A Review on Gold Nanoparticles (GNPs) and their Advancement in Cancer Therapy

The progress in the fi ctionalization of chemistry with innovative NPs and their differentiated uses in the cure of several human infections have focused worldwide [1]. Nanotechnology is vital for the delivery of drug materials, with numerous dormant uses in medical prescription and investigation. The extensive uses of NPs in areas of nanomedicine are vast, for example, cancer therapy, investigative methods and also for medicinal resolutions [2]. The selection of NPs for cancer therapy is extremely preferred by their distinctive physicochemical features that grip for future improvement of cure of infections in cancer therapy with negligible reverse infl uences. NPs units used in nanotechnology having size ranges between 1.0 nm to 100 nm and possess completely innovative or progressive possessions because of their higher size to volume ratio [3].


Introduction
The progress in the fi ctionalization of chemistry with innovative NPs and their differentiated uses in the cure of several human infections have focused worldwide [1]. Nanotechnology is vital for the delivery of drug materials, with numerous dormant uses in medical prescription and investigation. The extensive uses of NPs in areas of nanomedicine are vast, for example, cancer therapy, investigative methods and also for medicinal resolutions [2]. The selection of NPs for cancer therapy is extremely preferred by their distinctive physicochemical features that grip for future improvement of cure of infections in cancer therapy with negligible reverse infl uences. NPs units used in nanotechnology having size ranges between 1.0 nm to 100 nm and possess completely innovative or progressive possessions because of their higher size to volume ratio [3].
Metal NPs are the focus of investigation determinations as new platform for cancer therapy to a specifi ed target sites. Nano carriers are innovative tools for cancer in therapy specifi c target sites. Over the centuries, numerous distribution resources were intended built on diverse NPs, such as nano Citation: Hussain  the drug, drug carriers, target indications, reduction in toxicity, and tools optimization [5,6].
Nanoparticles, especially those of gold fi nd a special scope in cancer therapy. It has been accounted for likewise that GNPs have special synthetic and somatic features for carrying and releasing therapeutic agents [7,8]. The primary favorable position of GNPs as a medication transporter is that the gold center is basically latent and non-dangerous; additionally, the selection of GNPs is supported with blending ease and their position of functionalization, by and large, completes thiol links. Most prominently, from their photograph, somatic features can activate medication discharge [9] at a remote spot.

Gold Nanoparticles (GNPs)
Gold is one of the fi rst metals that have been exposed. The account of investigation and scope of Gold periods however some thousand years. Early evidence on colloidal gold may initiate in treatises by Arabic scientists, Chinese researchers, as well as Indian investigators, who worked to achieve the colloidal gold as timely as in the fi fth-fourth eras. The scientists used colloidal gold for therapeutic and further purposes. In Europe, colloidal gold was investigated and applied in all chemistry research centers. However, GNPs have been acknowledged as an attractive candidate for the delivery of drug particles to detected target cells. The receiving of GNPs as an outstanding candidate for delivery of therapeutic agents was due to its exceptional possessions particularly in transportation and release of drug to its target cells. Therapeutic particles delivered must be signifi cantly smaller in size embedded in drug particles or in large biomolecules, for example, amino acids, nucleic acids, RNA, or DNA and effi ciency of their discharge at the site is essential for effective treatment [11].
GNPs, usually have an extraordinarily higher surface-tovolume ratio, due to biocompatibility and inertness, and can be certainly functionalized with numerous other functional groups; so, they can also play a key role in the medical fi eld as adjuvant, reducing the toxic effects, increasing the immunogenic effects, and offering the storage stability of medicines and other drugs related to vaccinations, and also possess the excessive potential [12].
The GNPs have been become of greatest popularity due to their effectiveness in cancer therapy and drug delivery. GNPs had established their own way from fi nding to therapy in current day's drugs possess the basis of functional moieties and their profi ciencies in the distribution of amino acids, protein, nucleic acid, and gene therapy in vivo cure and symptoms [12]. For biomedical uses, outer functionalization of GNPs is essential so as for making the GNPs to explicit sickness zones, enabling to specifi cally interface with other cell or biomolecule.
The subsequent GNPs posses interesting characteristics [3], for example, measure and fi gure-subordinate visual and electronic attributes, a high surface zone to sum proportion, and surfaces that can be quickly changed with the ligands holding valuable assemblies, for example, amines, phosphines, and thiols, which display a preference for gold faces [14]. By methods for these practical gatherings to attach the ligands, extra moieties like antibodies, amino acids, proteins, and dinucleotides are utilized to report the prevalent usefulness [4]. The wide scope of use for GNPs depends on exceptional somatic as well as synthetic characteristics. Specifi cally, optical features of GNPs are controlled with their surface plasmon vibrations [2], which relates with joined excited conductive electrons and confi ned within a wide region, from noticeable to infrared (IR) area, contingent upon size, shape and the structure of molecule. In

