Recent progress in theranostic applications of hybrid gold nanoparticles

European Journal of Medicinal Chemistry 138 (2017) 221e233

Contents lists available at ScienceDirect

European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech

Review article

Recent progress in theranostic applications of hybrid gold nanoparticles Alireza Gharatape a, b, Roya Salehi c, * a

Department of Medical Nanotechnology, School of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran c Drug Applied Research Center and Department of Medical Nanotechnology, School of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 26 February 2017 Received in revised form 18 June 2017 Accepted 21 June 2017 Available online 23 June 2017

A significant area of research is theranostic applications of nanoparticles, which involves efforts to improve delivery and reduce side effects. Accordingly, the introduction of a safe, effective, and, most importantly, renewable strategy to target, deliver and image disease cells is important. This state-of-the-art review focuses on studies done from 2013 to 2016 regarding the development of hybrid gold nanoparticles as theranostic agents in the diagnosis and treatment of cancer and infectious disease. Several syntheses (chemical and green) methods of gold nanoparticles and their applications in imaging, targeting, and delivery are reviewed; their photothermal efficiency is discussed as is the toxicity of gold nanoparticles. Owing to the unique characterizations of hybrid gold nanoparticles and their potential to be developed as multifunctional, we predict they will present an undeniable role in clinical studies and provide treatment platforms for various diseases. Thus, their clearance and interactions with extra- and intra-cellular molecules need to be considered in future projects. © 2017 Elsevier Masson SAS. All rights reserved.

Keywords: Gold nanoparticle Theranostic Nanomedicine Imaging Photothermal Targeting and delivery

Contents 1. 2.

3.

4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221 Synthesis of GNPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222 2.1. Chemical synthesis methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 222 2.2. Green synthesis methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 2.3. Other synthesis methodologies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 Application of hybrid GNPs in nanomedicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 223 3.1. Bioimaging of hybrid gold nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 3.1.1. In-vivo study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 3.1.2. In-vitro study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 3.2. Targeting and delivery of hybrid gold nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224 3.3. Plasmonic photothermal therapy (PPTT) of hybrid gold nanoparticles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 Toxicity of GNPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 Conclusion and perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230

1. Introduction * Corresponding author. Drug Applied Research Center and Department of Medical Nanotechnology, School of Advanced Medical Science, Tabriz University of Medical Science, Tabriz, Iran. Tel.: þ984133363161; fax: þ984133363132. E-mail address: [email protected] (R. Salehi). http://dx.doi.org/10.1016/j.ejmech.2017.06.034 0223-5234/© 2017 Elsevier Masson SAS. All rights reserved.

Nanotechnology currently plays an important role in medical research (diagnosis and treatment) and has replaced old-style therapeutic methods. With progress in investigations,

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nanotechnology products have been allowed to enter the field of diagnosis and treatment. The main challenges facing nanotechnology are probably providing an operating platform for the treatment of cancers and bacterial/viral infections [1]. Accordingly, the application of nanotechnology in medical study for research and clinical usage is defined as “nanomedicine” [2]. Gold nanoparticles (GNPs), which are metallic nanometer-scale particles, are some of the most extensively studied nanomaterials. GNPs are capable of conjugating and delivering different biomolecules to targeted cells and providing a theranostic capability to diagnose simultaneously [3]. Hybrid nanomaterials are defined as a combination of organic or inorganic nanostructures (including differently shaped nanoparticles) with other molecular or macromolecular entities (polymers, protein, DNA) which have multiple or synergetic properties and unique characteristics [4e7]. The investigation of hybrid nanomaterials for both therapy and diagnostic application is expanding. Among well-known hybrid nanomaterials, hybrid gold nanoparticles are particularly important because of their unique properties which allow them to easily attach to different molecules [8]. The theranostic application of hybrid GNPs are discussed in detail in the following sections. Theranostics is defined as a combination of therapeutic and diagnostic methods to describe a new platform in both treatment and diagnosis. Hybrid GNPs have numerous applications in theranostic-based nanomedicine. The active surface and unique characteristics of GNPs give them extensive applications in cancer and infectious disease studies [9,10], particularly their ability to detect and destroy pathogenic bacteria that cause infectious diseases [11]. The current applications of hybrid GNPs have been generally divided into two categories: the diagnosis application and treatment usage. Both have been accompanied with great success. Hybrid GNPs have exclusive characteristics that predispose them to use in sensors, plasmonic photothermal and photodynamic therapies (PPPT and PDT), drug/gene delivery, magnetic resonance imaging (MRI), and x-ray computed tomography (CT) applications [3,12]. Since GNPs are appropriate agents for delivering and targeting a surface ligand or the whole cell, several studies have been conducted to consider the bioimaging application of hybrid GNPs [13,14]. Therefore, we can pursue two goals with the cited functionalized GNPs. The therapeutic effects of hybrid GNPs can be applied in three ways. First, GNPs demonstrate therapeutic effects alone. The mentioned group include PPTT, PDT and such cases which apply only effect of GNPs in therapeutic major [15e17]. Secondly, hybrid GNPs are used to exert a therapeutic effect, but the mentioned group differs because of the type of hybridization of materials (polymers, drugs, peptides, DNA aptameric and genes) with GNPs; each has a different mechanism [18e20]. Thirdly, the hybrid GNPs are used in both above-mentioned methods [21e23]. This review focuses on the theranostic application of hybrid GNPs in nanomedicine based on studies conducted between 2013 and 2016. The first part of this review focuses on the methodology of GNP synthesis (chemical, green, and other approaches). The second describes an application of hybrid GNPs in nanomedicine studies, and the third one considers the toxicity of GNPs. 2. Synthesis of GNPs 2.1. Chemical synthesis methodology In the past few decades, several methods for the chemical synthesis of GNPs have been presented. These methods have been used for the preparation of GNPs based on requirement applications in theranostic nanomedicine. Different synthesis methods present different properties of GNPs, the most important of which

