Targeted Drug Delivery Based on Gold Nanoparticle ...

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REVIEW ARTICLE

Targeted Drug Delivery Based on Gold Nanoparticle Derivatives Mazaher Gholipourmalekabadi1,2,3*, Mohammadmahdi Mobaraki4, Maryam Ghaffari4, Amir Zarebkohan5, Vahid Fallah Omrani3, Aleksandra M. Urbanska6 and Alexander Seifalian7,* 1

Cellular and Molecular Research Center and 2Department of Tissue Engineering & Regenerative Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; 3Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran; 4Biomaterials Group, Department of Biomedical Engineering, Amirkabir University of Technology, Tehran, Iran; 5Department of Medical Nanotechnology, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran; 6Division of Digestive and Liver Diseases, Department of Medicine, Irving Cancer Research Center, Columbia University, New York, NY, USA; 7Nanotechnology & Regenerative Medicine Commercialization Centre (Ltd), The London BioScience Innovation Centre, London, United Kingdom

ARTICLE HISTORY Received: January 18, 2017 Accepted: March 14, 2017 DOI: 10.2174/1381612823666170419105413

Abstract: Drug delivery systems are effective and attractive methods which allow therapeutic substances to be introduced into the body more effectively and safe by having tunable delivery rate and release target site. Gold nanoparticles (AuNPs) have a myriad of favorable physical, chemical, optical, thermal and biological properties that make them highly suitable candidates as non-toxic carriers for drug and gene delivery. The surface modifications of AuNPs profoundly improve their circulation, minimize aggregation rates, enhance attachment to therapeutic molecules and target agents due to their nano range size which further increases their ability to cross cell membranes and reduce overall cytotoxicity. This comprehensive article reviews the applications of the AuNPs in drug delivery systems along with their corresponding surface modifications. The highlighting results obtained from the preclinical trial are promising and next five years have huge possibility move to the clinical setting.

Keywords: Gold nanoparticle, Targeted delivery, Drug delivery, Nanoparticles, Surface modification, Nanotechnology. 1. INTRODUCTION Drug delivery systems are effective and attractive methods through which therapeutic substances are introduced into the body with more efficacy and safety by controlling the rate, time and release site of those active substances [1]. These unique characteristics can be achieved, for example, through the steady state of drug concentrations in the bloodstream. In fact, the constant level of drug concentration leads to improved overall bioavailability as well as the therapeutic index of drugs in addition to the reduction of numerous deleterious side effects [1, 2]. Over the past three decades, researchers have focused on introducing various carriers which can be applied to various payloads [1, 3]. Payloads are small molecules such as nucleic acids, drugs, and proteins [4] which are used as therapeutic substances. Carriers aid greatly to increase bioavailability and decrease side effects. Among nanoscale materials such as nanoparticles, nanowires, nanotubes and self-assembled monolayer films, the application and benefits of nanoparticles to modern medicine are numerous. Nanoscale materials are designed and developed for advanced functional medical devices as well as for a sophisticated replacement of natural tissues and other applications in modern medicine. The basic principle behind the nanoscale design lies in the ability to mimic a cell of a micrometer dimension to a nanometer scale to be able to reach all of its biochemical reactions. The development of nanoparticles is a result of the significance nanotechnology has in the biomedical research and their specific *Address correspondence to these authors at the Nanotechnology and Regenerative Medicine Ltd, The London BioScience Innovation Centre, London, U.K.; Tel/Fax: +44 7985 380 797; E-mail: [email protected] Department of Tissue Engineering & Regenerative Medicine, Iran University of Medical Sciences, Hemmat Highway, Tehran, Iran; E-mail: [email protected]

1381-6128/17 $58.00+.00

characteristics are contained within their nanometer scales. The nanoparticles’ properties originate from their excessive surface areas and their effects on chemical and physical properties of nanoparticles such as chemical reactivity, surface charge, magnetic and optical properties. Nanoscience and nanotechnology have been extremely helpful in this way since the potential of nanoscience and nanotechnology is to fabricate new nanomaterials with innovative properties. In addition, nanoscience and nanotechnology propose simple ways to modify the surface characteristics of nanoparticles with high stability [5]. One of the most stable nanoparticles is made of gold; it is also referred as gold colloids, a term coined by Thomas Graham in 1961 [6], gold is the most ancient material discussed in science. Gold was found in Bulgaria in the 5th millennium B.C., and in Egypt in 12001300 B.C. In ancient times, eating and drinking with gold utensils had been considered a sign of wealth. It was also believed that gold had medicinal properties. In great Persian medical schools, between 9th and 10th centuries, soluble gold and gold compounds were prescribed as a panacea by the Iranian pharmacist-physicians Yabir, Avicenna and Rhazes. Later, gold compounds were used in the treatment of tuberculosis in the 15th century and in the 20th century, gold thiopropanol sodium sulphonate was successfully used in the treatment of rheumatoid arthritis by European physicians [7]. The first book on colloidal gold and their medical use was published in 1618 by a doctor Francisci Antonii. Analysis of colloidal gold for the modern science was done by Michael Faraday’s in the 1850s. He identified that bulk gold and colloidal gold have different solution properties [8]. Since that work, investigations on the medical aspects of gold nanoparticles - AuNPs have been conducted in parallel with their industrial applications. In 2004, Paciotti et al. utilized AuNP vectors to target solid tumors in mice by delivering tumor necrosis factor (TNF) [9]. AuNPs with applications ranging from contrast agents in optical bioimaging to targeted delivery of drugs, peptides, nucleic acids © 2017 Bentham Science Publishers

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and other biological antigens are one of the most effective nanoparticles in nanomedicine [10, 11]. AuNPs can be easily synthesized and engineered in different ways to conjugate with different molecules and chemical moieties. In addition, they are relatively less cytotoxic in comparison to other metal nanoparticles. Such characteristics of AuNPs make them perfect candidates for nanomedicine studies, especially in targeted delivery systems. Investigations of AuNPs applications in targeted delivery systems have been widely pursued in current medical and biological research. This review will focus on the specific characteristics and the syntheses of AuNPs as well as the major contribution of AuNPs to the targeted delivery system. 2. NANOPARTICLES AS TARGETED DRUG DELIVERY SYSTEM The two available routes for drug entry into the target tissue include systematic circulation and targeted drug delivery system. Systematic drug delivery can also be classified as enteral and parenteral which can be accomplished via the intravenous, intraarterial, intra-muscular, subcutaneous, transdermal, intracerebral, or oral route. On the other hand, to improve the efficacy and reduce the adverse side effects of systemic routes, localized drug delivery systems, including topical, are applied directly. These routes of drug administration include epicutaneous, inhalation, enema, ophthalmic oral, and otic. Each of these administration routes faces various challenges such as anatomic, immunological, and mechanistic. The exact details of these challenges are beyond the scope of this review, but for a comprehensive review of challenges in oral drug delivery, please refer to Urbanska et al. [12]. Here, we review the role of nanoparticles in drug delivery systems with emphasis on AuNPs. 2.1. Nanoparticles and Anatomic Challenges Depending on the drug route of administration, there are various anatomic challenges which nanoparticles have to bypass in order to exhibit their optimal therapeutic effects. A number of biological processes including absorption, distribution, metabolism and excretion face nanoparticles on their way to the target tissue. For instance, in the oral delivery, the first challenge is the harsh and acidic environment of the stomach. Furthermore, various pH changes, presence of mucus and tight junctions of the small and large intestines. [13]. Nanoparticles are absorbed mainly through Peyer’s Patches of the small intestine, moreover; intestinal enterocytes play role in nanoparticles absorption. Florence [14] has reviewed factors like diameter, surface charge, surface ligands, shape, etc. which are determining factors in uptake and translocation of nanoparticles in oral administration. The Charge of nanoparticles has been demonstrated to have a great effect as well [14]. In addition, “the first-pass metabolism” is the second major challenge when it comes to oral route. In fact, before compounds can reach the systemic circulation they meet gastric enzymes, hepatic enzymes, and vast microbiome all of which are reducing the bioavailability of drugs. In fact, first, pass metabolism is essential to actively remove compounds from the blood. For nanoparticles, no evidence exist that this elimination mechanism plays a role [15]. Brain-blood barriers (BBB) is another example which presents an anatomic challenge in delivering therapeutic agents to the central nervous system (CNS). BBB is one of the formidable barriers composed of a number of different cell types like endothelial cells, pericytes, astrocytes and microglial cells. The highly restrictive tight junctions between the brain capillary endothelial cells are responsible for the permeability properties and limit the transport of almost all drugs [16]. The BBB was studied, with its translocation through the blood-brain barrier with a live-cell imaging on an in vitro model [17]. Besides clarifying the role of imperfections, holes and gaps in the barrier they have tried to study actual cell-barrier crossing. The most recent findings on brain delivery using gold nanoparticles have been covered in recent reviews [18-20].

