures are highly influenced by the surrounding environment that has got a significant role in the designing of these materials. Recently abundant attention has been given in controlling the shape and size of the nanostructure since all the magnetic, catalytic, electrical and optical properties of metal nanostructures are influenced by their shape and size [9-11]. Gold nanoparticles (AuNPs) are comparatively inert in the biologicalatmosphere and have a number of physical properties that are appropriate for many biomedical applications. The current uses of AuNPs in biomedical field includes photothermal therapy [12,13], drug delivery [14,15], photodynamic therapy [16], gene therapy [17-19], bio labeling [20], bio sensing [21,22], etc., (Figure 1). Gold nanoparticles (AuNPs) with controlled geometrical, optical, and surface chemical properties are the topic of intensive studies and applications in biology and drugs. Recent advances in synthetic chemistry make it possible to make gold nanoparticles with precise control over physicochemical and optical properties that are desired for specific clinical or biological applications. Even though gold is biologically inert and thus shows less toxicity, the comparatively low rate of clearance from circulation and tissues will result in health problems, and so, specific targeting of pathological cells and tissues should be achieved before AuNPs are used for biomedical applications.

Properties of gold nanoparticles are wine red solution that isentirelydifferent from bulk gold which is an inert yellow solid. Gold nanoparticles exhibit varied sizes starting from one nm to eight μm and they exhibit completely different shapes like spherical, sub-octahedral, octahedral, decahedral, polyhedron multiple twined, multiple twisted, irregular form, tetrahedral, nanotriangles, nanoprisms, hexagonal platelets, and nanorods. AuNPs are non-cytotoxic in nature with an additional advantage of a huge surface area, which makes their surfaces accessible for modification with targeting molecules, which make them advantageous over other nanoparticles for various biomedical applications. Gold nanoparticles have unique electric and magnetic properties due to their shape and size so they have been received great attention in research areas especially in the field of biological tagging, chemical and biological sensing, optoelectronics, photothermal therapy, biomedical imaging, DNA labelling, microscopy and photoacoustic imaging, surface-enhanced Raman spectroscopy, tracking and drug delivery, catalysis and cancer therapy. In the upcoming paragraphs, we discuss different biomedical applications of AuNPs in detail. Figure 2 gives the schematic representation of various therapeutic applications of gold nanostructures.

AuNps in Drug Delivery

When compared with traditional drug therapy, Targeted drug delivery is the most efficient one since it is possible to target only the affected cells or part. This minimizes the side effects of drugs. This is useful in treating diseases like cancer where the medicines can be delivered directly to the affected cells without damaging healthier cells in any way. Quantum dots [23], Fe3O4 [24,25] and ZnO [26] are effectively used for targeted drug delivery. Gold nanoparticles can be used for the bio-imaging of

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cancerous cells for treatment. Gold nanoparticles have a robust binding attraction for thiols [27], proteins [28], acid, aptamers [27] and disulfides so that they can easily bind with biomolecules like protein,amino acids, DNA sequences etc. Gold nanoparticles followed 3 main pathways for the cellular uptake consisting of receptor-mediated endocytosis, phagocytosis, and fluid phase endocytosis. The toxicity of gold nanoparticles depends on the size, shape, synthesis technique, surface charge, surface coating, and functionalized molecules however overall toxicity of gold nanoparticles is anacceptable level as gold nanoparticles are considered to be non-toxic agents. There are two factors, i.e. drug delivery and transport, which are vital for the economical drug delivery system. AuNPs can be engineered in different ways to detect a stimulus, such as molecular binding events or ionic concentration changes, and respond immediately by releasing cargo into the cells or tissue, degrading or even carrying out the chemical modification of drugs in vitro and in vivo.

Potential applications of AuNPs have been recently studied

and administrated in phase I & II clinical trials for cancer treatment [29]. The ease of tailoring AuNPs into different size, shape, and decorations with different functionalities encourages the researchers to explore the ultimate potentials of AuNPs for biomedicinal purposes, especially for drug delivery and imaging. The spherical AuNPs size (10nm) has a characteristic UV absorbance at 520nm, and the increase or decrease in sizes corresponds to red or blue shifts. As for gold nanorods (AuNPs), the absorbance will skew towards near infra-red range (690nm-900nm) [30]. These intrinsic optical properties provide the opportunity for AuNPs as composite theranostic agents in the clinic.

AuNPs in Biosensing and Bioimaging

AuNPs can be easily visualized by photometry and electron microscopy due to its high electron density, characteristic absorption well as scattering in the visible and NIR region, which make AuNPs as a potential candidate for cellular imaging and

Figure 1 Biomedical applications of Gold Nanoparticle.

Figure 2 (A) Various therapeutic applications of gold nanostructures. (B) Schematic presentation of two gold nanoparticle surface structures commonly employed in delivery applications.

