Indian J.Pharm.Biol.Res. 2015; 3(2):13-27
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Indian Journal of Pharmaceutical and Biological Research (IJPBR) Journal homepage: www.ijpbr.in Review Article
Gold Nanoparticles synthesis, properties, and forthcoming applications – A review Naveen Sharma1, Ganesh Bhatt1, Preeti Kothiyal2 1
Department of Pharmaceutics, Division of Pharmaceutical Sciences, Shri guru ram rai institute of technology and science, Patelnagar Dehradun, India 2 Department of Pharmacology, Division of Pharmaceutical Sciences, Shri guru ram rai institute of technology and science, Patelnagar Dehradun, India
Article history: Received: 30 April 2015 Received in revised form: 25 May 2015 Accepted: 18 June 2015 Available online: 30 June 2015 Keywords: Gold nanoparticles (AuNPs), Surface Plasmon resonance (SPR) or optical properties, diagnostic tool and cancer treatment
Gold nanoparticles (AuNPs) have several biomedical applications in diagnosis and treating of disease such as targeted chemotherapy and in pharmaceutical drug delivery due to their multifunctionality and unique characteristics. AuNPs can be conjugated with ligands, imaging labels, therapeutic drugs and other functional moieties for site specific drug delivery application. In this present review we are discussing the synthesis, properties, and forthcoming applications of gold nanoparticle (AuNPs) which is the most studied among all other metallic-nanoparticles. Here our main focus is to explain the AuNPs application in cancer treatment. AuNPs provides non-toxic carrier system for pharmaceutical drug and gene delivery applications. Currently various anticancer drugs are available but these are cause the necrosis of cancerous cell as well as normal cells. AuNPs cause the necrosis of only cancer cells therefore we can utilize it as a delivery vehicle as well as anticancer agent.
Introduction Delivery and programmed release of therapeutic materials to specific physiological targets is a key challenge for molecular and macromolecular therapeutics. Several drug delivery nanocarriers including liposomes, polymer micelles and vesicles, dendrimers, nanocapsules, and metal nanoparticles have been used as promising delivery vehicles. Recently, gold nanoparticles (AuNPs) have emerged as a promising delivery system for efficient transport and release of pharmaceuticals into diverse cell types. Owing to its unique physical and chemical properties compared to either small molecules or other bulk materials, it has multiple other applications in the fields of biomedical imaging and diagnostic for identification of various diseases. AuNPs are synthesized using chemical, physical and biological methods. Nevertheless, commonly used method for synthesis of AuNPs by the conversion of metallic gold into nano-particulate gold by chemical reduction. For stable and size controlled AuNPs synthesis, various chemical methods such as citrate mediated reduction described by Turkevich in 1951 and Fren’s in 1973, and sodium borohydride mediated reduction method described by Brust and Schriffin in 1990th
century. However, seed mediated growth described by Schmid et. al. in 1996 is the mostly used chemical method of synthesizing AuNPs. Hence, several chemical methods have been successfully employed for the synthesis of various gold nanostructures, but their toxicity limits their application in medicine. Therefore, eco-friendly or green chemistry and nontoxic biological or bio-mimetic methods have also been widely considered for synthesis of AuNPs. The characteristic properties earmarked for gold nanoparticles are their (a) small size (1–100 nm) and correspondingly large surface-to-volume ratio, (b) unique physical and chemical properties that can be changed according to requirements of size, composition, and shape, (c) high robustness shown by some of the nanostructure materials, and (d) quantitive and qualitative target-binding properties. Because of the increased surface area, AuNPs possess specific intrinsic reactivity and because of this, it is very important to make appropriate choice of materials for manufacturing the nanoparticle-based therapeutics. Nanomaterials, using their surface functionalities and depending on the particle size and shape, and state of aggregation, can interact with biological
Corresponding Author: Naveen Sharma, Department of Pharmaceutics, Division of Pharmaceutical Sciences, Shri Guru Ram Rai Institute of Technology and Science, Patelnagar, Dehradun, India E Mail: [email protected]
Sharma et al. / Indian J. Pharm. Biol. Res., 2015; 3(2):13-27 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, polymeric(albumin) and metallic(Au) nanoparticles have been approved for clinical trail as nanoparticle-based therapeutics. 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 therapy and imaging tool. 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 application. Recent advances in nanotechnology led to the development of AuNPs, which have been employed in diverse biomedical applications, including diagnostic assays, gene and drug delivery to target tissues or tumors and as enhancers/sensitizers of radiotherapy. Methods for the Synthesis of Gold nanoparticle (AuNPs) Chemical methods In chemical methods AuNPs generally produced by reduction of Hydrochloroauric acid (HAuCl4), using some sort of stabilizing agent. After dissolving HAuCl4, the solution is rapidly stirred while a reducing agent is added. This causes Au3+ ions to be reduced to neutral gold ions. In Turkevich method pioneered by Turkevich J. et al. in 1951 and refined by Frens G. in 1970s, is the simplest one available. Generally, it is used for producing modestly monodisperse spherical AuNPs suspended in water of around 10–20 nm in diameter. Larger particles also can be produced, but this comes at the cost of monodispersity. It