Biomedical Applications Of Gold Nanoparticles

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Central Bringing Excellence in Open AccessJSM Nanotechnology & NanomedicineResearch Article*Corresponding authorBiomedical Applications of GoldNanoparticlesKarthika Murali*, Neelakandan MS, and Sabu ThomasKarthika Murali, International and Inter UniversityCenter for Nanoscience and Nanotechnology,Mahatma Gandhi University, Kottayam, Kerala, India,Email:Submitted: 02 June 2018Accepted: 22 June 2018Published: 29 June 2018ISSN: 2334-1815International and Inter University Center for Nanoscience and Nanotechnology,Mahatma Gandhi University, IndiaCopyright 2018 Murali et al.AbstractOPEN ACCESSResearch interest on biocompatible gold nanoparticles has been highly increasedin recent years for potential applications in nanomedicine due to their fascinating sizedependent chemical, electronic and optical properties. Gold nanoparticles (AuNPs) withtheir biological inertness combined with various physical properties have accomplishedan astonishing impact in the biomedical field within a short span. Some of its relevantapplications like photothermal therapy, drug delivery, photodynamic therapy, genetherapy, biolabeling, biosensing, etc., are revolutionizing the field of biomedicine thatattracts enormous research attention. In this chapter, we are mainly discussing the currentapplications of gold nanoparticles in biomedicine and the properties that enable themto be a prospective candidate in the same field.INTRODUCTIONNanomedicine is one of the vital and rapidly developingfields of nanotechnology that accounts for a variety of potentialapplications [1,2]. Nanoscale structures have a size almost likemany biological molecules, show completely different physicaland chemical properties compared to either tiny moleculesor bulk materials that exhibit a wide range of uses within thefields of medicine, imaging and diagnosis and therapy [3-8]. Thebiological activities of these structures are highly influenced bythe surrounding environment that has got a significant role inthe designing of these materials. Recently abundant attention hasbeen given in controlling the shape and size of the nanostructuresince all the magnetic, catalytic, electrical and optical propertiesof metal nanostructures are influenced by their shape and size[9-11]. Gold nanoparticles (AuNPs) are comparatively inert in thebiologicalatmosphere and have a number of physical propertiesthat are appropriate for many biomedical applications. Thecurrent uses of AuNPs in biomedical field includes photothermaltherapy [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 controlledgeometrical, optical, and surface chemical properties are thetopic of intensive studies and applications in biology and drugs.Recent advances in synthetic chemistry make it possible to makegold nanoparticles with precise control over physicochemicaland optical properties that are desired for specific clinical orbiological applications. Even though gold is biologically inert andthus shows less toxicity, the comparatively low rate of clearancefrom circulation and tissues will result in health problems, andso, specific targeting of pathological cells and tissues should beachieved before AuNPs are used for biomedical applications.Keywords Gold nanoparticle Nano-medicine Drug delivery Photothermal therapy Photodynamic therapy BioimagingProperties of gold nanoparticles are wine red solution thatisentirelydifferent from bulk gold which is an inert yellow solid.Gold nanoparticles exhibit varied sizes starting from one nmto eight μm and they exhibit completely different shapes likespherical, sub-octahedral, octahedral, decahedral, polyhedronmultiple twined, multiple twisted, irregular form, tetrahedral,nanotriangles, nanoprisms, hexagonal platelets, and nanorods.AuNPs are non-cytotoxic in nature with an additional advantageof a huge surface area, which makes their surfaces accessiblefor modification with targeting molecules, which make themadvantageous over other nanoparticles for various biomedicalapplications. Gold nanoparticles have unique electric andmagnetic properties due to their shape and size so they havebeen received great attention in research areas especially inthe field of biological tagging, chemical and biological sensing,optoelectronics, photothermal therapy, biomedical imaging,DNA labelling, microscopy and photoacoustic imaging, surfaceenhanced Raman spectroscopy, tracking and drug delivery,catalysis and cancer therapy. In the upcoming paragraphs,we discuss different biomedical applications of AuNPs indetail. Figure 2 gives the schematic representation of varioustherapeutic applications of gold nanostructures.AuNps in Drug DeliveryWhen compared with traditional drug therapy, Targeteddrug delivery is the most efficient one since it is possible to targetonly the affected cells or part. This minimizes the side effects ofdrugs. This is useful in treating diseases like cancer where themedicines can be delivered directly to the affected cells withoutdamaging healthier cells in any way. Quantum dots [23], Fe3O4[24,25] and ZnO [26] are effectively used for targeted drugdelivery. Gold nanoparticles can be used for the bio-imaging ofCite this article: Murali K, Neelakandan MS, Thomas S (2018) Biomedical Applications of Gold Nanoparticles. JSM Nanotechnol Nanomed 6(1): 1064.