Gholipourmalekabadi et al.

2.2. Nanoparticles and Immunological Challenges One of the main roles of the immune system is to neutralize and clear foreign materials from the bloodstream and any organs. For instance, opsonization is an immune process where the presence of any particles, whether of micro or nanosize but of biological origin is targeted for destruction by an immune cell known as a phagocyte. Opsonization is the first step in the neutralization or clearance of nanoparticles. Nanoparticles get covered by opsonin proteins and become more visible to the mononuclear phagocytic system (MPS). The second step is when phagocytes attach to the nanoparticles. The attachment is facilitated by special receptors on phagocytes, nonspecific adherence and complement activation. And, the final step is the ingestion of nanoparticles by phagocytes. In terms of non-biodegradable nanoparticles, the clearance process takes place via renal system and neutralization is cleared through one of the MPS organs such as liver or spleen. Therefore a large number of research is devoted to effective camouflage of the nanoparticles from the immune system. Additional emphasis is placed on exploring and optimizing the size, shape, charge and surface ligands of these nanoparticles to overcome the above described challenges. 2.3. Nanoparticles and Mechanistic Challenges Mechanistic challenges in targeted drug delivery systems include the following: variation in cell membranes permeability and uptake, bio-therapeutic instability, uncontrolled drug elimination, poor drug loading and nonspecific drug delivery. Small size, high surface area-to-volume ratio, high tunability and multivalent surface structure of nanoparticles provide more opportunities to overcome these challenges. The cell membrane employs a number of transport mechanisms including passive osmosis, diffusion, transmembrane protein channels and transporters, endocytosis, and exocytosis. The permeability of cell membrane depends not only on size, shape and surface properties but also on the type of cell, its membrane integrity and charge of present nanoparticles [21, 22]. Efflux pump activities are responsible for moving compounds, like neurotransmitters, toxic substrate and antibodies, out of the cell. In the drug delivery concept, the efflux system is one of the main obstacles of biotheraputic instability and uncontrolled drug elimination. This mechanism limits the efficacy of chemotherapy and it is also responsible for multiple drug resistance. This obstacle can be minimized by customization of drug delivery systems. One such approach is to design and optimize nanoparticles using high concentration loading and long retention time of the drug in the plasma. Another method is to design a drug delivery system that inhibits or bypasses efflux pumps on the membrane and/or enhances endocytosis by the aide of targeted nanoparticles [23, 24]. Another big concern in drug delivery system is to reach the optimal therapeutic window. There are continued efforts to effectively administer large doses of therapeutic agents with no increase in toxicity. For instance, the high surface area-to-volume ratio of nanoparticles provides dense loading capacity of therapeutic agents. An example of such delivery was demonstrated by conjugation of 100 ligands onto the AuNPs with 2nm core diameter [25]. However, the thermodynamic properties may limit the amount of drug loading into biodegradable nanoparticle between 3 to about 25 wt% of the drug [26]. Some studies have demonstrated significant increase in loading capacity by employing nanoengineered microparticles and hierarchical nanoengineered surfaces [27, 28]. Currently, several studies have designed loading of multiple therapeutic agents [29-31] and imaging them at the same time [32, 33]. 2.4. Passive and Active Targeting for Drug Delivery Generally, there are two routes of active or passive delivery of nanoparticles to target areas which can be mediated by a spontaneous, external force or targeting moiety (Fig. 1).

Targeted Drug Delivery Based on Gold Nanoparticle Derivatives

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Fig. (1). Schematic diagram shows the passive and active targeting for delivery of nanoparticles. In passive targeting pathway, passage of nanoparticles from the blood circulation into the interstitial fluids depends on their size and the capillary pore diameter. Alternatively, in addition to size dependency in targeted delivery, the attached ligands on the nanoparticles affect their permeation and targeting efficacy.

Passive targeting occurs when the transport of nanocarriers enters targeted tissue by convection or passive diffusion. The passive targeting approach forms the basis for clinical therapy. The observation of the unique pathophysiological characteristics of tumor vessels more than 30 years ago opened a sight to passive targeting [34]. Different characteristics of diseased tissues in comparison with normal tissue can be used to design new therapies. These differences are vascular abnormalities, oxygenation, perfusion, pH, and metabolic states. For instance, some tumors show enhanced permeability and retention (EPR) effects, which can be exploited to deliver macromolecules with sizes larger than 100 nm (up to 400 nm) into surrounding tumor region. Stimuli-responsive drug delivery systems like thermosensitive nanocarriers, and pHsensitive drug released systems have been designed to be stable at the physiological condition, but degraded to release therapeutic agents at the pathological state [34, 35]. Nevertheless, passive targeting approaches suffer from several limitations: (i) Long-circulation of the drug to provide a sufficient level of accumulation in the targeted tissue. (ii) random nature makes it difficult to control the process. (iii) Some diseases or tumors do not exhibit much difference from normal tissues in terms of guiding principles. In order to improve the effect of passive targeting and overcome the limitations of it, active targeting has been suggested. Inactive targeting, affinity ligands such as nanoparticles bind only to specific receptors on the cell surface by employing conjugation chemistries [36]. These affinity ligands usually are referred to as targeting moieties or vector molecules. Monoclonal antibodies, antibody fragments, lectins, peptides, lipoproteins, hormones, aptamers, and small molecules are part of studied targeting moieties which bond to appropriate receptors overexpressing the target site to improve uptake of the nanocarriers [37-39]. Active targeting is particularly attractive for intracellular delivery of macromolecular payloads such as DNA, siRNA and proteins via receptor-mediated

endocytosis. Both targeted and non-targeted pathways are illustrated in Fig. 2. It is important to note that particle size, shape and surface properties (such as surface charge and surface hydrophobicity) of nanoparticles are crucial factors to be considered in drug delivery, both passive and active targeting [40]. 3. GOLD NANOPARTICLES The physical, chemical, optical, thermal and biological properties of metal-based nanoparticles make them highly suitable nanomaterials candidates to be utilized in medicine [41]. First and foremost, they bear one of the lowest cytotoxicity among other metals like copper or silver used in biomedical applications, as well as highest absorption rate [41]. Moreover, they display a high level of quality and reproducibility on a large synthesis scale [42, 43]. These attractive properties turned them into desirable biomaterials for various medical applications. The following are biomedical applications of AuNPs, including photomedicine, targeted delivery of drugs, tissue engineering, cellular probes, biosensors, optical contrast agents, surface modification agents, antimicrobial agents and destruction of cancer cells with their theranostic properties (Fig. 3). Here, we briefly describe each field and the targeted drug delivery which is the main focus of this review. Advanced design and preparation of interactions between biomaterials and biological environments at the surface of biomaterials are done in order to reach the desired in vivo applications. In fact, the types of surface modifications and surface coatings depend on the end applications. AuNPs as an osteogenic agents accelerate bone tissue regeneration [44]. Titanium implant surfaces were functionalized with AuNPs grafted via Au-S bonds. The gold enriched implants showed significantly enhanced osseous interface in animal testing. AuNPs have also been utilized as a passivation layer for coating iron nanoparticles leading to enhanced biocompatibility [45, 46].