involves the reaction of small amounts of hot HAuCl4 in the presence of reducing agents like citrate, [9, 10] amino acids, ascorbic acid or UV light. The colloidal gold will form because the citrate ions act as both a reducing agent, and a capping agent. To produce larger particles, sodium citrate amount should be less, possibly down to 0.05%, after which there simply would not be enough to reduce all the gold. The reduction in the amount of sodium citrate will reduce the amount of the citrate ions in solution, which is available for stabilizing the particles, therefore it will cause the small particles to aggregate into larger ones, until the total surface area of all particles becomes small enough to be covered by the existing citrate ions in solution. Brust method discovered by Brust and Schiffrin in early 1990s, and can be used to produce AuNPs in organic liquids that are normally not miscible with water (like toluene). It involves the reduction of HAuCl4 solution with tetra Review Article
octylammonium bromide(TOAB) solution in toluene and sodium borohydride (NaBH4) as an anti-coagulant and a reducing agent, respectively. Here, the AuNPs will be 2 to 6 nm in diameter. NaBH4 is the reducing agent, and TOAB is both the phase transfer catalyst and the stabilizing agent. The Brust method which is two-phase synthesis and stabilization with thiol, published in 1994, having ranks high among synthesis techniques since it makes possible both control of particle diameter and grain-size distribution and also functionalization of the particle surface with alkanethiols. The gold is then reduced using NaBH4 in presence of an alkanethiol. The alkanethiols stabilize the AuNPs, resulting in a color change of the reaction from orange to brown. Purification of AuNPs stabilized with dodecanethiol from TOAB was reported by Schriffin. Seeded growth method While the Turkevich and Brust methods can generate spherical AuNPs, but in Seeded growth method AuNPs can also exist in variety of nanostructures[15, 16] such as rods[17, 18], cubes[14,19],tubes. The most widely preferred technique to obtain AuNPs in other shapes is seed mediated growth. The basic principle of this technique is to first produce seed particles by reducing gold salts with a strong reducing agent like NaBH4. The seed particles are then added to a solution of metal salt in presence of a weak reducing agent (ascorbic acid) and structure directing agent to prevent further nucleation and accelerate the anisotropic growth of AuNPs. Geometry of AuNPs can be altered by reducing agents, structure directing agents and varying the concentration of seeds. Physical Methods γ- irradiation method was proved to be best for the synthesis of AuNPs with controllable size and high purity. The γirradiation method is adopted to synthesize AuNPS with size 2 - 40 nm. In this method natural polysaccharide alginate solution was used as stabilizer. Akhavan A. et. al. gave single step γ-irradiation method to synthesized AuNPS of size 2 - 7 nm by using bovine serum albumin protein as stabilizer. In addition, other utilized physical technique such as ultrasonic waves [24-26] microwaves[27, 28], laser ablation[29, 30], solvothermal method, electrochemical and photochemical reduction [32, 33] is available in literature for AuNPs synthesis. Biological Methods The development of eco-friendly technologies in AuNPs synthesis is of considerable importance to expand their biological applications. Nowadays, AuNPs with well-known size, shape, chemical composition and morphology have been synthesized by using various microorganisms, and their applications in many medical and technological areas have been explored. The biosynthesis of gold nanoparticles by microbes is thought to be safe, clean, nontoxic, and environmentally acceptable “green chemistry” procedures. The use of microbes for AuNPs synthesis including bacteria, fungi, yeast, and actinomycetes can be classified into 14
Sharma et al. / Indian J. Pharm. Biol. Res., 2015; 3(2):13-27 intracellular and extracellular synthesis according to the location where AuNPs are formed. In Biological synthesis several attempts had been made to synthesize AuNPs of fairly uniform size and shape using plant extracts and extracellular microbial extracts. Biological synthesis of AuNPs had been reported out using the bacteria Bacillus subtilis. AuNPs were synthesized both intra- and extracellularly. Sastry, Mukherjee and Chauhan et. al. reported the synthesis of AuNPs using different microbes, such as fungus Fusariumoxysporum, Candida albicans. Unique Properties of Gold nanoparticle Gold nanoparticles (AuNPs) have been extensively used for applications both in biomedical(e.g. bio-imaging and Drug delivery)[6, 38] and technology (e.g. photonics) due their unique optical properties. These optical properties are conferred by the interaction of light with electrons on the AuNP surface. At a specific wavelength (frequency) of light, collective oscillation of electrons (Fig.No.1a) on the AuNP surface cause a phenomenon called surface plasmon resonance, resulting in strong extinction of light (scattering and absorption). The particular wavelength of light where this occurs is strongly dependant on the AuNP size, shape, surface and agglomeration state. Some physicochemical properties of AuNPs, including size (surface area), shape, surface charge and coating, agglomeration, and dissolution rate, are particularly important for determining their biological interactions and impacts. Smaller particles have a larger surface area and therefore, have greater toxic potential. It is well known that the shape of gold nanostructures can dramatically affect their physical and chemical properties. Frequently utilized gold nanostructures in the biomedical field include gold spherical, nanowires, nanorods, nanoplates, and nanocubes.