in therapeutic- and diagnostic-based studies are size, shape, and morphology of nanoparticles which are synthesized by chemical or green reducing agents [24e27]. For instance, spherical-shaped NPs are ordinarily produced through the citrate (Turkevich) method, but rod-shaped NPs are obtained through the seed mediated growth method. In the following, several GNP synthesis methods which are used as chemical reducing agents are discussed. In the citrate (Turkevich) method, presented in 1951 by John Turkevich [28], trisodium citrate dehydrate (Na3C6H5O7$2H2O) was used as a reducing agent which reacted with gold salt (HAuCl4). Trisodium citrate was added at once to the HAuCl4 boiling solution under vigorous stirring. Then, through the reaction between HAuCl4 and trisodium citrate dehydrate, Au3þ was reduced to Au0, and GNPs were produced. In this procedure, the solution color changed from gold to wine-red. Citrate ions played a double role by reducing and stabilizing. Accordingly, they prevented the aggregation of nanoparticles. The gold salt-to-citrate concentration ratio controlled particle size. Verma et al. studied the citrate-based GNP synthesis method with different concentrations of gold salt/citrate ratio. They investigated the experimental parameters of temperature, mixing rate, pH, and gold salt and citrate concentrations on the size and morphology of the resultant GNPs. The optimal conditions to obtain 15e20 nm GNPs were suggested to be 20 mM HAuCl4, 1.5% citrate,  7.2 pH, and a temperature of 97 C [29]. In another study, Sahoo et al. investigated different concentrations of citrate and reported that GNP size depended on citrate concentration. Their results confirmed that when the citrate concentration is increased from 0.09375% to 1.5%, the particle size diminished from 230 nm to 27 nm [30]. Schulz et al. considered the adjustment of Turkevich method with set-out of pH and the use of a citrate buffer serving as the reducing agent. The optimized method presented a much narrower size than ordinary methods. Also, the modification of the synthesis method led to smaller nanoparticles in comparison with regular methods (Fig. 1) [31]. In an interesting study, Han
zi c et al. improved the citrate synthesis method by combining gammairradiation in the ambient temperature. The results indicated that synthesized GNPs in the presence of N2 were nearly two times smaller than synthesized nanoparticles in the presence of air. Moreover, increasing the radiation dose increased the absorption peak in the UV-spectrophotometer analysis as well as the size of the GNPs [32]. The Citrate method of GNPs synthesis is a straightforward, timeand cost-consuming method that is applied to different studies such as antibacterial activity of antibiotic conjugated GNPs [33]. Along with the citrate method, the other chemical method which uses NaBH4 as a reducing agent provides much smaller GNPs in comparison with the methods described above. In this method, citrate was the stabilizer, and NaBH4 served as a reducing agent [34]. Martin et al. introduced an ultrafast, simple method to synthesize monolayer-protected GNPs. They prepared a two-phase solution with toluene, ethanol, Hexadecyltrimethylammonium bromide, gold salt, and castor oil. Afterwards, NaBH4 was added to prepare the solution, and the synthesized GNPs were transferred to the oil phase. The average diameter of the resultant GNPs was less than 2 nm [35]. However, the other chemical synthesis method, called seed mediated growth, was used for the synthesis of gold nanorods [36,37]. Kumar et al. developed the seed mediated synthesis approach and produced monodispersed GNPs. They used hydroquinone and tri-sodium citrate as the reducing agent [38]. Regardless of the classical methods, several new studies were performed to synthesize GNPs with novel chemical reducing agents [39e43]. Ahmed et al. developed the synthesis of GNPs through biological buffers in order to obtain biocompatible and stable NPs. They discovered that morphological properties, like size and shape,