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biosensing and labelling. The various types of sensors exploit the optical properties (light absorption, scattering, fluorescence, reflectance, Raman scattering, and refractive index) of either bulk gold or individual nanoparticles [31]. Gold nanoparticles have been used as contrast agents in cellular or molecular imaging for a long time. The most common imaging techniques to visualize the intracellular organelles are an electron and confocal microscopy [32]. Owing to their high-electron density AuNP is an established candidate in electron microscopy for a long time. With advancement in technologies, many other methodologies like TPL imaging, came to deal with AuNPs to locate a target cell or molecule [32]. A novel sensor for the colourimetric detection of Salmonella typhimurium based colour change effect of gold nanoparticles was developed by Ma et al. [33]. Gold nanoparticles were functionalized with aptamers capable recognize S. typhimurium which acted as stabilizers for the AuNPs even at high concentrations of NaCl. In the presence of the S. Typhimurium bacteria the aptamers present on the nanoparticle surface bind to the bacteria which results in the aggregation of the AuNPs, thus a visible colour change [33].

Gold nanoparticles are extensively used in biosensing applications these days [21,22]. Determination of blood glucose level [34], detection of bacteria [35], viruses etc, detection of pollutants [36] and monitoring pathogens [37] can be effectively carried out by biosensing. A biosensor provides selective quantitative or semi-quantitative analytical information using a biological recognition element. Biological molecules such as antibodies, carbohydrates, nucleic acids, enzymes, etc., are employed as biological recognition elements. The general principle of a biosensor is associated with the transformation of changes associated with the binding of the analyte to the bioreceptors into optical, electrical or qualitative output signals with different signal transducers [38]. AuNPs can be effectively used in various biosensors as transducer due to its noble optoelectronic properties. The various roles that AuNPs play in different biosensors are listed in Table 1 [38].

A peculiarity of current use of the electron microscopic technique is the application of high-resolution transmission electron microscopes and systems for the digital recording and processing of images. The major application of immunoelectron microscopy in present-day medical and biological research is the identification of infectious agents and their surface antigens [21]. The techniques often employed for the same purposes include scanning atomic-force, scanning electron, and fluorescence microscopes [21].

For optical biosensing utilizing AuNPs, the optical properties provide a wide range of opportunities, all of which ultimately arise from the collective oscillations of conduction band electrons (‘‘plasmons’’) in response to external electromagnetic radiation. The most common optical sensing modalities for AuNP is the surface plasmon resonance (SPR) which in simple words is optical phenomenon arising from the interaction between an electromagnetic wave and the conduction electrons in themetal. Apart from SPR-based biosensors, AuNPs are also incorporated into other optical structures, like, interferometer-based biosensors [21]. Rosana AS and coworkers developed a nanostructured piezoelectric immunosensor for detection of

human cardiac Troponin T. Anti-human troponin T (anti-TnT) antibodies were covalently immobilized on the nanostructured electrode surface by thiol-aldehyde linkages [39]. In a solution, anti-TnT fixed in the QCM electrode capture TnT [39]. There is also gold nanoparticle related electrochemical biosensors made by coupling biological recognition elements with gold nanoparticle-modified electrochemical transducers. Gold nanoparticles can be deposited onto the transducer surface using electrochemical methods or by physical attachment procedures.

PHOTOTHERMAL THERAPYPhotothermal therapy is an effective therapeutic technique to

treat diseases like cancer. Here nanoparticles incorporated into tumour cells generate heat in response to light which is supplied externally. AuNP is widely employed for PTT because of a variety of reasons. These reasons are mentioned in the following sentences. AuNPs offer a variety of advantages including:

(1) Biocompatible nature with less cytotoxicity.

(2) Tiny dimensions that allowtumour penetration upon systemic delivery,

(3) Simple chemistry for the attachment of biomolecules,

(4) Light-to-heat conversion, and

(5) Tunability to absorb NIR light, that enters cells more efficiently.

One of the greatest benefits of PTT in cancer therapy, when compared with other conventional therapies, is the specificity of the treatment. Other techniques are unspecific in nature that ultimately leads to the destruction of the healthy cells along with the cancerous cells. In order to use for photothermal therapy, AuNPs must fulfil certain criteria, and properties like AuNPs used in photothermal applications must meet several properties such as having plasmon resonance tunability, high photothermal conversion efficiency, and simple surface functionalization or encapsulation chemistry. Based on these design criteria, nanoshells (NSs), nanorods (NRs), nanocages (NCs), and nanostars have emerged as the most common photothermal transducers. Huan li et al. [40], have an interesting work report on “mixed-charge self-assembled monolayers” as a facile method to design pH-induced aggregation of large gold nanoparticles for near-infrared photothermal cancer therapy. They introduced a facile way to endow gold nanoparticles (AuNPs) especially those large ones with tunable pH-aggregation behaviours by modifying the nanoparticle surface with mixed-charge self-assembly monolayers (SAMs) compromising positively and negatively charged thiol ligands [40]. Figure 4 represents the schematic illustration of MC-AuNPs aggregation in a tumour acidic pH-induced manner for photothermal cancer therapy.