Gold Nanoparticle optical properties The influence of AuNP size on the surface plasmon resonance is affect the absorption maximum (λ max) which increases from 520nm to 570nm for 20nm and 100nm spherical AuNPs respectively. Particles with sizes above 100nm have broader peaks spanning into the 600nm range due to the presence of both transversal and longitudinal surface plasmon resonances. In comparison, AuNPs with diameters below 2nm do not exhibit surface plasmon resonance. The difference in extinction between different sized and shapes (Fig. No.2) AuNPs can conveniently be utilized for multiplexing. In gold nanorods two spectrum is observed due to transversal and longitudinal Surface Plasmon Resonance. AuNPs have a broad absorption band in the visible region of the electromagnetic spectrum. Mie was the first researcher to formulate the nature of the optical band as a surface plasmon effect, in the so-called “Mie theory”. The characteristics of the band arise from the collective oscillation of free-conduction electrons induced by an interacting electromagnetic field, and their resonances are noted as surface plasmon (Fig.No.2a). In fact, the electric field of the incoming radiation causes the formation of a dipole in the nanoparticle. A compensation force for this dipole in AuNPs results in a resonance wavelength, as shown in Fig.No.1b. The specific resonance frequency depends on a number of parameters such as nanoparticle composition, morphology, concentration, solvent refractive index, surface charge, and temperature. Meanwhile, such a resonance wavelength for rod-shaped nanoparticles depends on the angle of the electric field. This results in two oscillations, transverse and longitudinal, that lead to two plasmon bands, as shown in Fig.No.1c. The transverse Surface Plasmon Resonance band occurs at a wavelength close to that of spherical AuNPs, while the longitudinal band is in the region 600–900 nm, depending on their aspect ratio (length/width).[42, 43]
Fig 1: Schematic representations of (a) localized Surface Plasmon Resonance, (b) electric oscillation of nanosphere, and (c) nanorod with respective extinction spectrum due to LSPR and TSPR. Review Article
Sharma et al. / Indian J. Pharm. Biol. Res., 2015; 3(2):13-27 A major determinant of the optical properties of AuNPs is their shape.(Fig.No.2) therefore synthesizing AuNPs of different shapes, the surface plasmon resonance(SPR) can easily be tuned to give absorption maxima from around 500nm into the near-infrared part of the spectrum. For example, spherical collodial gold have absorbance maxima between 515-570nm as described above, while irregular shaped
nanoparticles such as gold nanorods, and urchin shaped gold nanoparticles (also called gold nanostars) have absorption maximum in the near-infrared region of the spectra. The difference in absorption properties between spherical and irregular-shaped gold nanoparticles of the same average size is caused by an anisotropic (uneven) distribution of the surface electron layers.
Fig 2: Different Shapes of AuNPs Pharmacokinetics of gold nanoparticle Among various types of AuNPs, one special and most widely used form is the polyethylene glycol (PEG)-coated AuNPs because PEGylation prolongs circulation time. Cho et. al. studied the compartmental pharmacokinetics of 13nm PEGcoated AuNPs in mice after intravenous (i.v.) injection of 0.85 or 4.26 mg/kg at various time points up to 7 days. Plasma Cmax and Area Under Curve(AUC) were dose-dependent; terminal elimination T1/2, Mean Residence Time (MRT), total plasma clearance (Cl), and volume of distribution (Vd) were not affected by dosage. The blood T1/2 of the 4.26 and 0.85 mg/kg dose groups were 32.65 and 28.50 h, respectively. Cho et. al. then examined the influence of particle size (4, 13, and 100 nm) on the long-term kinetics of PEG-coated AuNPs after a single i.v. injection (0.85 mg/kg) in mice. Kinetics of small (4 and 13 nm) AuNPs showed similar patterns, i.e., plasma concentrations remained high for 24 h and dramatically dropped 7 days after injection. In contrast, large (100 nm) AuNPs had a much lower (∼100-fold) plasma concentration and were completely cleared at 24 h after injection. Biodistribution of AuNPs depends on multiple factors, including the size, surface modification, surface charge, opsonization including protein corona formation, and administration route. To increase biocompatibility, metallic nanoparticles are generally coated with natural or synthesized polymers (e.g., PEG) or peptides, which are normally distinct from the core. These surface-coating materials can be cleaved off and then degraded. This is a general metabolic pathway for bioconjugated AuNPs designed as drug carriers. AuNPs can be excreted from the body via renal and hepato-biliary clearance. Many factors can affect elimination of AuNPs, including size and surface chemistry. Excretion of AuNPs is generally low due to opsonization with persistent and primary accumulation in the liver, spleen, and mesenteric lymph node, even for small-size particles. For example, nearly ∼50% of 1.4 nm AuNPs was found in the Review Article
liver and only ∼9% were excreted into urine 24 h after i.v. injection in rats. Gold Nanoparticle Aggregation Aggregation state of AuNPs have an effect on their optical properties. This fact can be used to monitor AuNP stability, both over time, and upon addition of salt-containing buffers, which at high enough concentrations leads to particle aggregation, The red-shift or Bathochromic shift in absorption maximum caused by aggregation of nanoparticle, or particles in close proximity,which have successfully been utilized in many assays as a detection mechanism. Chegel V. et al. studied on the interactions between citrate-stabilized AuNPs and organic compounds bearing various functional groups in an aqueous medium. As a result, they had found that organic compounds containing both thiol and amine groups strongly promote the aggregation of AuNPs due to their cooperative functionalities. for cell uptake and toxicity of AuNP Albanese A. et. al. had developed a simple technique to produce transferrin-coated AuNP aggregates of different sizes and characterized their uptake and toxicity in three different cell lines. Surface Chemistry and Functionalization AuNPs are capped with citrate, tannic acid, or Polyvinyl pyrrolidone (PVP) capping agents. Citrate as capping agent weakly associates with the nanoparticle surface and is often used because the weakly bound capping agent provides long term stability and is readily displaced by a range of other molecules including amines, thiols polymers, proteins and antibodies. Tannic acid is a multidentate capping ligand that can be displaced with many thiol containing molecules. Tannic acid is generally used as a capping agent in applications where high particle concentrations are required. PVP is a polymer that binds strongly to the AuNP surface. It provides greater stability than citrate or tannic acid capping agents, but is more difficult to displace. It is important to remember the surface of most nanoparticles is dynamic and is 15
Sharma et al. / Indian J. Pharm. Biol. Res., 2015; 3(2):13-27 strongly influenced by the local environment. Different
conditions also affects the particle in different ways.