Methods for the synthesis of gold nanoparticles
Generally, the following methods have been followed for the synthesis of gold nanoparticles (GNPs): Chemical methods: A well known Turkevich method is the type of chemical method mostly used to synthesize the GNPs and very promising method as compared to others. In this technique, Au +3 ions are reduced by mild reducing agent like citrate [15], ascorbic acid [16], and tannic acid [17]. The biocompatible and small size GNPs are synthesized by Turkevich method as shown in Figure 2. It is necessary to control the parameters such as pH, temperature and concentration for the synthesis of GNPs during this process [18]. In 1944, the

Brust-Schiffrin method was introduced by Brust and Schiffrin.
This method is easy to synthesize the thermally stable and airstable GNPs of controlled and low dispersity. In this method, AuCl 4 was shifted to toluene from an aqueous using, tetraoctylammonium bromide (TOAB) as the phase-transfer and reduced by NaBH4, in the presence dodecanethiol. The use of reducing agents changes the color of organic phase from orange to deep brown [19]. Seeding growth method is another method for the synthesis of GNPs of diameter 5−40 nm and narrow size distribution. The particles size can be controlled by altering the ratio of seed to metal salts and hence the particles of 5-40 nm can be prepared [20]. This method has advantages due to a quick, simple and cost-effective [21].
Biological methods: Chemical methods are the most common techniques used for the synthesis of metallic nanoparticles. The cost of reducing agents and stabilizing agents limits their applications. Furthermore, the prepared nanoparticles by chemical methods may have toxic consequences in biomedical applications [22]. So, there is a requirement to develop easy and cost-effective procedures for the synthesis of nanoparticles that do not consume any toxic chemicals. The synthesis of nanoparticles by biological methods in current years has become the center of attention as green and eco-friendly methods. In biological methods, the synthesis of nanoparticles usually carried out by microorganisms, plants or plant extracts and enzymes [23]. In recent times, the use of plants for the synthesis of nanoparticles is preferred, because of less toxic, cost-effective and eco-friendly. The biosynthesis of nanoparticles in recent years by means of plants such as Azadirachta indica [22], Aloe Vera [24], Medicago sativa [25], Cinnamomum camphora [26], Coriandrum sativum [27], Pelargonium graveolens [22], Terminalia catappa [28], and lemongrass [22] have been used.
Using the extract of Zingiber offi cinale GNPs can be synthesized in the range of 5-15nm. Zingiber offi cinale plays a dual role as a reducing and stabilizing agent in the synthesis of GNPs [39].

Cancer therapy
In the last several years, great development in synthesis and applications of GNPs have been achieved for cancer treatment. GNPs are particularly appropriate to destruct the cancer cells thermally due to their surface activation and heating capability photothermally [1]. Tumor nanoscience is a multidisciplinary fi eld with extensive possible uses in the treatment of cancer, with cancer cell diagnosis, molecular-imaging, bio-informatics, and target therapy [40]. Conventional approaches for tumortherapy include the chemo-therapy, radiation treatment, and surgical treatment.
The development of specialized GNPs for use in fi nding and cure of cancer is increasing, due to their specifi c properties [41] like their ability to interact with different drugs, retention in tumor tissues, light absorbance in near-infrared light and their interaction with radiations [42]. GNPs particularly have greatly focused on for cancer research in previous years due to their simplistic fabrication as well as surface variations, greatly improved and changeable optical features including outstanding biocompatibility for clinical approaches [43].
As a developing idea that enables instantaneous prediction and cure, the execution of therapeutic NPs bear the strong potential for enhanced tumor therapy and decreased negative infl uences [12]. GNPs are used in cancer treatment, due to their specifi c properties, like their ability to interact with different drugs, retention in tumor tissues, light absorbance in IR light and their contact with radiations. Having the advantages of their exclusive features, several types of research of cancer treatment by GNPs have been applied photo-thermally to destruct the tumor cell or tissues which may contain the potential for clinical use [44]. When the cancer cells are bombarded with focused laser light of appropriate wavelength, GNPs can destruct the structure of bacterial cells and tumor tissues [45].
For effective application of GNPs in the treatment of cancer, gold nanostructure must contain biocompatibility and display superiorpointing of tumor cells over healthy cells [46]. drug to the target by using various suitable affi nity reagents like as those mediated by a ligand-receptor, lecithin-carbohydrate or antigen-antibody recognition [49].
Conservative chemotherapy is actually infl uensive but also famous due to its severe bad impacts due to somewhat random endorsement of chemotherapeutic agents into healthy cells as well as into malignant cells in tissue and organ systems [50]. Major enhancement has been established in latest years with the beginning of nano-size medicines, that provide a signifi cant association with chemotherapy as a novel drug.