Fig. (2). Schematic diagram shows the targeted and non-targeted pathways for drug delivery system. The physicochemical properties of nanoparticles determine their cellular uptake mechanism(s), in non-targeted delivery systems. In targeted pathway, the specific receptors/markers mediate the cellular internalization of nanoparticles.

Photomedicine is the science of studying and applying light either alone or in combination with photosensitive agents in diagnostic and therapeutic fields [47]. AuNPs are of special interest in the field of photomedicine because of their unique optical properties such as distinctive extinction bands in the visible region due to surface plasmon oscillation of free electrons and the quantum size effect which results in the specific size dependent optical properties. The potential of AuNPs in the field of photomedicine has been explored in numerous scientific imaging areas including X-ray, fluorescence, surface enhanced Raman spectroscopy, optical, photoacoustic, photothermal therapy and radiotherapy [32, 40, 48]. Antimicrobial intrinsic property of AuNPs has been widely studied and reviewed [49]. Incorporating AuNPs as functional nanoparticles with tissue engineering has emerged as one of the most exciting research topics in this field. Electrical and plasmonic properties of AuNPs have also received much attention. The electrical properties of AuNPs were utilized in designing skeletal muscle composite scaffolds in order to create biodegradable, biocompatible and electrically conductive scaffolds [50]. AuNPs have also been studied in conjugation with electrospun fibers in series of studies for cardiac tissue engineering [51], skin wound healing [52, 53] and treatment of osteoporosis [54].

3.1. Gold Nanoparticle Physico-Chemical Properties Vascular system is the first step in targeted delivery. The next step is to reach the site at the destination level, which is achieved by crossing the capillary walls, reaching the extracellular fluid of the tissues and then finishing by crossing the targeted cell walls. The optical, spectroscopic, thermal, surface plasmon, cellular uptake, selective toxicity, targeted and controlled drug delivery properties of AuNPs depend on their size, shape and surface properties (Fig. 4). Surface, especially within nanometer scale, can play an important role in adhesion due to increased contact area for Van der Waals attraction. Moreover, gravitational force is much smaller to nanoparticles therefore they can be kept in a liquid suspension. However, thermal fluctuation (the Brownian motion) of nanoparticles is greater than their settling velocity; and as a result, nanoparticle suspensions do not settle down [55]. Selection of desired routes of drug administration plays an important role; particles size and surface properties are considered to be the most crucial parameters in achieving specific and efficacious access to targeted cells. Table 1 highlightes the recent studies that tried to determine the optimal nanoparticle size which could prevent their rapid clearance from



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Fig. (3). The main biological and medical applications of gold nanoparticles (AuNPs). AuNPs can attenuate the X-ray because of the high atomic number of Au atoms. Consequently, they are used in molecular imaging modalities such as CT-scan, PET-CT, and etc. AuNPs also are used for delivery of wide range of therapeutic agents. Moreover, because of their attractive physical properties such as localized Surface Plasmon Resonance (LSPR) phenomenon, AuNPs are the suitable choice for design and fabrication of different types of nanobiosensors. AuNPs turn the near infra-red (NIR) radiation to thermal energy, which known as photothermal effect and widely evaluated in many studies. Reprinted with permission from [104, 84]. Scale bar = 50 nm.

circulation and most efficient uptake of organs including the liver and spleen [56-58]. AuNPs can be categorized as spherical or non-spherical. Nonspherical nanoparticles have been synthesized into various shapes like nanorods [59], nanocages [60, 61], nanostars [62] or naoclusters (Fig. 5). Although the shapes of AuNPs play very important role in delivery mechanisms, some special coatings and surface modifications are often applied to further improve the targeted drug delivery. In fact, surface modifications of AuNPs with oligos polymers, photoactive dyes, antibodies, enzymes, proteins, nucleic acids and drugs have emerged as attractive candidates for theranostic nanomedicine [63-66]. Surface modifications are employed for the following reasons: improved circulation, decreased aggregation rates, enhanced attachment of therapeutic molecules and target agents, greater ability to cross cell membranes and reduced cytotoxicity [67]. For instance, it has been showed that positively charged nanoparticles penetrate skin 2-6 times better when compared to negatively charged nanoparticles. It has also been observed that peptide-coated AuNPs penetrate the skin in larger numbers (up to 10 times more) in comparison to PEGylated nanoparticles [67]. New strategies for the development of targeted drug delivery based on the size and surface properties of nanoparticles is currently being evaluated by numerous studies and several clinical trials are currently under evaluation (Table 2).

their size and shape can affect their properties. Because the fabrication of AuNPs varies in size between 1 nm to >500 nm, they have been widely useful in biological applications as carriers for drug delivery systems. For instance, they can be transformed into spherical, rod-like and core-shell shapes. To control shape of the AuNPs, additional surfactants are often required. For example, the use of sodium dodecylsulfonate, cetyltrimethylammonium bromide (CTAB), and poly (vinylpyrrolidone) (PVP) [69] is often employed. There are two approaches for the synthesis of AuNPs: “top down” and “bottom up” [68]. These approaches are in contradiction with each other. In the “top down” methodology, strong ion irradiation or arc force is being used to break the bulk gold. “Bottom up” approach consists of a wet chemical process. The chemical reduction of chloroauric anions is the general procedure in wet-chemical synthesis method [70]. Citrate reduction of AuCl4- in aqueous solution was described by Turkevich method in 1951 [68]. Some parameters like speed of reduction, temperature and others can affect the properties of AuNPs in wet-chemical synthesis method. For instance, the controlling the size by adjustment of the Turkevich method using NaBH4- in lower temperature could lead to synthesis of AuNPs within a 3-5nm range [71]. The smallest diameter nanoparticles are typically made by reduction of gold with a strong reducing agent in the presence of thiol molecules [72]. Usually nucleation and successive growth are two steps of synthesis and they yield several functions of AuNPs.

3.2. Gold Nanoparticle Synthesis For the last two decades, the main focus in synthesizing AuNPs is focused on the ability to control the size, structure, shape and other tunable surface properties [68]. It is important to understand the synthesis and functionalization of AuNPs due to the fact that

4. GOLD NANOPARTICLE APPLICATIONS IN TARGETED DRUG DELIVERY Nowadays, applications of nano-based drug delivery systems enhance the pharmacokinetics and pharmacodynamics properties of various types of therapeutics. Numerous investigations have shown



Fig. (4). The effects of size, shape and surface properties of gold nanoparticles on their optical, spectroscopic, thermal, surface plasmon, cellular uptake, selective toxicity and targeted and controlled drug delivery properties. Different syntehsis methods result in different shape and size of nanoparticles, which remarcably affect their cytotoxicity, targeting strategy and applications. (Reprinted with permission from [61, 63, 70, 129, 85]. Scale bar for nanospheres, nanorods, nanocages, nanoshell and nanostars are 50 nm, 100 nm, 100 nm (insert: 20 nm), 10 nm and 50 nm, respectively.