Fig 3:Schematic presentation of the AuNP surface structures commonly employed in delivery applications. AuNPs used in biological applications are commonly coated with polyethylene glycol (PEG), bovine serum albumin (BSA), proteins, peptides, oligonucleotides or numerous other polymer. Binding molecules to a gold surface can be accomplished by physisorption or by taking advantage of extremely stable thiol-gold bonds. Gold particles can be functionalized with molecules that 'flip' the surface charge of the negatively charged AuNPs to a positively charged surface. Particles can also be functionalize to provide a reactive groups (for example, amine- or carboxy-terminated surfaces) for subsequent conjugation by the customer. Dielectric shells (for example, silica, aluminium oxide, and TiO2) with a precisely controlled thickness can be used for encapsulating the particles.
of X-rays by AuNPs has led to their use in computed tomography imaging and as adjuvants for radiotherapy. AuNPs have many other applications in imaging, diagnostic and drug therapy systems. The advanced state of AuNPs synthesis offers precise control over physicochemical and optical properties. AuNPs can be incorporated into larger structures such as polymeric nanoparticles or liposomes that deliver large payloads for enhanced diagnostic applications and efficiently encapsulate drugs for concurrent therapy or additional imaging labels. Here we covers the basic principles and recent findings in AuNP applications for imaging, and diagnostics, with a focus on reports of multifunctional AuNPs. In vivo imaging
Particle Stability Preventing AuNPs aggregation can be very challenging depending on the application. AuNPs are either sterically stabilized or charge stabilized. Because of charge stabilized particles, the zeta potential value is a measure of the particle’s stability. Typically, AuNPs with zeta potentials greater than 20 mV or less than -20mV have sufficient electrostatic repulsion to remain stable in solution. Highly acidic or basic solutions can also increase the dissolution rate of the AuNPs into an ionic form that can re-deposit onto existing nanoparticles changing the average diameter and size distribution. Particle stability can be accurately tracked using UV-Visible spectroscopy or Dark Field Microscopy, as well as Dynamic Light Scattering. Biomedical Application of Gold Nanoparticle Gold nanoparticle as a diagnostic material for disease Gold nanoparticles (AuNPs) have a unique physical properties like Magnetic and Plasmonic properties that make them appealing for medical applications. For example, attenuation Review Article
Plasmonic AuNPs can also exhibit strongly enhanced radiative properties compared with bulk gold i.e. light absorption, scattering, and fluorescence. While electromagnetic field enhancement has been widely used in surface enhanced Raman scattering (SERS), absorption, scattering and fluorescence enhancements make AuNPs potential multimodal imaging agents. Here we outline main modalities in cellular and in vivo imaging, including near infrared-fluorescence (NIRF) and Raman spectroscopy. The application of conventional fluorescent probes is limited because they generally display only modest fluorescence changes, thus providing insufficient resolution. The limited degree of resolution is mainly attributed to the low fluorescence-quenching efficiency and specificity of the probes. Therefore, a high quenching efficiency and specific recognition properties by the target biomolecules are essential for the development of supersensitive fluorescence-based probes. Among the diverse candidates, biocompatible AuNPs offer a considerable advantage in obtaining optical images through their NIRF quenching properties. Lee et. al. reported 128
Sharma et al. / Indian J. Pharm. Biol. Res., 2015; 3(2):13-27 that Protease sensitive self-quenched and gold nanosphere quenched probes shown to enable visual monitoring of the activities of both proteases and protease inhibitors in vitro and in vivo. This technique can also be applied to other proteases by using the appropriate peptide substrate as the spacer, which took advantage of the self-quenching properties of organic fluorescent dyes, like Jaffer et. al. reported that Optical Visualization of Cathepsin K Activity in Atherosclerosis With a Novel, Protease-Activating Fluorescence and Weissleder et. al. developed a method to image tumor-associated lysosomal protease activity in a xenograft mouse model in vivo using auto quenched NIRF probes. NIRF probes bounded to a long circulating graft copolymer consisting of poly-L-lysine and methoxy polyethylene glycol succinate. Intravenous injection, the NIRF carrier probe accumulated at solid tumors due to its long circulation time and leakage through tumor neovasculature and intratumoral NIRF signal was generated by lysosomal proteases in tumor cells that cleave the macromolecule, hence releasing previously quenched fluorochrome. In vivo imaging showed a 12-times increase in NIRF signal, allowing the detection of tumors with sub millimeter-sized diameters. In vitro diagnostic assay Oligonucleotide-capped AuNPs have been reported for polynucleotide or protein such as p53, which