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depended on the buffer type. Cell viability results showed that among all of the as-prepared GNPs through buffers, PIPES, MES, TAPS, TEA, and BTP buffers had the highest safety rates for the synthesis of GNPs [39]. Rawat et al. introduced a novel synthesis approach which was applied to 1-amino-2-naphthol-4-sulphonic acid (ANSA) as a reducing agent. In their study, GNPs e ANSA had reportedly larger particles along with various shapes in comparison with citrate e GNPs [40]. Rodrigues et al. investigated a GNP synthesis method based on hydrogel. They added the aqueous solution of HAuCl4$3H2O to 1,3-bis[(3-octadecyl-1-imidazolio) methyl] benzene dibromide (1.2Br). Afterwards, the aqueous solution of NaBH4 was added to it. They introduced this as a simple method with low particle size [41].

2.2. Green synthesis methodology Green synthesis of gold nanoparticles means that the reducing agent is a natural component [44e48]. Thus, it can be extracted from plants, bacteria, fungi, and other natural compounds [48e54]. Interestingly, several advantages and disadvantages are to be mentioned for the green synthesis of GNPs, each of which becomes particularly important depending on the conditions and applications of asesynthesized GNPs. Green synthesis methods provide a cost-effective, simple, and safe approach to synthesize GNPs. In contrast to the mentioned merits, being time-consuming, the presence of unnecessary or excessive substances, and the lower stability compared to chemical synthetic methods are some of their grave disadvantages. However, some interesting and novel studies on the green synthesis of GNPs are discussed in this literature review. Various bacteria strain like Streptomyces sp [55], Streptomyces clavuligerus [56] and Bacillus subtilis [57] are used for the green synthesis of GNPs. Radtsig et al. investigated the production of GNPs through several species of Anabaena, Nostoc, and Azotobacter. After a thorough consideration, they suggested two mechanisms (enzymatic mechanism and reduction due to organic compounds produced during bacterial growth stages) for GNPs synthesis (Fig. 2) [58] Furthermore, Singh et al. developed the synthesis of silver and gold nanoparticles with the Sporosarcina koreensis DC4 strain. The results showed the average sizes of silver and gold nanoparticles were 102 nm and 92 nm, respectively. Finally, they tested the antibacterial efficiency of as-prepared nanoparticles on several pathogenic bacteria [59]. In addition to bacteria, other studies have been conducted on fungi. Tidke et al. used Fusarium

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acuminatum for the biosynthesis of GNPs. They introduced this method as a novel approach which presents spherical and small GNPs with 13.6 mV Zeta potential. In addition to the profit size, the polydispersity of particles was 8e28 nm [60]. In another study, Dhanasekar et al. synthesized GNPs through Alternaria sp fungus. Their presented method was simple and feasible. The results showed that increasing the concentration of HAuCl4 from 0.3 mM to 1 mM caused an increase in the size of nanoparticles from 13 nm to 93 nm. Furthermore, the morphologies of GNPs changed to square, rod, and pentagonal [61]. During the last two years, several studies including Polygala tenuifolia roots extracts [62], Mentha piperita extract [63], Dendropanax morbifera [64], caffeic acids [65], Crocin [66] and Apple juice [67] were done on plant-based GNPs synthesis. Mukherjee et al. developed the green synthesis of GNPs using an extract of Peltophorum pterocarpum leaves. The resultant GNPs were inexpensive, highly stable, and biocompatible and profit carrier to conjugation with doxorubicin (Dox). After conjugation, they tested the effect of GNPs-DOX on cancerous cells and tumors. The results showed the significant effect of as-prepared nanoparticles in cell viability and tumor volume decreases [68]. In an interesting study, Elia et al. prepared GNPs using Salvia officinalis (SO), Lippia citriodora (LC), Pelargonium graveolens (PeG), and Punica granatum (PuG) extracts. However, the average size of the as-prepared GNPs indicated that PeG and SO had the highest and lowest particle size, respectively [69]. In addition to bacteria, fungi, and plants, other studies based on amino acids and biopolymers have been conducted to synthesize GNPs [70e76]. A number of studies have been published that used Leucine [70], Poly-L-Lysine [71] and Asparagine [72] for the synthesis of GNPs. Some studies have investigated several different amino acids to synthesize GNPs [73,74]. They compared size, morphology, and other properties of the resultant GNPs. 2.3. Other synthesis methodologies As well as chemical and green synthesis, other studies have been developed based on radiation methods. Shang et al. synthesized GNPs through the reduction of HAuCl4 through UV-radiation without alternative reductants. They also used a number of cationic and anionic surfactants serving as controllers and stabilizers. The results showed that the anionic surfactant presented smaller nanoparticles than the cationic one [77]. After a few years, Teixeira et al. developed the photochemical synthesis of GNPs by using polyethylenimine (PEI) as a stabilizer under UV radiation. They succeeded in controlling the nucleation step of nanoparticles with PEI and produced positively charged nanoparticles between 8 nm and 100 nm. Then, the cytotoxicity of the resultant GNPs was investigated through in vitro tests on MCF-7 cell lines [78]. Yusof et al. used High Intensity Focused Ultrasound (HIFU) for the reduction of Au3þ to Au0 and GNPs formation. They observed that the particle shape was irregular at 30 W and icosahedral at 50 W. Furthermore, they found that, after 70 W, the particle shape changed to rod-shape [79]. 3. Application of hybrid GNPs in nanomedicine