Murali et al. (2018)E-mail: Central Bringing Excellence in Open AccessFigure 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.cancerous cells for treatment. Gold nanoparticles have a robustbinding attraction for thiols [27], proteins [28], acid, aptamers[27] and disulfides so that they can easily bind with biomoleculeslike protein,amino acids, DNA sequences etc. Gold nanoparticlesfollowed 3 main pathways for the cellular uptake consisting ofreceptor-mediated endocytosis, phagocytosis, and fluid phaseendocytosis. The toxicity of gold nanoparticles depends on thesize, shape, synthesis technique, surface charge, surface coating,and functionalized molecules however overall toxicity of goldnanoparticles is anacceptable level as gold nanoparticles areconsidered to be non-toxic agents. There are two factors, i.e.drug delivery and transport, which are vital for the economicaldrug delivery system. AuNPs can be engineered in different waysto detect a stimulus, such as molecular binding events or ionicconcentration changes, and respond immediately by releasingcargo into the cells or tissue, degrading or even carrying out thechemical modification of drugs in vitro and in vivo.Potential applications of AuNPs have been recently studiedJSM Nanotechnol Nanomed 6(1): 1064 (2018)and administrated in phase I & II clinical trials for cancertreatment [29]. The ease of tailoring AuNPs into different size,shape, and decorations with different functionalities encouragesthe researchers to explore the ultimate potentials of AuNPsfor biomedicinal purposes, especially for drug delivery andimaging. The spherical AuNPs size (10nm) has a characteristicUV absorbance at 520nm, and the increase or decrease in sizescorresponds to red or blue shifts. As for gold nanorods (AuNPs),the absorbance will skew towards near infra-red range (690nm900nm) [30]. These intrinsic optical properties provide theopportunity for AuNPs as composite theranostic agents in theclinic.AuNPs in Biosensing and BioimagingAuNPs can be easily visualized by photometry and electronmicroscopy due to its high electron density, characteristicabsorption well as scattering in the visible and NIR region, whichmake AuNPs as a potential candidate for cellular imaging and2/6