is a tumor suppressor gene detection using various detection/characterization methods such as atomic force microscopy, gel electrophoresis, chronocoulometry , amplified voltammetric detection, SPR imaging, scanometric assay, and Raman spectroscopy. In some reports, very small quantity like picomolar or femtomolar concentrations of DNA targets have been detected. Bifunctional DNA-based adsorbate molecules have been evaluated as molecular rulers, which is based on the SERS signals that vary independently in intensity as a function of the distance from the gold nanoshell surface. Gold nanoparticles as Biomolecule and drug delivery vehicles AuNPs have been used in exploratory drug delivery applications due to the following properties: (i) the high surface area of nanoparticles provides sites for drug loading and enhances solubility and stability of loaded drugs, (ii) the ability to functionalize nanoparticles with targeting ligands to enhance therapeutic potency, decrease side effects and improve solubility, (iii) the advantage of multivalent interactions with cell surface receptors or other biomolecules, (iv) enhanced ADME and tumor tissue accumulations compared to free drugs, and (v) biological selectivity which allows nanoscale drugs to preferentially accumulate at tumor sites due to their ‘‘leaky’’ blood vessels—the so-called enhanced permeability and retention (EPR) effect which first described by Maeda in 1986. Non-metallic nanoparticles such as liposomes, polymeric nanoparticles, and protein-based nanoparticles(albumin NPs) also having physical properties Review Article
such as size and high surface area, but lack the unique optical and photothermal properties as AuNPs. Thus, AuNPs are new agents that are being evaluated for biological sensing, drug delivery, and cancer treatment. Delivery of Pharamceutical Agent via Direct conjugation with AuNPs Curcumin having number of therapeutic application treating neurodegenerative disease like Parkinsonism and Alzheimer disease, anticancer agent, and their antioxidant properties play pivotal role for improving therapeutic efficiency. Poddar P. et. al. developed functionalized AuNPs with curcumin and evaluated the antioxidant properties of curcumin by the simple reduction of Au3+ ions using curcumin itself in an aqueous phase. This type conjugation states that enhance the solubility and availability of curcumin with potential antioxidant activity. Theoretical results of the study also propose that due to breakage of intramolecular H-bonding that probably leads to the increased availability of curcumin in the presence of Au ions and water molecules. Saha B. et al. studied on AuNPs with Conjugated on some Antibiotics which act as a self capping agent. Bactericidal efficacy of AuNPs conjugated with antibiotics such as ampicillin, streptomycin and kanamycin evaluated. AuNPs conjugated with these antibiotics, during the synthesis of nanoparticles utilizing the combined reducing property of antibiotics as well as sodium borohydride. The drug conjugate has confirmed by dynamic light scattering (DLS) and electron microscopic (EM) studies. Such AuNPs conjugated antibiotics showed greater bactericidal activity in standard agar well diffusion assay. Therefore study indicated that AuNPs conjugated antibiotics are more efficient and might have significant therapeutic implications. Where as AuNPs itself having less antibacterial agent as compared to silver nanoparticle which come under broad spectrum. Delivery of Pharamceutical Anticancer agent via Surface modification Several studies have reported the use of AuNPs as drug delivery vehicles. In addition to facile surface modification and their large surface-to-volume ratio, AuNPs also possess a number of additional properties that can be used in drug delivery applications. AuNPs have been conjugated to a variety of antitumor drugs, including paclitaxel, cisplatin ,camptothecin, doxorubicin[74, 75], curcumin and others. The most common antitumor substances conjugated with AuNPs, together with the method of functionalization or surface modification is reported by Dykman and Khlebtsov in their review, which stated that worldwide effort and open challenges in the research to defeat cancer. Functionalization and surface modifications of AuNPs for biomedical applications follows largely on work initially conducted by Nuzzo and Whitesides on the formation of selfassembled monolayers (SAMs) of molecules on planar 18
Sharma et al. / Indian J. Pharm. Biol. Res., 2015; 3(2):13-27 gold and later by Murray in studying the dynamics and conformations of these assemblies by electrochemical, scanning probe, and mass spectrometric methods. A rich variety of functional molecular linkers are currently employed in the conjugation of AuNPs used in biomedical applications; however, these groups utilized for attachment of these molecules to the gold surface generally include: thiolate,
dithiolate, dithiocarbamate, carboxylate, selenide, isothiocyanate, amine, or phosphine moieties. Recent evidence suggests that direct Au–C bond formation may be achieved by way of a trimethyl leaving group; however its use in biomedical or nanoparticle-based applications has yet to be tested.