Fig. (5). TEM images of spherical (Reprinted with permission from [63]) and non-spherical AuNPs for targeted delivery systems include nanorods (modified with permission from [70]), nanocages (Reprinted with permission from [61]), nanostars (Reprinted with permission from [129]) (left to the right). Diferent synthesis methods lead to formation of AuNPs in various shape. Scale bar for spherical, nanorods, nanocages and nanostars are 50 nm, 100 nm, 100 nm (insert: 20 nm) and 50 nm, respectively.

that in cancer therapy, the use of different types of nanoparticles such as metallic, carbon and composites nanoparticles affect the therapeutic efficacy by enhancing drug circulation time in the tumor microenvironments, specific targeting and drug-loading. On the other hand, nanoparticles, as smart payloads delivery systems, improve effectiveness of the delivery and enhance uptake and controlled release of the payloads. Previous studies have shown that the combination of nanotechnology with biology has opened a new window of hope to achieve less toxicity, greater safety and biocompatibility while maintaining therapeutic effects of various drugs. Consequently, the applications of bio-nanotechnology helped to speed up the development of new generation of safe medicine. The

conjugation of AuNPs to specific payloads is critical and several studies are undergoing to establish an effective strategy in this matter. In general, two main strategies have been developed of drug conjugation to AuNPs, namely, directly conjugation of AuNPs to payloads and conjugation of payloads to surface-modified AuNPs. These two strategies will be discussed in the next section. 4.1. Direct Conjugation of Gold Nanoparticles with Payloads In direct conjugation, a physical interaction between payloads and AuNPs occurs. This interaction depends on ionic force (between the negatively charged gold and the positively charged payloads), hydrophobic band (between gold surface and hydrophobic


Table 1.


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Summary of selected publications on AuNpsfor drug delivery systems. Keys: II, Intravenous Injection.

Route of Administration

Size (nm)

Shape

Surfaces Modification/Conjugation

Nanoparticle Behavior

References

II

10,50,100,250

NA

NA

Biodistribution

[122]

Oral

1.4,5.15.80.200

NA

Carboxyl, Amine groups

Biodistribution

[123]

II

15,102,198

NA

NA

Biodistribution

[40]

II

Aspect ratio:4.4

Nanorods

Poly(sodium 4-styrenesulfonate)

Higher loading and Controlled released

[124]

Transdermal

15

Nanospheres/nanorodes


Depth of penetration

[67]

II

Aspect ratio:5.9

Nanorods

Polyethyleneglycol

Stealth character

[125, 126]

II

NA

Nanocages

Smart polymer (Poly(Nisopropylacrylamide)

Controlled released

[127]

Intratumoral injection

NA

Nanostars

TAT-nanostars

Cellular uptake

[128]


NA

Nanostars

Cucurbit[n]urils

Controlled released

[130]


258

Nanocluster

Cyclodextrin hyaluronic acid

Cellular uptake

[131]


NA

Nanocluster

Folic acid Amphiphilic hyperbranched block copolymer

Cellular uptake

[132]

Transdermal

10

NA

NA


[133]

Percutaneous

5

NA

Polyvinylpyrrolidone-coated gold


[134]

Transdermal

12.6

Spherical

Citrate


[135]

Inhalation

70,90

NA


Cellular uptake

[136]

Topical

4

NA

Sodium 3-mercapto-1propansulfonate

Percutaneous absorption

[137]

Table 2.

Summary of selected clinical trials on nanoparticles for drug delivery systems.

Clinical Trials Number

Route of Administration

Drug delivery system

Drug

Phase

NCT01523314

Eye drops

Cyclodextrin nanoparticles

Dexamethasone

Phase2

NCT02369198

Intravenous Injection

Nonliving bacterial minicells (nanoparticles)

TargomiRs

Phase 1

NCT020033447

Intratumoral Injection

Nanoparticles

Magnetic Iron

Phase 0

NCT02194829

Intravenous Injection

Albumin-stabilized nanoparticle

Paclitaxel

Phase 2

NCT012700139

Transplant

Silica-AuNP

Stem cells

Completed

section of cargo), and a co-ordinate or dative covalent bond between gold conducting electrons and load sulfur atoms. the chemical interaction between payloads and external surface of nanoparticle is attained through chemisorption (by means of thiol derivatives), bi-functional linkers and adapter molecules such as biotin and streptavidin [73, 74]. 4.2. Gold Nanoparticle Modification for Drug Delivery A number of surface modifications have been performed to accommodate and optimize AuNPs for their applications in drug

delivery. The functional coating made the nanoparticles more biocompatible and stable in the physiological environment. For instance, the interaction between the immune system and nanomaterial can be significantly reduced by coating the nanoparticle with a layer of poly-ethyleneglycol (PEG). In this regard, the PEG may be applied alone or in conjunction with other molecules such as biotin, oligonucleotides and peptides to facilitate the internalization of gold nanoparticles to the target cells [75-82]. In order to figure out the effects of different physicochemical properties (size, ligand and polyethylene glycolylation (PEGylation)) of AuNPs on the stability,



Fig. (6). The functionalization of gold nanoparticles with PEG and a targeting ligand (galactose). Amount of different nanoparticles in b) blood and c) liver.

efficacy and relevant side effects of drug delivery, Bergen et al. [83] conjugated PEG to AuNPs, and then grafted Galactose-PEGthiols to PEG-NP to fabricate Gal-PE-AuNPs constructs. Gal-PEAuNPs constructs were engineered for active targeting of hepatocytes in the liver. At 2h post-injection, the samples were collected from blood and liver and analyzed. The results revealed that PEGylation significantly increased the stability of the construct in blood and the presence of Galactose as a ligand profoundly facilitated infiltration of the delivery system into hepatocytes (Fig. 6). 4.2.1. Core-Shell Gold Nanoparticles Modifications Core-shell nanoparticles (CSNs) are a group of nano-materials which have recently received a substantially increased consideration due to their interesting properties and a broad range of applications in catalysis, biology, materials chemistry and sensors [103105]. By applying a simple chemical modification to the cores as well as the shells of such materials, a range of CSNs can be generated with tolerable properties that can play important roles in various catalytic reactions and offer a sustainable answer to current energy issues [43, 84]. Gold nano-shells (GNSs) have extensively been studied since their invention in photothermal therapy which has been explored and demonstrated both in vitro and in vivo [43, 84-86]. A variety of synthetic methods of preparing different classes of CSNs includes the solvothermal method, Stöber approach [84, 87, 88] and one-pot based synthetic method involving surfactants [87, 88] . The roles of various classes of CSNs are well described for both catalytic and electrocatalytic applications, including oxidation, reduction and coupling reactions [84, 89, 90].

4.2.2. AuNPs for Gene Delivery Gene therapy is an interesting strategy for treatment of many diseases. In the future, this technique may allow clinicians to treat a disorder by inserting a gene into a patient’s cells instead of using drugs or surgery [91]. In general, nucleic acid delivery systems are usually divided into two classes: biological delivery vectors and synthetic vehicles. The use of vectors (viral and non-viral) plays an essential role to transfer foreign genes into somatic cells [92, 93]. The use of viral components as a vehicle for gene therapy is now well established [94]. However, several data has confirmed the disadvantages associated with virus-based vectors delivery systems such as irregular cytotoxicity, host immune response, non-specific targeting of defects, short DNA carrying ability and capacity, carcinogenicity, and complexity in manufacturing and packaging [11, 92, 95]. In contrast, the synthetic vectors such as those based on nanoparticles; cationic lipids [96, 97], polymer [98, 99] and dendrimers [100] have been successfully used for intracellular nucleic acid delivery. These non-viral gene delivery systems aid to develop optimal stability and distribution in the host and in vivo environments. Such characteristics offer a high-quality feature to use these materials as drug delivery vehicles to carry nucleic acids [101]. Despite their efficacy in transformation, transfection and large-scale production ability, nucleic acid delivery system based on nanoparticles still has limitations in clinical applications, e.g., the lack of precise targeting, limitations of in vivo tracking/monitoring [102]. Several studies recommend the use of AuNPs-scaffolds for delivery of nucleic acids. In addition to the DNA delivery, AuNPs also have been used as siRNA delivery vehicles to target cells and/or tissues [103].