Murali et al. (2018)E-mail: Central Bringing Excellence in Open Accessbiosensing and labelling. The various types of sensors exploitthe optical properties (light absorption, scattering, fluorescence,reflectance, Raman scattering, and refractive index) of eitherbulk gold or individual nanoparticles [31]. Gold nanoparticleshave been used as contrast agents in cellular or molecularimaging for a long time. The most common imaging techniques tovisualize the intracellular organelles are an electron and confocalmicroscopy [32]. Owing to their high-electron density AuNP isan established candidate in electron microscopy for a long time.With advancement in technologies, many other methodologieslike TPL imaging, came to deal with AuNPs to locate a target cellor molecule [32]. A novel sensor for the colourimetric detectionof Salmonella typhimurium based colour change effect of goldnanoparticles was developed by Ma et al. [33]. Gold nanoparticleswere functionalized with aptamers capable recognize S.typhimurium which acted as stabilizers for the AuNPs even at highconcentrations of NaCl. In the presence of the S. Typhimuriumbacteria the aptamers present on the nanoparticle surface bind tothe bacteria which results in the aggregation of the AuNPs, thus avisible colour change [33].Gold nanoparticles are extensively used in biosensingapplications these days [21,22]. Determination of blood glucoselevel [34], detection of bacteria [35], viruses etc, detection ofpollutants [36] and monitoring pathogens [37] can be effectivelycarried out by biosensing. A biosensor provides selectivequantitative or semi-quantitative analytical information usinga biological recognition element. Biological molecules suchas antibodies, carbohydrates, nucleic acids, enzymes, etc., areemployed as biological recognition elements. The generalprinciple of a biosensor is associated with the transformationof changes associated with the binding of the analyte to thebioreceptors into optical, electrical or qualitative output signalswith different signal transducers [38]. AuNPs can be effectivelyused in various biosensors as transducer due to its nobleoptoelectronic properties. The various roles that AuNPs play indifferent biosensors are listed in Table 1 [38].A peculiarity of current use of the electron microscopictechnique is the application of high-resolution transmissionelectron microscopes and systems for the digital recording andprocessing of images. The major application of immunoelectronmicroscopy in present-day medical and biological research is theidentification of infectious agents and their surface antigens [21].The techniques often employed for the same purposes includescanning atomic-force, scanning electron, and fluorescencemicroscopes [21].For optical biosensing utilizing AuNPs, the optical propertiesprovide a wide range of opportunities, all of which ultimatelyarise from the collective oscillations of conduction bandelectrons (‘‘plasmons’’) in response to external electromagneticradiation. The most common optical sensing modalities forAuNP is the surface plasmon resonance (SPR) which in simplewords is optical phenomenon arising from the interactionbetween an electromagnetic wave and the conduction electronsin themetal. Apart from SPR-based biosensors, AuNPs are alsoincorporated into other optical structures, like, interferometerbased biosensors [21]. Rosana AS and coworkers developed ananostructured piezoelectric immunosensor for detection ofJSM Nanotechnol Nanomed 6(1): 1064 (2018)human cardiac Troponin T. Anti-human troponin T (anti-TnT)antibodies were covalently immobilized on the nanostructuredelectrode surface by thiol-aldehyde linkages [39]. In a solution,anti-TnT fixed in the QCM electrode capture TnT [39]. There is alsogold nanoparticle related electrochemical biosensors made bycoupling biological recognition elements with gold nanoparticlemodified electrochemical transducers. Gold nanoparticles canbe deposited onto the transducer surface using electrochemicalmethods or by physical attachment procedures.PHOTOTHERMAL THERAPYPhotothermal therapy is an effective therapeutic technique totreat diseases like cancer. Here nanoparticles incorporated intotumour cells generate heat in response to light which is suppliedexternally. AuNP is widely employed for PTT because of avariety of reasons. These reasons are mentioned in the followingsentences. AuNPs offer a variety of advantages including:(1) Biocompatible nature with less cytotoxicity.(2) Tiny dimensions that allowtumour penetration uponsystemic delivery,(3) Simple chemistry for the attachment of biomolecules,(4) Light-to-heat conversion, and(5) Tunability to absorb NIR light, that enters cells moreefficiently.One of the greatest benefits of PTT in cancer therapy, whencompared with other conventional therapies, is the specificityof the treatment. Other techniques are unspecific in nature thatultimately leads to the destruction of the healthy cells along withthe cancerous cells. In order to use for photothermal therapy,AuNPs must fulfil certain criteria, and properties like AuNPsused in photothermal applications must meet several propertiessuch as having plasmon resonance tunability, high photothermalconversion efficiency, and simple surface functionalizationor encapsulation chemistry. Based on these design criteria,nanoshells (NSs), nanorods (NRs), nanocages (NCs), andnanostars have emerged as the most common photothermaltransducers. Huan li et al. [40], have an interesting work reporton “mixed-charge self-assembled monolayers” as a facile methodto design pH-induced aggregation of large gold nanoparticles fornear-infrared photothermal cancer therapy. They introduced afacile way to endow gold nanoparticles (AuNPs) especially thoselarge ones with tunable pH-aggregation behaviours by modifyingthe nanoparticle surface with mixed-charge self-assemblymonolayers (SAMs) compromising positively and negativelycharged thiol ligands [40]. Figure 4 represents the schematicillustration of MC-AuNPs aggregation in a tumour acidic pHinduced manner for photothermal cancer therapy.PHOTODYNAMIC THERAPYPhotodynamic therapy (PDT), has been utilized forthe treatment for a spread of oncological, cardiovascular,dermatologic and ophthalmic diseases. It includes a mix of 2basic therapeutic elements: a photosensitizer (PS) drug anda nonthermallight. Light irradiation elevates ps to an excitedstate where this energy is later transferred to molecular oxygento form reactive oxygen species (ROS), primarily composed3/6