Table 1: Common functionalization methods of AuNPs and their applications Ligands/Carrier Molecule functional group Polyvinyl pyrolidone (PVP) Polyethylene Glycol (PEG) attached through thiol group Amine Group PEG Proteins, Carboxyl group as functional group Peptide Cell surface receptors
PVP binds strongly to the AuNP surface Adherence to the cell membrane
Improve Bioavailability of lipophilic drugs Cellular and intracellular targeting, biodistribution studies Useful in RNAi technology
Smaller size, label fidelity
Antisense DNA oligonucleotides
Depending on the protein Cellular and intracellular targeting, Bioimaging of cancer cells Immunoassays and diagnosis e.g.antibodies against aflatoxins Bio imaging, gene delivery
3. 4. 5.
siRNA Carrier Glutamic acid as a reducing agent Cytoplasmic and nuclear translocation
The following few examples among many other reported in the literature are illustrative of the aims and perspectives. As pointed out by Mohsen M.M. et. al. studied that, AuNPs are interacting strongly with lipid membrane. AuNPs -loaded liposomes application in liposomal drug delivery systems having more advantages as compared to conventional liposomal drug delivery system. Future studies will evaluate the pharmacokinetics and biodistribution of the AuNPs-loaded liposomes in vivo as well as their efficacy to enhance their therapeutic applications. Furthermore, targeting ligands can be easily conjugated to the surfaces of the AuNPs-loaded liposomes to pursue active targeting to specific cell. And AuNPs-loaded liposomes will also useful applications as a nanomedicine with diagnostic and therapeutic ability owing to the dual drive to reduce the toxicity and side effects of existing treatments and increase efficacy by selective targeting of tumours. Delivery of gene As we have shown, drug delivery systems based on AuNPs offer some opportunities to improve the solubility, optimal bio-distribution, in vivo stability, and ADME or pharmacokinetics of drugs. On the other hand AuNP can also be used to carry nucleic acids. Generally, the use of Review Article
nucleic acids to treat and control diseases is termed ‘gene therapy’. This type of therapy can be carried out by using viral and non-viral vectors to transport foreign genes into somatic cells to treat defective genes or provide additional biological functions. The use of viruses as a vehicle for gene therapy is now well known, however, viral vectors have disadvantages such as the stimulation of an immune response, irregular cytotoxicity, limitations in targeting specific cell types, low DNA carrying capacity, lack of ability to infect non-dividing cells, and difficulties in production and packaging. AuNPs have long been regarded as alternative nonviral vectors and attracted a great interest as non-viral gene delivery because of their unique properties. Successful transfection of DNA/RNA requires effective condensation of the genetic materials, protection from nuclease in cytoplasm, delivery of the DNA to the nucleus, and cellular uptake through endocytosis coupled with endosomal escape. AuNPs provides an attractive platform for DNA/RNA delivery due to its high surface-to-volume ratio maximizing the payload/carrier ratio. For gene delivery the high surface area an important parameter which also enables efficient DNA/RNA compaction. Improve gene delivery using AuNPs has been reported by Sang-Mi Ryou et. al. who reported the ability of functionalized AuNP to deliver RNA aptamers into the nuclei 19
Sharma et al. / Indian J. Pharm. Biol. Res., 2015; 3(2):13-27 of the human cells. In vitro-synthesized RNA aptamer specific to the β-catenin protein delivered into the HepG2 human cell line more efficiently via functionalized AuNP as compared to liposomal-based delivery, and resulted in nearly complete inhibition of β-catenin binding to the p50 subunit of NF-ҡβ in the nucleus. Another interesting approach to improve gene delivery using AuNPs has been reported by Jeehyeon Bae et al. who used AuNPs modified with thiolated RNA I oligos (aRNA I oligo) can efficiently load and deliver antisense DNAs to redirect gene splicing or double-stranded DNAs to gene transcription by transcriptional factors into mammalian cells and in vivo animals, indicating that innovated AuNP GDS can be used to control different nuclear gene expression events. Delivery of proteins and peptides The key property of protein-nanoparticle conjugates is the bioactivity of the protein. The protein activity of the AuNP preparation can thus be increased, which is of great importance in the study on the interface of protein utilized for enzyme immobilization, drug delivery, and biocatalysis.[6, 90, 93]. AuNPs can be utilize as nanocarriers for peptides and proteins. Delivery of functional proteins inside living cells has been limited scope due to their poor permeability through the cell membrane. Stability of the protein against digestion by enzymes having another challenge for delivery. Potentially, AuNPs with engineered monolayer are able to overcome these restrictions. Whereas non covalent conjugation with AuNP can retain the structure and activity of the protein, but covalent approaches have also been applied without altering the protein's activity. An interesting nanoscale interfacial phenomenon mediated by AuNPs was found, in that co-administration with AuNPs enables percutaneous delivery of protein drugs. The AuNPs with a mean size of 5 nm revealed to be skin permeability due to the bio-interaction with skin lipids and the consequent