Fig. 1. Size distributions diagram of synthesized GNPs with two methods (invers and optimized methods). The mean diameter of optimized GNPs was 11.7 ± 0.7 nm, whereas for inverse method GNPs the mean diameter were 12.0 ± 1.5 nm. A section of a TEM image of optimized GNPs. (Reprinted with permission from Ref [31] Copyright 2014, American Chemical Society).

GNPs have exceptional properties which can affect their applications. Particularly, GNPs provide an appropriate surface to connect different molecules such as drug, linker, ligand, antibody, aptamer, and polymeric molecules which can produced hybrid GNPs [7,31]. In addition to surface properties, GNPs have photothermal, photoacoustic, and photochemical properties. In this section, some applications of hybrid GNPs in theranostic-based nanomedicine are reviewed. Due to the extensive amount of

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Fig. 2. Electron micrograph (SEM) of Anabaena sp. PCC 7120 wt (a) and Nostoc sp. PCC 6310 (b) during incubation with gold salt solution (0.25 mM). (Reprinted with permission from Ref [58] Copyright 2016, Springer).

content, a number of studies are presented in tables. 3.1. Bioimaging of hybrid gold nanoparticles As mentioned above, hybrid GNPs have numerous applications for bioimaging. Since hybrid GNPs presented appropriate tolerability and compatibility in cellular and tumor microenvironments, interest in the use of hybrid GNPs has increased [80,81]. X-ray computed tomography (CT) is one of the noninvasive methods that uses hybrid GNPs to enhance the signal-to-noise ratio toward other convenient organic molecules. Hybrid GNPs serve as contrasting agents, provide higher X-ray absorption, controllable size and shape and possibility of surface modification [82]. In the following, several in-vivo and in-vitro studies are discussed. 3.1.1. In-vivo study In an interesting study, Hayashi et al. synthesized silica-coated GNPs (GNPs@SiO2) to investigate the tomography of Lymphatic System. They believed the suggested method can be used to design a surgery plane through visualization (Fig. 3) [83] Silvestri et al. functionalized GNPs with thiolated polyethylene glycols (HS-PEG) and used them as a probe for in-vivo CT analysis [84]. In early 2016, Manohar et al. injected bare GNPs without any modification to tumors to identify and quantify nanoparticles in in-vivo x-ray fluorescence computed tomography. Biodistribution of GNPs showed the kidney had the highest percentage of nanoparticles while the tumor had one-tenth of the kidney [85]. More x-ray computed tomography imaging of hybrid GNPs is depicted in Table 1. In addition to the mentioned techniques, others include Photoacoustic (PA) Imaging [86e88] and Magnetic Resonance Imaging [89,90]. When the GNPs are excited through absorption of light or near-infrared (NIR) spectrum, they provide desirable conditions to PA imaging [81]. Liu et al. investigated the PA imaging effect of hollow GNPS and chained polymer modified hybrid GNPs. They observed that chain hybrid GNPs demonstrated higher PA imaging efficiency than non-chain. They further suggested chain polymer modified hybrid GNPs for the encapsulation of macromolecules such as drugs to offer a new platform for theranostic-based studies (Fig. 4) [86] Sun et al. suggested a new method to induce photothermal therapy (PTT) and photothermal/photoacoustic imaging. Their method was based on the in-situ aggregation of hybrid GNPs in a tumor environment. Interestingly, the presented method provided highly photothermal conversion efficiency in comparison to currently prevalent methods [91].