4.2.3. AuNPs as Antibacterial Agents Since discovery of the first antibiotic in 1928, various antibiotic resistant mechanisms have been identified in bacteria [104]. Overuse or misuse of available antibiotics has resulted, over the years, a development of multi-drug resistant bacteria [105, 106]. The incidence rate of such resistant bacteria is significantly higher than the rate of discovering new effective antibiotics [107]. For instance, it is widely known that during surgeries especially organ transplantation, physicians struggle with finding most suitable and efficacious antibiotics for patients [108]. Until today, many efforts have been made to develop a novel antibacterial agent with strong antibacterial activity and high safety [109]. Recently, the strong and broadspectrum antibacterial properties of metal nanoparticles and oxides such as Au, Ag, and ZuO have attracted the attentions of researchers for fabrications of novel antibacterial agents [110-113]. Favorable and inherent characteristics of AuNPs such as synthesis feasibility, high biocompatibility, high ability in being mixed with functional molecules and other nanoparticles, overall safety and easy of use have made them promising candidates for developing the antibacterial agents [105, 114, 115]. Zhou et al. [116] showed high antibacterial activity of AuNPs against Escherichia coli and Mycobacterium bovis. Lima et al. [117] investigated the antibacterial properties of various forms of AuNPs (faujasite zeolites, mordenite and clinoptilolite) against Escherichia coli and Salmonella typhi. According to their results, the AuNPs in zeolite forms showed stronger and faster antibacterial activity in comparison with mordenite and clinoptilolite. They concluded that destruction feature of AuNPs highly depends on the size, nanoparticles morphology and roughness [136]. The effects of concentration and size on antibacterial property of AuNPs against enteric human intestinal pathogens were studied by Shamaila et al. [118]. Their results revealed that AuNPs within size range of 6-40 mm had the highest bactericidal activity. In addition, the concentration of AuNPs highly affected their antibacterial activity as well [118]. Payne and coworkers [105] showed that the antibacterial property of kanamycin (an aminoglycoside bacteriocidal antibiotic) can be significantly enhanced when conjugated onto AuNPs. They reported that the increased antibacterial activity of kanamycinconjugated to AuNPs may be associated with increased destruction of bacterial membrane surface, leakage of cytoplasm contents and improved bacterial death [105]. With a substantial increasing number of studies on metal nanoparticles, we expect more mechanisms being postulated, more features to be explored, and a wider list of applications being generated. Future research in the areas relevant to the synthesis of antibacterial materials can open up new ways for effective cure of resistant infections to the currently available antibiotics. 4.2.4. Peptide/Protein-Coated AuNPs Proteins are vital macromolecules in biological systems that are indispensable to the proper functioning of cells and organisms. The impact of AuNPs in living organisms at the protein level is a serious issue that attracts great attention of researchers. Due to their clear structure and biodegradable natural properties, proteinconjugated AuNPs (protein-AuNPs) offer large possibilities for the surface modifications and covalent binding to drugs and ligands [119, 120]. Gelatin, albumin, gliadin, legumin, zein and soy are some of the most important proteins that are usually used for AuNPs formulations. Peptide-AuNPs have numerous advantages which make them attractive for therapeutic applications [121]. In fact, their small size minimizes the overall radius of the resulting peptide-AuNPs [120]. In addition, their tiny volume reduces immunogenicity in vivo. Their production is also economical. Moreover, peptide nanoparticles are known to be biocompatible, derived from naturally occurring protein precursors, and can act exceptionally specific. In addition, they also bind tightly to their receptors [121].


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4.2.5. Carbohydrate-Coated AuNPs Animal cell surfaces are covered with a dense coating of carbohydrates that are involved in cellular processes including cell-cell recognition, pathogenesis, inflammation, cancer, and immune surveillance of tumors [121, 131]. The following are additional processes of these interactions: protein-carbohydrate and carbohydratecarbohydrate. Carbohydrate coated AuNPs have proved to be an efficient therapeutic material. Conjugating carbohydrates on AuNP surfaces improves their biocompatibility, targeting, and efficacy [121]. CONCLUSION The potential of AuNPs as a drug delivery vehicle has been confirmed in many in vitro and pre-clinical assessments, with promising results such as high cellular uptakes of AuNPs conjugated with drugs, and low immunogenicity and toxicity levels. In addition to these successful studies, a popular research aim is to investigate the most optimum surface modification of AuNPs which is vital to maximize the efficiency of drug delivery. This is reflected in the rising number of in vitro and pre-clinical studies being carried out by various research groups. Many studies showed that AuNPs have desirable properties to use them in many biotechnology applications, including as organic photovoltaics, sensory probes, therapeutic agents, imaging, and more specifically drug delivery for treating cancer cells as well as other diseases. Nanomedicine is an emerging field, which constitutes a new direction in the treatment of many diseases. Nanotechnology sector, a multibillion-dollar industry, has the ability to take basic scientific concepts and extend their value by moving them into clinical trials with possible products in future. CONFLICT OF INTEREST The authors declare that there is no conflict of interests regarding the publication of this paper. ACKNOWLEDGEMENTS Declared none. REFERENCES [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]

Park K. Controlled drug delivery systems: past forward and future back. J Controlled Release 2014; 190: 3-8. Ranade VV, Cannon JB. Drug delivery systems. CRC press 2011. Han G, Ghosh P, De M, Rotello VM. Drug and gene delivery using gold nanoparticles. Nanobiotechnology 2007; 3: 40-45. Han G, Ghosh P, Rotello VM. Functionalized gold nanoparticles for drug delivery. Future Med 2007; 2: 113-23. Grace AN, Pandian K. Antibacterial efficacy of aminoglycosidic antibiotics protected gold nanoparticles—A brief study. Colloids Surf. Physicochem. Eng Aspects 2007; 297: 63-70. Graham T. Liquid diffusion applied to analysis. Philos. Trans. R. Soc. London, 1861; 151: 183-224. Kean W, Kean I. Clinical pharmacology of gold. Inflammopharmacology 2008; 16: 112-25. Mody VV, Siwale R, Singh A, Mody HR. Introduction to metallic nanoparticles. J Pharm Bioallied Sci 2010; 2: 282. Paciotti GF, Myer L, Weinreich D, et al. Colloidal gold: a novel nanoparticle vector for tumor directed drug delivery. Drug Deliv 2004; 11: 169-83. Dykman L, Khlebtsov N. Gold nanoparticles in biomedical applications: recent advances and perspectives. Chem Soc Rev 2012; 41: 2256-82. Ghosh P, Han G, De M, Kim CK, Rotello VM. Gold nanoparticles in delivery applications. Adv Drug Del Rev 2008; 60: 1307-15. Urbanska AM, Karagiannis ED, Au AS, Dai SY, Mozafari M, Prakash S. What's next for gastrointestinal disorders: No needles? J Control Release 2016; 221: 48-61. Araújo F, Shrestha N, Granja PL, Hirvonen J, Santos HA, Sarmento B. Safety and toxicity concerns of orally delivered nanoparticles as drug carriers. Expert Opin Drug Metab Toxicol 2015; 11: 381-93.

10 Current Pharmaceutical Design, 2017, Vol. 23, No. 00 [14] [15] [16] [17]

[18] [19] [20] [21] [22] [23] [24] [25]

[26] [27] [28] [29] [30]

[31] [32] [33] [34] [35] [36] [37] [38]