induction of transient and reversible openings on the skin layer i.e. stratum corneum, when simultaneously applied with AuNPs, the protein drugs also granted the ability to penetrate the barrier and migrate into the deep layers of skin. This indicated that co-administration of skin-permeable AuNPs could mediate proteins across the barrier of skin. Such codelivery effect highlights a simple yet effective method for overcoming the skin barrier for percutaneous protein drug delivery. Using this method, a non-invasive vaccine delivery strategy has developed, and by topically co-administrating antigens with AuNPs, robust immune responses has elicited in the tested animals. The results promise for achieving a needleless and self-administrable trans-cutaneous vaccination  In another study novel method for synthesis of gold nanoparticles employing a natural, biocompatible and biodegradable polymer, chitosan has developed. Use of chitosan serves dual purpose by acting as a reducing agent in the synthesis of AuNPs and also promotes the penetration and uptake of peptide hormone insulin across the mucosal layer. To demonstrate the use of chitosan reduced AuNPs as carriers for drug delivery such as transmucosal delivery of insulin loaded AuNPs. Targeting gold nanoparticles to diseased sites Successful delivery of therapeutic material to disease sites is a major challenge in drug delivery system. There are two strategies for targeting therapeutics: ‘passive’ targeting depends upon the leaky vasculature of the diseased tissues (e.g. tumor) to provide EPR effect to the carrier systems; ‘active’ targeting involves the attachment of functionality group to the delivery vehicle for interaction with specific cell and receptors. Targeting moiety to a disease site can signal the presence of the disease, block a function there, or deliver a appropriate amount of drug to it. Targeted nanocarriers must navigate through various body drug distribution barriers like blood-tissue barriers, varying in strength between organs and maximum in the brain, to reach target cells.[96-98]
Fig 4:Advantages of AuNPs as TDDS system Review Article
Sharma et al. / Indian J. Pharm. Biol. Res., 2015; 3(2):13-27 the tumor interstitium, in the case of solid tumors is limited to The idea of targeted drug delivery is attractive since it implies very short distances (a few cell diameters and can be worse for minimal systemic exposure and thus decreased side effects; at nanoparticle with low diffusivity), (ii) passive targeting is the same time it implies high local concentration of dependent on the size of the nanoparticles and optimal size for therapeutics at the desired target sites for maximum EPR can vary from tumor to tumor. The active targeting efficacy. Passive targeting takes advantage of the strategies augment passive targeting effects by decorating disordered vasculature characteristic of tumors, which allow nanoparticles with recognition moieties which enhance their for selective accumulation for nanoparticles based on the size accumulation at tumor sites. Various recognition moieties (which cannot cross normal blood vessels with endothelial have been used with gold nanoparticles including antibodies, tight junctions). This effect is also known as the EPR small peptides, aptamers, and small molecules.[99-101] effect; however, passive targeting, alone, is not very effective due to the following reasons: (i) penetration of molecules into Table 2: Common conjugation of functional moieties with AuNPs for targeting to specific organ and their applications S.No. 1.
Conjugation Folic acid-modified dendrimer entrapped gold nanoparticles (Au-DENPs-FA) PEGylated-gold nanoparticles (AuNPs) Gold-PEGGalactose nanoparticle Gold nanoparticles (AuNPs) Glutathione-coated luminescent gold nanoparticles (GS-AuNPs) Transferrin peptide (Tfpep)-gold nanoparticles Spherical gold cores covalently coupled to F19 Monoclonal antibodies
Targeting Site Human lung adencarcinoma cells
Application Nanoprobes for in vitro and in vivo targeted computed tomography (CT) imaging of human lung adencarcinoma.
Brain tumors such as glioblastoma multiforme (GBM) Specific liver parenchymal cell delivery Liver
Radiation-induced BBB disruption, result in augmented delivery of nanometer-scale agents to brain tumors in a targeted manner Potential vector for active-targeting therapy
Long tumor retention and fast normal tissue Clearance Brain cancer cell lines Human pancreatic carcinoma tissue
Toxicology of gold nanoparticle Now a days, rapid development of AuNPs technology holds great promise for future applications due to their specific properties like optical, Surface Plasmon Resonancee and large volume specific surface areas with high diverse surface activities. These properties have made AuNPs of great importance in the field of a wide range of biomedical and environmental applications. Therefore, huge impact arising from the physiochemical properties of AuNP has given rise to new concerns for future health status. On the other hand, there is dearth information on AuNPs health effects and no regulatory information, safety and guidelines relating their properties to toxicities. However, assessing the safety issues of nanoparticles is quite challenging, because of the vast physiochemical properties (like Different size, shape, dose, Review Article
Detection and treatment of cancer cells in the liver Detect tumor more rapidly than the dye molecules without severe accumulation in reticulo endothelial system which is very promising for cancer diagnosis and therapy Brain tumor therapies and noninvasive imaging. Optical detection of antibodyconjugated nanoparticles bound to surgically resected human pancreatic cancer tissue
and surface capping of AuNPs) that confound their biomedical and toxicological profiles. Pharmaceutical drugs have different functional groups within their chemical structure that determine their physicochemical properties like solubility, stability, pharmacological, and pharmacokinetics properties. Similarly, AuNPs are multicomponent systems that may have surface capping agents, antifouling agent, recognition molecules, and stabilizing agent etc. The simplest AuNP solution contains the gold(Au) as core material and surface-bound stabilizing agent, and potential chemicals from the synthesis. Observed toxicity from AuNPs may be arise from any of these attaching components, and therefore evaluating the contribution of each component is essential to understand the cause of toxicity.[110, 111] A huge physicochemical properties of AuNP that favor nanomaterial application, are the prime cause that AuNPs cannot be 21