More examples of these studies are shown in Table 1. MRI is another noninvasive diagnostic device which can present higher quality images by using hybrid GNPs as nanocarrier for gadolinium chelates [80]. Tian et al. designed a nanocomposite to serve as the contrast agent in order to improve CT and MR imaging. First, they synthesized Gd metal-organic framework. Secondly, the surface of as-prepared particles was modified by poly (acrylic acid) (PAA) chains. In the third step, GNPs were attached to PAA. They successfully suggested an appropriate method which worked better than the clinically utilized MRI contrast agent [89]. 3.1.2. In-vitro study Huang et al. synthesized copolypeptide nanocapsules that were cross-linked by GNPs in order to cell image the fibroblast 3T3 cells. They used FITC-dextran loaded into vesicles as a fluorescent compound [100]. Cai et al. prepared lysozymeedextran nanogels to reduce gold salt to GNPs and then loaded DOX to the resultant particles. Afterwards, they evaluated the imaging of KB cells by both fluorescence and dark field imaging (Fig. 5) [101] In an interesting study, Zhang et al. designed multifunctional hybrid GNPs by oligodeoxynucleotide (ODN) which could be conjugated with complementary peptide nucleic acids (PNAs). These PNAs were conjugated with DOTA, Cu, PEG, and Cy5. Finally, fluorescence imaging of MCF10A cells was done [102]. GNPs have high quenching efficiency. Moreover, they have exceptional two-photon properties. These properties convinced Wang et al. to design a sensing system based on hybrid Graphene quantum dot/GNPs for sensing and imaging cyanide. For the first time, they succeeded in presenting a sensing system with a 0.52 mM limit of detection. Due to the great potential of the suggested method, they offered to develop the presented method for food safety testing [103]. 3.2. Targeting and delivery of hybrid gold nanoparticles In addition to imaging, targeting and delivery are other domains of the application of hybrid GNPs to theranostic-based nanomedicine [80,104]. The use of hybrid GNPs has recently intensified because of the surface characteristics of GNPs. They can be a profit carrier for drugs, genes, DNA/RNA strand, peptides, antibodies, and other small molecules which can target cells or deliver loaded molecules [105e107]. Below, this paper focuses on the delivery and targeting studies presented in the text and Table 2. Du et al. synthesized hybrid GNPs coated with pH-Sensitive Liposome in order to design new gene vectors. After

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Fig. 3. Fluorescence images of intradermally injected mouse with gold/silica core@shell nanoparticles into the left paw: A) before injection, B) 1 min after injection (yellow arrow showed the location of the injection), C) 30 min after injection, D) 1 h after injection, E) 4 h after injection (signals were observed in neck (green circle) and armpit (pink circle)), and F) 18 after injection (in addition to green and pink circles, the neck signal spread upward to the right and left (blue circles)). (Reprinted with permission from Ref [83] Copyright 2013, John Wiley and Sons). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Table 1 In-vivo bioimaging of gold nanoparticles. Imaging method

Type of particle

Ref

X-ray CT

s-GNP@SiO2,c-GNP@SiO2 PEGylated c-GNP@SiO2 Gum Arabic stabilized GNPs Bare GNPs Bare GNPs (Photosensitizer) Ce6-loaded gold vesicles PEG-b-PCL modified GNPs DNA-Gd@GNPs dithiolated diethylenetriamine pentaacetic acid (DTDTPA) GNP@DTDTPA-Gd

[92]

X-ray CT X-ray Micro CT x-ray fluorescence (XRF) PA PA MRI MRI

consideration of cellular uptake, they found the proposed method could increase the internalization of GNPs/DNA hybrids [108]. In another study, Ren et al. modified the surface of hollow gold nanoparticles (HGNPs) with polyamidoamine (PAMAM) and conjugated microRNA (miR-21i) and DOX on the surface to investigate the synergistic efficacy. Interestingly, they considered two cell lines (MDA-MB-231 and MCF-7 cells) and evaluated several gene expressions, including cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, p53, Bax, Bcl-2, AIF, and FasL (Fig. 6) [109]. Deng et al. employed hybrid GNPs to knockdown the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor 1 (PAC1R) gene which is responsible for the outgrowth of PC12 cells. For this purpose, they conjugated cholera toxin B (CTB) and doublestranded morpholinos (MOs) oligonucleotide using electrostatic and covalent binding, respectively. After internalization, they applied UV radiation and evaluated the release of antisense MOs [110]. Wu et al. used cysteamine-functionalized hybrid GNPs in order for the delivery of TGF-b1, siRNA into HepG2 cells. They observed that cell apoptosis increased and tumor cell proliferation was inhibited by reducing the level TGF-b1 expression or downstreaming through the signaling pathway [111]. Along with gene/ DNA/RNA delivery, special attention has been given to GNPsmediated drug delivery. Kumar et al. functionalized green synthetic GNPs with Hyaluronic acid (HA). Then, they loaded

[93] [94] [95] [96] [97] [98] [99]