PHOTODYNAMIC THERAPYPhotodynamic therapy (PDT), has been utilized for

the treatment for a spread of oncological, cardiovascular, dermatologic and ophthalmic diseases. It includes a mix of 2 basic therapeutic elements: a photosensitizer (PS) drug and a nonthermallight. Light irradiation elevates ps to an excited state where this energy is later transferred to molecular oxygen to form reactive oxygen species (ROS), primarily composed

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Figure 3 (a) TEM image of a Listeria monocytogenes cell labeled with an antibody-colloidal gold conjugate (b) A scanning atomic-force microscopy image of tobacco mosaic virus labeled with an antibody- colloidal gold conjugate [21].

Figure 4 Schematic illustration of MC-AuNPs aggregation in a tumor acidic pH-induced manner for photothermal cancer therapy [40].

Table 1: Different functions of AuNPs in Biosensor systems [38].

Types of biosensors Principle of detection Functions of GNPs Properties used Sensor

advantages Typical examples

Optical biosensor Changes in optical properties

Enhancement of refractive index

changesEnhancement of electron transfer

large dielectric constant, high density, high molecular weightConductivity, quantum

dimension

Improved sensitivityImproved sensitivity

DNA sensor with GNPs responses 1000 times more sensitive than

withoutElectron transfer rate of 5000 per second with GNPs, while 700 per

second without GNPs

Electrochemical biosensor

Changes in electrical

characteristics

Immobilization platform

Catalysis of reactions

Biocompatibility, large surface area

High surface energy, interface-dominated

properties

Improved sensitivity and

stabilityImproved

sensitivity and selectivity

Glucose biosensor with GNPs achieves detection limit of 0.18 µMNADH sensor based on GNPs shows

780 mV over potential decrease without any electron transfer

mediators

Piezoelectric biosensor Changes in mass

Biomolecule Immobilization,

amplification of mass change

Biocompatibility, high density, Large surface-

to-volume ratio

Improved sensitivity

DNA sensor using GNPs as amplification tags with detection

limit of 10-16 mol/L

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of singlet oxygen, then induces each apoptosis and necrosis that ultimately leads to the destruction of affected cells. Lack of suitable PS is limiting the use of PDT to emerge into the mainstream for cancer treatment, blessed with its superior optoelectronic properties, biocompatible nature, and high scope of surface functionalization, AuNPs can be an effective candidate as a ps. Yaminyang and coworkers [41] found out that AuNPs can enhance 5-aminolevulinic acid (5-ALA)-induced ROS formation and the enhancement is size-dependent and can be further improved by the intracellular formation of gold nano-aggregates, which suggest that plasmonic AuNPs may amplify photonic energy absorbed and then transfer the energy to neighboring PSfor enhancing ROS formation [41].

Maldonado-Alvarado Elizabeth et al. [42], determined the efficiency of PDT using AuNPs and protoporphyrin IX (PpIX) induced and not induced by the aminolevulinic acid (ALA). It was found the conditions of synthesis of hydrosoluble AuNP and were characterized by transmission electronic microscopy (TEM) and UV-VIS spectroscopy. It was realized a kinetic by TEM to determine the cellular incorporation time of AuNP, the maximum incorporation of np-Au was 16 h. PDT was applied using different doses of np-Au and photosensitizers. It was observed that the use of PDT simultaneously with AuNP did not increase the mortality of HeLa cells [42]. The adoption of functionalized Au NPs in current cancer PDT represents a promising strategy to enhance therapeutic effectiveness and improve treatment selectivity. Targeted delivery of Au NPs into mitochondria provides vital steerage and critical proof on the effectiveness of intracellular targeting for any optimisation of drug delivery and improvement of therapeutic efficaciousness. Additionally, the surface plasmonic resonance of AuNPs will be extended to the near-infrared range by calibrating their structures, probably enabling PDT with deep light penetration [42].

CONCLUSIONOwing to the success of the fast development of technologies

for the chemical synthesis of AuNPs throughout the past decade, investigators presently have at their disposal a colossal diversity of accessible particles with needed parameters in respect of size, shape, structure, and optical properties. Moreover, the question that currently on the agenda is that the primary modeling of a nanoparticle with desired properties and also the subsequent development of a procedure for the synthesis of a theoretically foreseen nanostructure. Gold nanoparticles (AuNPs) are comparatively inert in the biologicalatmosphere and have a number of physical properties that are appropriate for many biomedical applications. The current uses of AuNPs in the biomedical field include photothermal therapy, drug delivery, photodynamic therapy, gene therapy, biolabelling, photodynamic therapy, biosensing, etc. It is ought to be stressed that AuNPs are biodegradable. Therefore, the biodistribution and excretion dynamics have to be compelled to be studied comprehensively for various animal models. Because the excretion of accumulated particles from the liver and spleen will take up to 3-4 months, the question on the injected doses and doable inflammation processes continues to be of vital importance. Bioaccumulated AuNPs will interfere with completely different diagnostic techniques, or accumulated AuNPs will exhibit catalytic properties. All these

concerns, in conjunction with potential toxicity, are massive limitations of AuNPs on a successful clinical translation.

In summary, there should be more effort for an effective research a to establish correlations between the particle parameters (size, shape, and functionalization with various molecular probes), the experimental parameters (model; doses; method and time schedule of administration; observation time; organs, cells and subcellular structures examined; etc.), and the observed biological effects.

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