Murali et al. (2018)E-mail: Central Bringing Excellence in Open AccessFigure 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].Principle ofTypes of biosensorsFunctions of GNPsdetectionOptical ensorChanges in opticalpropertiesEnhancement ofrefractive indexchangesEnhancement ofelectron transferChanges atalysis of reactionsChanges in massBiomoleculeImmobilization,amplification of masschangeJSM Nanotechnol Nanomed 6(1): 1064 (2018)Properties usedSensoradvantageslarge dielectricconstant, high density,high molecular weightConductivity, vityBiocompatibility, largesurface areaHigh surface ty, highdensity, Large surfaceto-volume ratioImprovedsensitivity andstabilityImprovedsensitivity andselectivityImprovedsensitivityTypical examplesDNA sensor with GNPs responses1000 times more sensitive thanwithoutElectron transfer rate of 5000 persecond with GNPs, while 700 persecond without GNPsGlucose biosensor with GNPsachieves detection limit of 0.18 µMNADH sensor based on GNPs shows780 mV over potential decreasewithout any electron transfermediatorsDNA sensor using GNPs asamplification tags with detectionlimit of 10-16 mol/L4/6

Murali et al. (2018)E-mail: Central Bringing Excellence in Open Accessof singlet oxygen, then induces each apoptosis and necrosisthat ultimately leads to the destruction of affected cells. Lackof suitable PS is limiting the use of PDT to emerge into themainstream for cancer treatment, blessed with its superioroptoelectronic properties, biocompatible nature, and high scopeof surface functionalization, AuNPs can be an effective candidateas a ps. Yaminyang and coworkers [41] found out that AuNPs canenhance 5-aminolevulinic acid (5-ALA)-induced ROS formationand the enhancement is size-dependent and can be furtherimproved by the intracellular formation of gold nano-aggregates,which suggest that plasmonic AuNPs may amplify photonicenergy absorbed and then transfer the energy to neighboringPSfor enhancing ROS formation [41].Maldonado-Alvarado Elizabeth et al. [42], determined theefficiency of PDT using AuNPs and protoporphyrin IX (PpIX)induced and not induced by the aminolevulinic acid (ALA). It wasfound the conditions of synthesis of hydrosoluble AuNP and werecharacterized by transmission electronic microscopy (TEM)and UV-VIS spectroscopy. It was realized a kinetic by TEM todetermine the cellular incorporation time of AuNP, the maximumincorporation of np-Au was 16 h. PDT was applied using differentdoses of np-Au and photosensitizers. It was observed that the useof PDT simultaneously with AuNP did not increase the mortalityof HeLa cells [42]. The adoption of functionalized Au NPs incurrent cancer PDT represents a promising strategy to enhancetherapeutic effectiveness and improve treatment selectivity.Targeted delivery of Au NPs into mitochondria provides vitalsteerage and critical proof on the effectiveness of intracellulartargeting for any optimisation of drug delivery and improvementof therapeutic efficaciousness. Additionally, the surface plasmonicresonance of AuNPs will be extended to the near-infrared rangeby calibrating their structures, probably enabling PDT with deeplight penetration [42].CONCLUSIONOwing to the success of the fast development of technologiesfor the chemical synthesis of AuNPs throughout the past decade,investigators presently have at their disposal a colossal diversityof accessible particles with needed parameters in respect ofsize, shape, structure, and optical properties. Moreover, thequestion that currently on the agenda is that the primarymodeling of a nanoparticle with desired properties and alsothe subsequent development of a procedure for the synthesisof a theoretically foreseen nanostructure. Gold nanoparticles(AuNPs) are comparatively inert in the biologicalatmosphereand have a number of physical properties that are appropriatefor many biomedical applications. The current uses of AuNPs inthe biomedical field include photothermal therapy, drug delivery,photodynamic therapy, gene therapy, biolabelling, photodynamictherapy, biosensing, etc. It is ought to be stressed that AuNPsare biodegradable. Therefore, the biodistribution and excretiondynamics have to be compelled to be studied comprehensivelyfor various animal models. Because the excretion of accumulatedparticles from the liver and spleen will take up to 3-4 months, thequestion on the injected doses and doable inflammation processescontinues to be of vital importance. Bioaccumulated AuNPs willinterfere with completely different diagnostic techniques, oraccumulated AuNPs will exhibit catalytic properties. All theseJSM Nanotechnol Nanomed 6(1): 1064 (2018)concerns, in conjunction with potential toxicity, are massivelimitations of AuNPs on a successful clinical translation.In summary, there should be more effort for an effectiveresearch a to establish correlations between the particleparameters (size, shape, and functionalization with variousmolecular probes), the experimental parameters (model; doses;method and time schedule of administration; observation time;organs, cells and sub

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].

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