Radiotherapy
Radiotherapy is the main therapy and is valuable to cure around 50% of all types of cancer infected. The cure depends on the deposition of drug dose in cancer cells, usually by the bombardment of either gamma radiations or high energy X-rays or by a beam of high energy ions which may enough to irradiate the tumor cells or either their cell membrane and fi nally cause their death [45]. Furthermore, the use of NPs in nanosize drugs, that have effectively enhanced therapeutic action, is the characteristic of recent chemotherapeutics in current years. The impact of the GNPs in the development of chemotherapeutic effi cacy is determined by the dose enhancement factor (DEF). The DEF of GNPs is well-defi ned as "fraction of chemotherapeutic drug intake by cancer cells in the availability of GNPs to the fraction of drug intake by the cancer cells in lack of GNPs".It can alter with quantity and effectiveness of GNPs and their site inside infected cells. Gold Nanoparticles (GNPs) have may advantages because they possess straightforward synthesis, good biocompatibility, wide range sizes, simple and easy functionalization by the attachment of ligands neeeded to target cancer cells and their organelles or better life time in the blood stream [51].

Hyperthermia
It has been newly announced as a modern treatment method for tumor cells and has great potential to fi ght this infection. It can be defi ned as a cure method in which infected cells are exposed to a higher temperature which either terminates cancer cells [52]. This rise in temperature of cancer cells alters vascular penetrability, enhances the fl ow of current and ultimately leads to cancer oxygenation [12]. Hence, hyperthermia alleviates tissue hypoxia and could be concurrently applied with radioactive drugs or anticancer drugs to increase their cytotoxic impacts on cancer. In old hyperthermia, the site of the individual body having cancer is heated to a temperature of 40-45°C, some degrees beyond physical temperature [47]. Heat is produced outside by means of tools that generates electromagnetic radiations or ultrasound radiations [53]. Traditional hyperthermia is applied combined with chemotherapy as well as radiation treatment mechanism, for the treatment of different kinds of cancers in numerous clinical applications [12]. The heat produced from gold-based NPs can be applied in cancer treatment to destruct tumor tissues.
The variation between traditional photo-thermal treatment mechanism [54] and hyperthermia is a heat treatment that may happen photothermally in the area of gold-based NPs, and cell temperature can raise up to hundred of centigrade over body temperature [43]. It has been suggested that photothermal heat treatment can be further effective to cancer cells instead of healthy cells to overcome the bad impacts of cancer treatment methods [55]. Traditionally, hyperthermia is applied, in association with radiotherapy as well as chemotherapy, for the extermination of a diversity of cancer categories in numerous experimental tests. The heat produced from GNPs is used in cancer therapy to stop the growth of tumor cells. The difference between traditional [52] and photo-thermal treatment is that photo-thermal treatment only occurs in zone straight about GNPs, and limited temperature =-098nges can raise to a hundred degree over physical temperature. It indicates photo-thermal therapy can more target cancer cells somewhat healthy tissues to potentially decrease the bad impacts of cancer treatments [6].

General applications of gold naoparticles
Gold nanoparticles as drug delivery agents to targeted cancer cells: GNPs are the best nanocarriers for therapeutic due to their ease of synthesis, functionalization and biocompatibility [56]. In cancer therapy, GNPs are corrently used as potential drug delivery mediators for introduction into tumor cells [57]. The cells take up colloidal gold nanoparticles of different sizes and shapes [58] through ligandreceptor interaction or nonspecifi c means. In order to confi rm the specifi c destruction of cancer cells, gold nanoparticles are conjugated with suitable surface ligands which directed them only to tumor cells as shown in Figure 3.
There are two methods for tumor targeting that have been described: the fi rst concerned the conjugation of AuNPs to Polyethylene glycol (PEG) and the second involved the conjugation of AuNPs with a specifi c antibody that binds distinctive biomarkers indicated on tumor cells. PEG inhibited GNPs agglutination and increasesd the retention in blood. The accumulation of AuGNPs in tumor cells due to the high permeability of poorly differentiated blood vessels around tumors as described in Figure 4.
Drug delivery systems (DDSs) give good attributes to a "free'' drug by enhancing solubility, in vivo stability, and biodistribution. They can also change the bad pharmacokinetics of certain "free' drugs. Further, large loading of pharmaceuticals on DDSs can render ' drug reservoir, for restricted and sustained release to sustain the drug level within the therapeutic window [60].

Gold nanoparticles applications in biosensor
A biosensor has been designed by g1old nanoparticles that are functionalized with a thiolated biomolecule that causes a change in the optical absorption of GNPs after identifying the complementary biomolecules. Gold nanoparticles functionalized with antigen (antibody) combined when matching antibody (antigen) binds as a result cause change in the Plasmon absorption [61].   [63].