Florence AT. Nanoparticle uptake by the oral route: fulfilling its potential? Drug Discov Today: technologies 2005; 2: 75-81. Hagens WI, Oomen AG, de Jong WH, Cassee FR, Sips AJ. What do we (need to) know about the kinetic properties of nanoparticles in the body? Regul Toxicol Pharmacol 2007; 49: 217-29. Begley DJ. Delivery of therapeutic agents to the central nervous system: the problems and the possibilities. Pharmacol Ther 2004; 104: 29-45. Bramini M, Ye D, Hallerbach A, Nic Raghnaill M, Salvati A, Åberg C, Dawson KA. Imaging approach to mechanistic study of nanoparticle interactions with the blood-brain barrier. ACS nano 2014; 8: 4304-12. Alyautdin R, Khalin I, Nafeeza MI, Haron MH, Kuznetsov D. Nanoscale drug delivery systems and the blood-brain barrier. Int J Nanomed 2014; 9: 795-811. Wohlfart S, Gelperina S, Kreuter J. Transport of drugs across the blood-brain barrier by nanoparticles. J Control Release 2012; 161: 264-73. Gabathuler R. Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases. Neurobiol Dis 2010; 37: 48-57. Alkilany AM, Murphy CJ. Toxicity and cellular uptake of gold nanoparticles: what we have learned so far? J Nanopart Res 2010; 12: 2313-33. Cartiera MS, Johnson KM, Rajendran V, Caplan MJ, Saltzman WM. The uptake and intracellular fate of PLGA nanoparticles in epithelial cells. Biomaterials 2009; 30: 2790-8. Xue X, Liang X-J. Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology. Chin J Cancer 2012; 31: 100. Christena LR, Mangalagowri V, Pradheeba P, et al. Copper nanoparticles as an efflux pump inhibitor to tackle drug resistant bacteria. RSC Adv 2015; 5: 12899-909. Hostetler MJ, Wingate JE, Zhong CJ, et al. Alkanethiolate gold cluster molecules with core diameters from 1.5 to 5.2 nm: core and monolayer properties as a function of core size. Langmuir 1998; 14: 17-30. Kumar V, Prud'Homme RK. Thermodynamic limits on drug loading in nanoparticle cores. J Pharm Sci 2008; 97: 4904-14. Fischer KE, Jayagopal A, Nagaraj G, et al. Nanoengineered surfaces enhance drug loading and adhesion. Nano Lett 2011; 11: 1076-81. Fischer KE, Nagaraj G, Daniels RH, et al. Hierarchical nanoengineered surfaces for enhanced cytoadhesion and drug delivery. Biomaterials 2011; 32: 3499-506. Hu C-MJ, Aryal S, Zhang L. Nanoparticle-assisted combination therapies for effective cancer treatment. Ther Deliv 2010; 1: 323-34. Meng H, Wang M, Liu H, et al. Use of a lipid-coated mesoporous silica nanoparticle platform for synergistic gemcitabine and paclitaxel delivery to human pancreatic cancer in mice. ACS nano 2015; 9: 3540-57. Sun R, Liu Y, Li SY, et al. Co-delivery of all-trans-retinoic acid and doxorubicin for cancer therapy with synergistic inhibition of cancer stem cells. Biomaterials, 2015; 37: 405-14. Kim D, Jeong YY, Jon S. A drug-loaded aptamer− gold nanoparticle bioconjugate for combined CT imaging and therapy of prostate cancer. ACS nano 2010; 4: 3689-96. Dong H, Du SR, Zheng XY, et al. Lanthanide nanoparticles: from design toward bioimaging and therapy. Chem Rev 2015; 115: 10725-815. Bertrand N, Wu J, Xu X, Kamaly N, Farokhzad OC. Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology. Adv Drug Del Rev 2014; 66: 2-25. Kanamala M, Wilson WR, Yang M, Palmer BD, Wu Z. Mechanisms and biomaterials in pH-responsive tumour targeted drug delivery: A review. Biomaterials 2016; 85: 152-67. Bamrungsap S, Zhao Z, Chen T, et al. Nanotechnology in therapeutics: a focus on nanoparticles as a drug delivery system. Nanomedicine 2012; 7: 1253-71. Shargh VH, Hondermarck H, Liang M. Antibody-targeted biodegradable nanoparticles for cancer therapy. Nanomedicine 2016; 11: 63-79. Torchilin V P, Lukyanov A N. Peptide and protein drug delivery to and into tumors: challenges and solutions. Drug Discov Today 2016; 8: 259-66.

Gholipourmalekabadi et al. [39] [40] [41] [42] [43] [44]

[45] [46] [47] [48] [49] [50]

[51] [52] [53] [54] [55] [56] [57] [58] [59]

[60] [61] [62] [63] [64]

Liu J, Wei T, Zhao J, et al. Multifunctional aptamer-based nanoparticles for targeted drug delivery to circumvent cancer resistance. Biomaterials 2016; 91: 44-56. Sonavane G, Tomoda K, Makino K. Biodistribution of colloidal gold nanoparticles after intravenous administration: effect of particle size. Colloids Surf B Biointerfaces 2008; 66: 274-80. Hamblin MR, Avci P. Applications of Nanoscience in Photomedicine. Elsevier 2015; 220. Vigderman L, Zubarev ER. Therapeutic platforms based on gold nanoparticles and their covalent conjugates with drug molecules. Adv. Drug Del Rev 2013; 65: 663-76. Duncan B, Kim C, Rotello VM. Gold nanoparticle platforms as drug and biomacromolecule delivery systems. J Control Release 2010; 148: 122-7. Heo DN, Ko W-K, Lee HR, et al. Titanium dental implants surface-immobilized with gold nanoparticles as osteoinductive agents for rapid osseointegration. J Colloid Interface Sci 2016; 469: 129-37. Chen M, Yamamuro S, Farrell D, Majetich SA. Gold-coated iron nanoparticles for biomedical applications. J Appl phys 2003; 93: 7551-3. Mikalauskaitė A, Kondrotas R, Niaura G, Jagminas An. Goldcoated cobalt ferrite nanoparticles via methionine-induced reduction. J Phys Chem C 2015; 119: 17398-407. Kah J, Yeo E, He S, Engudar G. Gold nanorods in photomedicine. Applications Nanosci Photomed 2015: 221. Mieszawska AJ, Mulder WJ, Fayad ZA, Cormode DP. Multifunctional gold nanoparticles for diagnosis and therapy of disease. Mol Pharm 2013; 10: 831-47. Zhang Y, Shareena Dasari TP, Deng H, Yu H. Antimicrobial activity of gold nanoparticles and ionic gold. J Environ Sci Heal C 2015; 33: 286-327. McKeon-‐Fischer K, Freeman J. Characterization of electrospun poly (L-‐lactide) and gold nanoparticle composite scaffolds for skeletal muscle tissue engineering. J Tissue Eng Regen Med 2011; 5: 560-8. Fleischer S, Shevach M, Feiner R, Dvir T. Coiled fiber scaffolds embedded with gold nanoparticles improve the performance of engineered cardiac tissues. Nanoscale 2014; 6: 9410-4. Akturk O, Kismet K, Yasti AC, et al. Wet electrospun silk fibroin/gold nanoparticle 3D matrices for wound healing applications. RSC Adv 2016; 6: 13234-50. Aktürk Ö, Keskin D. Collagen/PEO/gold nanofibrous matrices for skin tissue engineering. Turk J Biol 2016; 40: 380-98. Fischer RL, McCoy MG, Grant SA. Electrospinning collagen and hyaluronic acid nanofiber meshes. J Tissue Eng Regen Med 2012; 23: 1645-54. Wu L, Zhang J, Watanabe W. Physical and chemical stability of drug nanoparticles. Adv Drug Del Rev 2011; 63: 456-69. Ernsting MJ, Murakami M, Roy A, Li S-D. Factors controlling the pharmacokinetics, biodistribution and intratumoral penetration of nanoparticles. J. Control Release 2013; 172: 782-94. Sa LTM, de Souza Albernaz M, de Carvalho Patricio BF, et al. Biodistribution of nanoparticles: initial considerations. J Pharm Biomed Anal 2012; 70: 602-4. Alric C, Miladi I, Kryza D, et al. The biodistribution of gold nanoparticles designed for renal clearance. Nanoscale 2013; 5: 5930-9. Alkilany AM, Thompson LB, Boulos SP, Sisco PN, Murphy CJ. Gold nanorods: their potential for photothermal therapeutics and drug delivery, tempered by the complexity of their biological interactions. Adv Drug Del Rev 2012; 64: 190-9. Xia Y, Li W, Cobley CM, et al. Gold nanocages: from synthesis to theranostic applications. Acc Chem Res 2011; 44: 914-24. Chen J, Wiley BJ, Li Z, et al. Gold nanocages: engineering their structure for biomedical applications. Adv Mater 2005; 17: 2255-61. Sironi L, Borzenkov M, Collini M, D’Alfonso L, Bouzin M, Chirico G. Interactions of Gold Nanostars with Cells. In: ed.êds., Gold Nanostars. Springer 2015; pp. 61-74. Perrault SD, Chan WC. Synthesis and surface modification of highly monodispersed, spherical gold nanoparticles of 50− 200 nm. J Am Chem Soc 2010; 132: 11824. Nativo P, Prior IA, Brust M. Uptake and intracellular fate of surface-modified gold nanoparticles. ACS nano 2008; 2: 1639-44.