Metformin (MET) on the resultant modified nanoparticles and considered the cell viability of HepG2-treated cells [112]. Delivery of peptides and proteins is the third use of hybrid GNPs. Some of the peptides are used as drugs, and others known as a cell penetrating peptide (CPP) can facilitate the cell internalization of carrier molecules. Surface charge and amine groups are two important factors which can affect CPP performance [113,114]. Kim et al. reported peptide delivery into lung cancer cells through DNA aptamer-conjugated GNPs. Their results demonstrated that the suggested method reduced cell proliferation in comparison to untreated cells [115]. Similar to the above-mentioned study, Yeom et al. used DNA aptamer-conjugated hybrid GNPs to deliver antimicrobial peptide to S. Typhimurium. They used this method against S. Typhimurium-infected HeLa cells. Interestingly, the viability of infected cells increased with the elimination of S. Typhimurium [116]. More examples of applications for hybrid GNPs in the delivery of molecules are presented in Table 2. 3.3. Plasmonic photothermal therapy (PPTT) of hybrid gold nanoparticles PPTT is a non-invasive therapeutic method which can destruct cells, tumors, and other microorganisms with the hyperthermia

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Fig. 4. Self-assembly of block copolymer-GNPs into hollow chain and nonchain vesicles. Nonchain vesicles display one absorption peak at 590 nm, while, the chain vesicles establish two distinct absorption peaks at 545 nm and 780 nm (aec). Enhanced PA imaging with release of therapeutic agents in chain vesicles (d). In-vivo 2D PA imaging of mouse tissue preand postinjection of chain vesicles (e, f) or non-chain vesicles (g, h). Both of the vesicles containing 50 mg which were injected in nude mice subcutaneously. (Reprinted with permission from Ref [86] Copyright 2015, John Wiley and Sons).

effect [126]. Because of the surface plasmonic properties of GNPs, they can easily absorb visible and near infra-red (NIR) light regions and reach an excited state. However, since the excited state is unstable and the electrons tend to reach their ground state, the absorbed photon energy is released as light (IR) and heat. Visible or NIR radiation is applied in two continuous waves (CW) or pulsed wave modes [127]. In pulsed wave mode, the nanobubbles are formed around GNPs, which have a very short lifespan (nanoseconds). In contrast to pulsed lasers, CW lasers are cheap, but timeconsuming (minutes). There are several variable factors, like power density, exposure time, intensity or energy density, and

particle size/shape that are discussable in PPTT in order to present a treatment platform [128]. Since the PPTT does not follow the drug strategy (drug free method) to cell destruction, the multi-drug resistance or extensive-drug resistance (MDR or XDR) mechanisms will be effective in boosting resistance to aggressive agents. Today, PPTT studies are conducted in-vitro and in-vivo on cancers and pathogenic agents. To provide a platform for treatment, we encounter two important questions. First, how are we going to target the cells and internalize the PPTT agent into the cell membrane or plasma? Second, what mechanisms and physical parameters are going to destroy our cells? The induction of cell death can

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Fig. 5. (a) Schematic illustration of the production of doxorubicin encapsulation into Au@Lyse Dex(lysozymeedextran) Nanogels. (bed) Optical microscopy images of KB cells in dark field (b), fluorescence (c), and overlapped images (d) modes 4 h post-incubation with Dox/Au@LyseDex nanogels at 370C. The scale bar is 50 mm. (Reprinted with permission from Ref [101] Copyright 2013, Royal Society of Chemistry).

Table 2 Gold nanoparticle application in targeting and delivery of different molecules. Delivered molecule

Significant remarks

Ref

DNA DNA/drug Gd(III) chelates siRNA Drug Drug Drug Peptide drug Peptide

In-vitro study of DNA transfection with pyridinium cationic lipids coated GNPs DNAGNP conjugated used as delivery agent for DNA and DOX into HeLa cells (in-vitro) DNA modified GNPs delivered Gd to HaloTag reporter protein into U-2 OS HT-ECS cell (in-vitro) that is detected by MRI GNPs combined with oligonucleotide and penetrating peptide to deliver siRNA into CD4þ CD25 þ regulatory T cells GNPs used to delivery Recombinant human endostatin (rhES) e protein- to H22 cell line and tumor (in-vitro and in-vivo) GNPs attached to bioactive glass composite and capsulated by biodegradable polymer for DOX delivery in C6 glioma cells Protein-polymer GNPs prepared to delivery of small drug molecules (curcumin) to MCF-7 cells. Peptide functionalized GNPs used to intracellular delivery of PKCd inhibitor peptide for in-vitro and in-vivo study. CPP-GNPs used as delivery agent for Calcein molecules which was triggered by laser irradiation(in-vitro)