Sharma et al. / Indian J. Pharm. Biol. Res., 2015; 3(2):13-27 considered “generally safe.” Pan Y. et. al. summarized some basic concept to assess AuNPs toxicity, death pathways, cell cycle, and oxidative stress in response to nanoparticle exposure of cells. but inhibition of AuNP cytotoxicity upto some extent also available in literature. Inhibition of Cellular Toxicity of AuNPs, Zeng Q. et al. modified the surface of AuNP by Silica Shell for Hepatocarcinoma Cell and toxicity of those AuNPs without silica encapsulating is observed to be dependent on dosage, size, shape, and surface group. After the surface silica encapsulation, the cellular survival rate for all those AuNPs can be improved from not more than 20% to over 90%. Gioria S. et. al. studied the Size-dependent toxicity and cell interaction mechanisms of AuNPs on mouse fibroblasts. and investigated the in vitro effects of AuNPs on Immortalized mouse fibroblast cell line (Balb/3T3). Colony Forming Efficiency(CFE) assay on Balb/3T3 cells revealed that cytotoxicity only in cells treated for 72 hr with AuNPs 5 nm at concentration higher than 50 µM, while no cytotoxic effects was found in cells exposed to AuNPs 15 nm. Future prospectus and challenges for gold nanomaterials in Biomedical application Multifunctionality of the AuNP is the key advantage over conventional approaches of therapeutic drug delivery and biomedical. Targeting ligands or biomaterials, imaging labels, therapeutic drugs, and many other functional group can all be conjugate into the AuNP to allow for targeted delivery, molecular imaging and molecular therapy for various disease. AuNP is unique in a sense because of its intriguing optical properties which can be exploited for both imaging (for diagnose the disease) and therapeutic applications (for treating the disease). The future of nanomedicine lies in multifunctional nanoplatforms which combine both therapeutic components and molecular imaging. Nanoparticlebased agents can allow for efficient, specific or targeted in vivo drug delivery without any kind of systemic toxicity, and the dose delivery as well as the therapeutic accuracy and efficacy can be measured noninvasively over time is ultimate goal. Much remains to be done before this can be a clinical reality, safety and many factors need to be optimized simultaneously for the best clinical outcome for AuNPs. AuNPs, owing to the rapid development of the technologies for their chemical synthesis and their characteristics such as stability, tunable surface monolayers, functional flexibility and low toxicity, are promising new vehicles for drug and gene delivery. Their diverse functionalities fulfill a variety of aims that can be achieved by tuning the size, shape, structure and optical properties. A series of different approaches, offering opportunities in anti-cancer treatments and involving photothermal therapy, drug delivery, gene therapy and cell cycle regulation, have been investigated so far. However, although a lot of investigation remains to be done and, to date, the physiological destination of nanoparticles in vivo is still far from completely understood, nanoparticles definitely have the
potential to revolutionize medical therapies, particularly in the case of cancer multimodal treatment. A number of issues to be overcome before AuNPs mediated delivery can be applied in clinical trials. Accurate mechanisms of uptake for AuNPs should be known to facilitate optimization of AuNP platforms for efficient delivery at delivery site. The mechanism of cellular uptake of AuNPs is likely to differ for different classes of AuNPs based on their surface monolayer structure, size, shape and surface charge. For example, little is known about the uptake mechanism of negatively charged AuNPs that might involve a different set of proteins and identification of which still remains a challenge. Also, the continued effort for the development of the AuNPs has been directed to address the important challenge of targeting specific cells and eventually organs and tissues. Addition of targeting moieties such as aptamers, antibodies, peptides, and small molecules can be potentially useful. However, addition of the only targeting moiety without compromising functionality of the monolayer is efficient. Taken together, there remains a need for continued improvement in the design and synthesis of AuNPs to achieve the ultimate goals of serving as effective delivery vehicles. Therefore, it is highly possible that AuNP could provide a bright future for biotechnology and the pharmaceutical industry for improving various life threatening disease like cancer and HIV. So far, several AuNPs-based drugs are undergoing clinical trials including TNF-α-conjugated AuNPs for solid tumors. The limitations of AuNPs-based drug carriers include cytotoxicity, interactions with healthy cells, aggregation in the bloodstream, and non-biodegradability nonporous Surface modification alters bio-distribution, pharmacokinetics Lack of information on toxicity and interaction to living cells. Even though many reports and studies indicate that AuNPs are relatively safe to use in clinical applications, some contradictory results suggest that we need to pay more attentions to AuNPs-induced cytotoxicity. Therefore, more cytotoxicity assessments of AuNPs in vivo should be performed. Conflict of interest statement We declare that we have no conflict of interest. References 1.
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Cite this article as: Naveen Sharma, Ganesh Bhatt, Preeti Kothiyal. Gold Nanoparticles synthesis, properties, and forthcoming applications – A review. Indian J. Pharm. Biol. Res.2015; 3(2):13-27.
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