Targeted Drug Delivery Based on Gold Nanoparticle Derivatives [65] [66] [67] [68] [69] [70] [71] [72] [73] [74]

[75] [76] [77]

[78] [79]

[80] [81] [82] [83]

[84]

[85] [86]

[87]

[88]

Pissuwan D, Niidome T, Cortie MB. The forthcoming applications of gold nanoparticles in drug and gene delivery systems. J Control Release 2011; 149: 65-71. Cobley CM, Au L, Chen J, Xia Y. Targeting gold nanocages to cancer cells for photothermal destruction and drug delivery. Expert Opin Drug Deliv 2010; 7: 577-87. Fernandes R, Smyth NR, Muskens OL, et al. Interactions of skin with gold nanoparticles of different surface charge, shape, and functionality. Small 2015; 11: 713-21. Valcárcel M, López-Lorente ÁI. Gold nanoparticles in analytical chemistry. Elsevier. 1st Edition 2014; 66: 642. Grzelczak M, Pérez-Juste J, Mulvaney P, Liz-Marzán LM. Shape control in gold nanoparticle synthesis. Chem Soc Rev 2008; 37: 1783-91. Jana NR, Gearheart L, Murphy CJ. Wet chemical synthesis of high aspect ratio cylindrical gold nanorods. J Physical Chem 2001; 105: 4065-7. Samal AK, Sreeprasad TS, Pradeep T. Investigation of the role of NaBH4 in the chemical synthesis of gold nanorods. J Nanopart Res 2010; 12: 1777-86. Zhao P, Li N, Astruc D. State of the art in gold nanoparticle synthesis. Coord Chem Rev 2013; 257: 638-65. Shah KB. Non-directional conjugation of fluorescent antibodies to gold nanoparticles for stem cell therapy. In: ed. University of Arkansas, Fayetteville 2016; pp. 40. Jazayeri MH, Amani H, Pourfatollah AA, Pazoki-Toroudi H, Sedighimoghaddam B. Various methods of gold nanoparticles (GNPs) conjugation to antibodies. Sen Biosensing Res 2016; 9: 17-22. Moghimi SM, Hunter AC, Murray JC. Nanomedicine: current status and future prospects. FASEB J 2005; 19: 311-30. Love JC, Estroff LA, Kriebel JK, Nuzzo RG, Whitesides GM. Selfassembled monolayers of thiolates on metals as a form of nanotechnology. Chem Rev 2005; 105: 1103-69. Takae S, Akiyama Y, Otsuka H, Nakamura T, Nagasaki Y, Kataoka K. Ligand density effect on biorecognition by PEGylated gold nanoparticles: regulated interaction of RCA120 lectin with lactose installed to the distal end of tethered PEG strands on gold surface. Biomacromolecules 2005; 6: 818-24. Khalil H, Mahajan D, Rafailovich M, Gelfer M, Pandya K. Synthesis of zerovalent nanophase metal particles stabilized with poly(ethylene glycol). Langmuir 2004; 20: 6896-903. Otsuka H, Akiyama Y, Nagasaki Y, Kataoka K. Quantitative and reversible lectin-induced association of gold nanoparticles modified with alpha-lactosyl-omega-mercapto-poly(ethylene glycol). J Am Chem Soc 2001; 123: 8226-30. Olivier JC, Huertas R, Lee HJ, Calon F, Pardridge WM. Synthesis of pegylated immunonanoparticles. Pharm. Res 2002; 19: 1137-43. Otsuka H, Nagasaki Y, Kataoka K. PEGylated nanoparticles for biological and pharmaceutical applications. Adv Drug Deliv Rev 2003; 55: 403-19. Shimmin RG, Schoch AB, Braun PV. Polymer size and concentration effects on the size of gold nanoparticles capped by polymeric thiols. Langmuir 2004; 20: 5613-20. Bergen JM, Von Recum HA, Goodman TT, Massey AP, Pun SH. Gold nanoparticles as a versatile platform for optimizing physicochemical parameters for targeted drug delivery. Macromol Biosci 2006; 6: 506-16. Maltzahn J-V, Park J-H, Agrawal A, Bandaru N-K, Sailor M-J, Bhatia S-N. Computationally guided photothermal tumor therapy using long-circulating gold nanorod antennas. Cancer Res 2009; 69: 3892-900. Pham T, Jackson J-B, Halas NJ, Lee T-R. Preparation and characterization of gold nanoshells coated with self-Assembled monolayers. Langmuir 2002; 18: 4915-20. Park H, Yang J, Seo S, Kim K, Suh J, Kim D, Haam S, Yoo KH. Multifunctional nanoparticles for photothermally controlled drug delivery and magnetic resonance imaging enhancement. Small, 2008; 4: 192-6. Khanadeev V, Khlebtsov B, Khlebtsov N. Optical properties of monodisperse gold nanoshells on silica cores. In: ed.êds., Saratov Fall Meeting 2015. Int Soc Optic Photonics 2016; pp. 991719991719-6. Iqbal M, Usanase G, Oulmi K, et al. Preparation of gold nanoparticles and determination of their particles size via different methods. Mater Res Bull 2016; 79: 97-104.

Current Pharmaceutical Design, 2017, Vol. 23, No. 00 [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100] [101] [102] [103]

[104]

[105] [106]

[107] [108] [109] [110] [111]

[112] [113]

[114]