[117] [118] [119] [120] [121] [122] [123] [124] [125]

be caused by the denaturation of proteins, DNA/RNA breakage, cavitation-induced perforation of the cell wall/cell membrane, preparation of reactive oxygen singlet (ROS), and decomposition of organelles which are generally divided into two categories: apoptosis and necrosis [127,129]. As well as the destruction of diseased cells and tumors, the destruction of infectious pathogenic bacteria is another PPTT usage that has been developed recently. Along with PPTT, photosensitizer (PS) molecules can be used as photodynamic agents. Photodynamic agents induce photodynamic therapy (PDT) through the fabrication of ROS. Consequently, the combination of PPTT and PDT introduces a synergistic effect on the photoablation of targeted cells. This application of hybrid GNPs was explored in several new studies which are discussed below [130]. Moreover, we presented a comprehensive study about engineered GNPs and the photothermal application of them in cancerous and

bacteria infectious diseases in a previous study [131]. Mackey et al. investigated the effect of hybrid GNRs on PPTT in in-vitro experiments. They focused on size variation and GNR concentration to adjust the efficiency of PPTT on cell viability both theoretically and experimentally. They discovered that, after 2 min radiation at 5.8 W/cm2, only 28 nm particles could reduce HSC cell viability to under 20% [22]. One year later, Frazier et al. considered the heating parameter and the relationship between heat and the polymer accumulation profile on PPTT. They observed that polymer  accumulation was enhanced at 49 C or 30-min heat duration [132]. Ding et al. developed PPTT using PEGylated hybrid GNRs and luminescent nanoparticles modified by poly-L-lysine. They recorded temperature increases with an epi-fluorescence microscope through the luminescence nanoparticles after the NIR radiation of hybrid GNRs [133]. In some studies, PPTT was combined with

Fig. 6. (I) Schematic illustration of the preparation of gold nanoparticle-based co-delivery system in order to delivery sequential miR-21and DOX. After internalization of complex GNPs to the tumor cells, at first miR-21i was released and then, DOX burst released due to stimulated by NIR. Accordingly, tumor cells conducted to apoptosis pathway by synergistic response. (II) in order to investigation of intracellular distribution of DOX and miR-21i in MDA-MB-231 and MCF-7 cell lines, GNPs labeled by Cy5.5 and conjugated with miR-21i which was labeled by FITC and Dox was loaded into mentioned nanoparticles. (II-A) obtained 1 h after incubation of MDA-MB-231 cells with the resultant nanoparticles and (II-B) MCF-7 cells. (II-C, D) obtained 4 h after incubation of MDA-MB-231 and MCF-7 cells, respectively. (Reprinted with permission from Ref [109] Copyright 2016, Elsevier).

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chemotherapy. Generally, the combination of these two methods can demonstrate a synergistic effect. Li et al. researched the development of PAMAM dendrimers that are conjugated by PEG and DOX. Then, some of the as-prepared nanoparticles were conjugated on GNRs surface. This pH-responsive designed polymer releases DOX into intracellular and acidic organelle space. In-vitro and in-vivo results confirmed the extensive potential of PEGDOX-PAMAM-GNRs (Fig. 7) [134]. In another study, Liao et al. combined PPTT and chemotherapy using hybrid GNRs. They fabricated self-assembled block copolymers of mPEG-PCL as polymersomes and co-loaded DOX and GNRs into them. They also studied tumor cell ablation and observed that the mentioned method irreversibly improved the therapeutic efficacy in comparison to chemotherapy or PPTT, individually [135]. Although the combination of PPTT and chemotherapy presented a significant therapeutic result, the combination of PPTT and PDT has provided arguable effects which are discussed in the following. Kim et al. developed a hybrid GNRs complex with anionic PS and cationic polymer (poly (allylamine hydrochloride)). Then, they considered the effect of PPTT and PDT after NIR radiation. Their results verified that PDT or PPTT cannot significantly reduce A549 cell viability alone, but a combination of dual methods introduced a synergistic effect and decreased cell viability to <40% (Fig. 8) [136]. Another study conducted by Gharatape et al. investigated the bactericidal effect of biocompatible AuNPs core and polymers shell nanoparticles due to the induction of a plasmonic photothermal effect with laser therapy. They worked on three

Fig. 7. (a) Schematic illustration of the preparation of modified gold nanorods with DOX conjugated to PEGylated PAMAM dendrimers for combination of chemotherapy and photothermal therapy. (b) Cell viability of HeLa cells which were treated by PEG PAMAMGNRs without exposure (black dense column) and with exposure (black solid column) at 808 nm wave length and PEG-PAMAM-GNRs without exposure (red dense column) and with exposure (red solid column). Also free DOX treated groups (blue dense column). (Reprinted with permission from Ref [134] Copyright 2016, Elsevier). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