11

Ballarin B, Barreca D, Cassani MC, et al. Gold nanoparticlesdecorated fluoroalkylsilane nano-assemblies for electrocatalytic applications. Appl Surf Sci 2016; 362: 42-8. Alex S, Tiwari A. Functionalized gold nanoparticles: synthesis, properties and applications—a review. Journal of nanoscience and nanotechnology 2015; 15: 1869-94. Naldini L. Gene therapy returns to centre stage. Nature 2015; 526: 351-60. Roy K, Mao HQ, Huang SK, Leong KW. Oral gene delivery with chitosan--DNA nanoparticles generates immunologic protection in a murine model of peanut allergy. Nat Med 1999; 5: 387-91. Luo D, Saltzman WM. Synthetic DNA delivery systems. Nat Biotechnol 2000; 18: 33-7. Yeh P, Perricaudet M. Advances in adenoviral vectors: from genetic engineering to their biology. FASEB J 1997; 11: 615-23. Check E. A tragic setback. Nature 2002; 420: 116-8. Sershen SR, Westcott SL, Halas NJ, West JL. Temperaturesensitive polymer-nanoshell composites for photothermally modulated drug delivery. J Biomed Mater Res 2000; 51: 293-8. Zhang S, Zhao B, Jiang H, Wang B, Ma B. Cationic lipids and polymers mediated vectors for delivery of siRNA. J Control Release 2007; 123: 1-10. Gupta P, Vermani K, Garg S. Hydrogels: from controlled release to pH-responsive drug delivery. Drug Discov Today 2002; 7: 569-79. Vasir JK, Reddy MK, Labhasetwar VD. Nanosystems in Drug Targeting: Opportunities and Challenges. Curr Nanosci 2005; 1: 47-64. Pissuwan D, Valenzuela SM, Killingsworth MC, Xu X, Cortie MB. Targeted destruction of murine macrophage cells with bioconjugated gold nanorods. J Nanopart Res 2007; 9: 1109-24. Felnerova D, Viret JF, Gluck R, Moser C. Liposomes and virosomes as delivery systems for antigens, nucleic acids and drugs. Curr Opin Biotechnol 2004; 15: 518-29. Pissuwan D, Niidome T, Cortie MB. The forthcoming applications of gold nanoparticles in drug and gene delivery systems. J Control Release 2011; 149: 65-71. Bonoiu AC, Mahajan SD, Ding H, et al. Nanotechnology approach for drug addiction therapy: gene silencing using delivery of gold nanorod-siRNA nanoplex in dopaminergic neurons. Proc Natl Acad Sci U S A 2009; 106: 5546-50. Fahimi-Kashani N, Hormozi-Nezhad MR. Gold nanoparticle-based colorimetric sensor array for discrimination of organophosphate pesticides. Anal Chem 2016; Just accepted manuscript. DOI: 10.1021/acs.analchem.6b01616. Payne JN, Waghwani HK, Connor MG, et al. Novel Synthesis of Kanamycin Conjugated Gold Nanoparticles with Potent Antibacterial Activity. Front Microbiol 2016; 7: 607. Gholipourmalekabadi M, Sameni M, Hashemi A, Zamani F, Rostami A, Mozafari M. Silver-and fluoride-containing mesoporous bioactive glasses versus commonly used antibiotics: Activity against multidrug-resistant bacterial strains isolated from patients with burns. Burns 2016; 42: 131-40. Giamarellou H, Poulakou G. Multidrug-resistant Gram-negative infections: what are the treatment options? Drugs 2009; 69: 1879-901. Huwaitat R, McCloskey AP, Gilmore BF, Laverty G. Potential strategies for the eradication of multidrug-resistant Gram-negative bacterial infections. Future Microbiol 2016; 11: 955-72. Tillotson GS, Theriault N. New and alternative approaches to tackling antibiotic resistance. F1000prime reports 2013; 5: 51. Seil JT, Webster TJ. Antimicrobial applications of nanotechnology: methods and literature. Int J Nanomedicine 2012; 7: 2767-81. Gholipourmalekabadi M, Nezafati N, Hajibaki L, et al. Detection and qualification of optimum antibacterial and cytotoxic activities of silver-doped bioactive glasses. IET Nanobiotechnol 2015; 9: 209-214. Rostami A, Mozafari M, Gholipourmalekabadi M, et al. Optimization of fluoride-containing bioactive glasses as a novel scolicidal agent adjunct to hydatid surgery. Acta Trop 2015; 148: 105-14. Nezafati N, Moztarzadeh F, Hesaraki S, et al. Effect of silver concentration on bioactivity and antibacterial properties of SiO2-CaOP2O5 sol-gel derived bioactive glass. In: ed.êds., Key Engineering Materials. Trans Tech Publ 2012; pp. 74-9. Hur YE, Park Y. Vancomycin-Functionalized Gold and Silver Nanoparticles as an Antibacterial Nanoplatform Against Methicil-


[115] [116] [117] [118] [119] [120] [121] [122]

[123]

[124]

[125]

lin-Resistant Staphylococcus aureus. J Nanosci Nanotechol 2016; 16: 6393-9. Hornos Carneiro MF, Barbosa F, Jr. Gold nanoparticles: A critical review of therapeutic applications and toxicological aspects. J. Toxicol. Environ. Health. B Crit Rev 2016; 19: 129-48. Zhou Y, Kong Y, Kundu S, Cirillo JD, Liang H. Antibacterial activities of gold and silver nanoparticles against Escherichia coli and bacillus Calmette-Guerin. J Nanobiotechnol 2012; 10: 19. Lima E, Guerra R, Lara V, Guzman A. Gold nanoparticles as efficient antimicrobial agents for Escherichia coli and Salmonella typhi. Chem Cent J 2013; 7: 11. Shamaila S, Zafar N, Riaz S, Sharif R, Nazir J, Naseem S. Gold Nanoparticles: An Efficient Antimicrobial Agent against Enteric Bacterial Human Pathogen. Nanomaterials 2016; 6: 71. Han G, Martin CT, Rotello VM. Stability of gold nanoparticlebound DNA toward biological, physical, and chemical agents. Chem. Biol. Drug Des 2006; 67: 78-82. Ghosh PS, Han G, Erdogan B, Rosado O, Krovi SA, Rotello VM. Nanoparticles featuring amino acid-functionalized side chains as DNA receptors. Chem Biol Drug Des 2007; 70: 13-8. Rana S, Bajaj A, Mout R, Rotello VM. Monolayer coated gold nanoparticles for delivery applications. Adv Drug Deliv Rev 2012; 64: 200-16. De Jong WH, Hagens WI, Krystek P, Burger MC, Sips AJ, Geertsma RE. Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 2008; 29: 1912-9. Schleh C, Semmler-Behnke M, Lipka J, et al. Size and surface charge of gold nanoparticles determine absorption across intestinal barriers and accumulation in secondary target organs after oral administration. Nanotoxicology 2012; 6: 36-46. Venkatesan R, Pichaimani A, Hari K, Balasubramanian PK, Kulandaivel J, Premkumar K. Doxorubicin conjugated gold nanorods: a sustained drug delivery carrier for improved anticancer therapy. J Mater Chem B 2013; 1: 1010-8. Niidome T, Ohga A, Akiyama Y, et al. Controlled release of PEG chain from gold nanorods: targeted delivery to tumor. Biorg Med Chem 2010; 18: 4453-8.

Gholipourmalekabadi et al. [126] [127] [128]

[129] [130] [131] [132] [133] [134] [135] [136]

[137]

Niidome T, Yamagata M, Okamoto Y, et al. PEG-modified gold nanorods with a stealth character for in vivo applications. J Control Release 2006; 114: 343-7. Yavuz MS, Cheng Y, Chen J, et al. Gold nanocages covered by smart polymers for controlled release with near-infrared light. Nature mater 2009; 8: 935-9. Yuan H, Fales AM, Vo-Dinh T. TAT peptide-functionalized gold nanostars: enhanced intracellular delivery and efficient NIR photothermal therapy using ultralow irradiance. J Am Chem Soc 2012; 134: 11358-61. Barbosa S, Agrawal A, Rodrı´guez-Lorenzo L, et al. Tuning size and sensing properties in colloidal gold nanostars. Langmuir 2010; 26: 14943-50. Han Y, Yang X, Liu Y, et al. Supramolecular controlled cargo release via near infrared tunable cucurbit [7] uril-Gold Nanostars. Sci Rep 2016; 6. Li N, Chen Y, Zhang YM, et al. Polysaccharide-gold nanocluster supramolecular conjugates as a versatile platform for the targeted delivery of anticancer drugs. Sci Rep 2014; 4: 4164. Chen T, Xu S, Zhao T, et al. Gold nanocluster-conjugated amphiphilic block copolymer for tumor-targeted drug delivery. ACS Appl Mater Interfaces 2012; 4: 5766-74. Krishnan G, Edwards J, Chen Y, Benson HA. Enhanced skin permeation of naltrexone by pulsed electromagnetic fields in human skin in vitro. J Pharm Sci 2010; 99: 2724-31. Huang Y, Yu F, Park YS, et al. Co-administration of protein drugs with gold nanoparticles to enable percutaneous delivery. Biomaterials 2010; 31: 9086-91. Larese Filon F, Crosera M, Adami G, Bovenzi M, Rossi F, Maina G. Human skin penetration of gold nanoparticles through intact and damaged skin. Nanotoxicology 2011; 5: 493-501. Seydoux E, Rodriguez-Lorenzo L, Blom RA, et al. Pulmonary delivery of cationic gold nanoparticles boost antigen-specific CD4+ T Cell Proliferation. Nanomed Nanotechnol Biol Med 2016; 12: 1815-26 Bessar H, Venditti I, Benassi L, et al. Functionalized gold nanoparticles for topical delivery of methotrexate for the possible treatment of psoriasis. Colloids Surf Biointerfaces 2016; 141: 141-7.