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different biocompatible polymers and two strains of pathogenic bacteria. Their results demonstrated that, after applying several laser dosages, the survival rate of treated groups decreased; in some conditions, the survival rate reached zero [137]. 4. Toxicity of GNPs Since hybrid GNPs are widely used in theranostic-based nanomedicine, the toxicity of hybrid GNPs is an important and challengeable issue. In fact, everything can be toxic in high doses, so the concentration of GNPs used in the treatment platform is important. In addition to GNPs concentration, the morphology of nanoparticles, cell lines, crystallinity, incubation time, and surface modification are other significant parameters [81]. Several studies have investigated the toxicity of GNPs. It was revealed that GNPs have rather little toxicity, and the suitable surface modification of GNPs has been advocated to solve the mentioned issue [138,139]. In the following, some studies on GNPs toxicity, have been briefly considered. Gopinath et al. considered the cytotoxicity and anti-bacterial efficiencies of biosynthesized GNPs. GNPs were synthesized by Tribulus terrestris fruit extract. TEM analysis showed the average size of nanoparticles was about 55 nm. They reported that the resultant GNPs did not show any toxic effect at the minimum inhibitory concentration (MIC) of H. pylori on AGS cell lines [140]. In the same year, Hau et al. investigated the cytotoxic effect of GNPs with different radiation voltages in 2D and 3D cell cultures. Notably, the results showed non-toxic effects at concentrations of 10e25 mg/ml for GNPs, but at 50 mg/ml of GNPs with 1 and 2 Gray

Fig. 8. (a) Schematic illustration of the GNRePS complex. An anionic PS layer and a PAH polymer layer used to preparation of GNRePS/PAH in order to PTT and PDT. (b) Cell viability of A549 cells measured by MTT assay analysis after 12 h incubation time at several concentration of PS (1, 5, 10, 20 mm) with two energy density (2 J/cm2 for PDT and 120 J/cm2 for PTT at 710 and 808 nm wave length, respectively). (Reprinted with permission from Ref [136] Copyright 2015, John Wiley and Sons).

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(Gy) exposure, cell viability decreased significantly. The size and zeta-potential of as-prepared GNPs were 10 nm and 5.4 mv, respectively [141]. Sultana et al. compared the toxicity of two different shapes of GNPs (flower-shaped and spherical). They considered different shapes and sizes of GNPs. The PEGs polymer used to surface modification of GNPs served as a stabilizing agent. Their results demonstrated that the toxic concentration threshold of spherical GNPs was 10pM, while it was 1pM for flower-shaped GNPs. Consequently, they believed that the roughness was the main parameter of the GNPs' toxicity in HUVEC cells [142]. In another study, Saleh et al. investigated the toxicity of GNPs irradiated by pulsed laser. They incubated rat kidney cells (RKCs) with GNPs and irradiated by 532 nm pulsed laser (5 ns pulse duration, 50 mJ/pulse energy for 1, 3, and 5 min). Then, after the endocytosis or interaction of GNPs with cell membrane, increases of lactate dehydrogenase (LDH), alkaline phosphatase (ALP) and ROS were observed. This approach induced cell death by apoptosis and led to subcellular damage in normal kidney cells [143]. Jain et al. explored the interaction, toxicity, and uptake of GNPs with MDA-MB-231 breast cancer cells in hypoxic conditions. Their results demonstrated that the cellular uptake of GNPs under hypoxic conditions was considerably lower than under normal conditions. Moreover, hypoxic breast cancer cells which were incubated with GNPs showed a reduction in MDA-MB-231 cell proliferation. These results were important, because they paved the way for the next research in GNPs cancer therapy [144]. 5. Conclusion and perspective Nanomedicine has numerous applications in theranostic-based medicine. In the past few decades, many studies have investigated the use of nanomedicine in medical research. Although more research is necessary to confirm a medicinal product to be used in the clinical treatment platform, at the moment, there are a number of nanotechnology products which have already entered the consumer market serving as drugs and sensors. Hybrid GNPs are metallic-based nanoparticles used in the clinical therapy of cancer and infectious diseases. GNPs take several various molecules, such as drugs, genes, antibodies, polymers, and other ligands, for targeting or delivering molecules. Today, multifunctional hybrid GNPs are used as theranostic agents which provide diagnostic and therapeutic purposes, simultaneously. Furthermore, GNPs induce plasmonic photothermal therapy as a non-invasive method to treat diseased cells. All of these applications of GNPs stem from their unique optical, chemical, and physical properties. However, further detailed and accurate studies are needed to propose a comprehensive method. For example, the hybrid GNPs can be conjugated or immobilized by drugs, genes, antibodies and biocompatible polymers in order to deliver and target molecules or image agents. Moreover, more principal studies need to focus on the surface functionalization of GNPs to increase the safety and reduce the toxicity of GNPs along with the design therapies that generally arise in photothermal and photodynamic therapies. Some researchers believe that the toxicity of GNPs is related to the concentration, shape, and size of the nanoparticles that are used in studies. This functionalization has a direct connection to cellular connectivity and uptake. Today, many studies are being conducted to provide and optimize a green method for the synthesis of GNPs. Nevertheless, one critical question is how a multifunctional system of hybrid GNPs (with an appropriate size and shape) can be prepared for use in diagnostic and therapeutic applications while having the least toxicity and most effectiveness. Future investigations on theranostic-based GNPs applications should be done to explore molecular mechanisms and their relationship with the surface

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