 
{"id":474,"date":"2019-09-10T05:23:24","date_gmt":"2019-09-10T05:23:24","guid":{"rendered":"https:\/\/materials.international\/?p=474"},"modified":"2019-09-17T19:04:09","modified_gmt":"2019-09-17T19:04:09","slug":"tailored-gold-nanoparticles-for-cancer-imaging-and-therapy","status":"publish","type":"post","link":"https:\/\/materials.international\/?p=474","title":{"rendered":"Tailored Gold Nanoparticles for Cancer Imaging and Therapy"},"content":{"rendered":"\n<p>Materials International, 2019, 1, 1, 0013-0024,  <a href=\"https:\/\/doi.org\/10.33263\/Materials11.013024\" target=\"_blank\" rel=\"noreferrer noopener\" aria-label=\"https:\/\/doi.org\/10.33263\/Materials11.013024 (opens in a new tab)\">https:\/\/doi.org\/10.33263\/Materials11.013024<\/a> <\/p>\n\n\n\n<p><strong>M\u0103d\u0103lina Elena David<sup>1,*<\/sup>, Alexandru Mihai\nGrumezescu<sup>2<\/sup><\/strong><a href=\"http:\/\/orcid.org\/0000-0003-3036-094X\"><sup><\/sup><\/a><strong><\/strong><\/p>\n\n\n\n<ol class=\"wp-block-list\"><li>National Research &amp; Development Institute\nfor Chemistry and Petrochemistry\u2013ICECHIM, 202 Splaiul Independentei, Sector 6,\nBucharest 060021, Romania<\/li><li>Department\nof Science and Engineering of Oxide Materials and Nanomaterials, Faculty of\nApplied Chemistry and Materials Science, Politehnica University of Bucharest,\n060042 Bucharest, Romania<\/li><\/ol>\n\n\n\n<p><strong>*<\/strong>&nbsp; Correspondence: <a href=\"mailto:madalina.e.david@gmail.com\">madalina.e.david@gmail.com<\/a><\/p>\n\n\n\n<div class=\"wp-block-file aligncenter\"><a href=\"https:\/\/materials.international\/wp-content\/uploads\/2019\/09\/2668572811013024.pdf\" class=\"wp-block-file__button\" download>Download<\/a><\/div>\n\n\n\n<hr class=\"wp-block-separator\"\/>\n\n\n\n<p><strong>Abstract: <\/strong>In recent years, nanomedicine focused on the development of\nfunctional AuNPs for biomedical imaging, attributed to the intriguing optical properties\nof these nanoparticles, which are discussed in this review. Moreover, are presented\nthe most important <em>in vivo<\/em> diagnostic\ntechniques which have benefited from the development of engineered AuNPs, such\nas computed tomography and photothermal\/photoacoustic imaging. Another\nimportant advantage related to these nanoparticles refers to their excellent\nperformance in recent <em>in vivo<\/em> studies\nand clinical trials. Also, side effects of conventional drugs have been\nminimized by conjugation of AuNPs.<\/p>\n\n\n\n<p><strong>Keywords: <\/strong>gold\nnanoparticles, biomedical imaging, biocompatible nanoparticles.<\/p>\n\n\n\n<p><strong>Abbreviations:<\/strong> DOX: doxorubicin, PVP: Polyvinyl\npyrrolidone, Hyd: Hydrazone, PEG: Polyethylene glycol, BLM: Bleomycin, CPP:\nCell penetrating peptides, MTX: Methotrexate, 3-MPA: 3-mercaptopropionic acid,\nTAM- tamoxifen, FA: Folic acid, BHC: Berberine hydrochloride, Gem: gemcitabine,\nC225: cetuximab, DOD: dodecylcysteine, LL2: Lewis lung carcinoma, EAC:\nEhrlich-Lettre ascites carcinoma.<\/p>\n\n\n\n<table class=\"wp-block-table\"><tbody><tr><td>\n  \u00a9\n  2019 by the authors. This article is an open-access article distributed under\n  the terms and conditions of the Creative Commons Attribution (CC BY) license\n  (http:\/\/creativecommons.org\/licenses\/by\/4.0\/).\n  <\/td><\/tr><\/tbody><\/table>\n\n\n\n<p class=\"has-text-color has-accent-1-color\">1. <strong>Introduction<\/strong><\/p>\n\n\n\n<p>Presently, numerous nanoparticles and nanomaterials synthesized either biologically or physiochemically have emerged from different bulk elements such as gold, silver, iron, copper, in order to be used in advanced nanotechnology and medical science [1, 2]. One of the main advantages of these nanoparticles is represented by the ability to control their properties (physical, chemical and biological), which offer many possibilities to explore these nanoparticles in applications like drug delivery, as image contrast agents and for diagnostic purposes [3]. In comparison with others nanoparticles, gold nanoparticles (AuNPs) offer unique optical and Surface Plasmon Resonance (SPR) properties, which make them suitable to be used in biological and pharmaceutical fields, such as imaging-based therapeutic techniques and ultrasensitive detection for the treatment of cancer [4, 5].<\/p>\n\n\n\n<p>Cancer\nis caused by abnormal cell growth and is the second leading cause of death\nglobally, being responsible for an estimated 9.6 million deaths in 2018.\nAccording to the World Health Organization (WHO) about 1 in 6 deaths is due to\ncancer [6]. Presently, the treatment of cancer is based on chemotherapeutic\ndrugs, with the aim of killing the cancer cells. It has been demonstrated in\nseveral studies that these treatments often result in side effects due to the\ndamage caused to the surrounding healthy tissues [3]. <\/p>\n\n\n\n<p>\nIn the last several years, AuNPs (bare\nor functionalized) have received important attention in nanotherapeutic cancer\ntreatment (Figure 1) due to their unique properties, which make them suitable\ncandidates for conjugation with targeting ligands, imaging labels, and\ntherapeutic drugs. Also, it has been demonstrated that functionalized AuNPs can\nbe used for targeted molecular imaging and localized surface plasmon resonance\n(LSPR) [7-9].\n\n<\/p>\n\n\n\n<p>There are two processes are involved in differentiating malignant and nonmalignant cells: passive targeting and active targeting. Passive targeting takes advantage of the enhanced permeability and retention (EPR) effect observed in tumors to increase the concentration of AuNPs. The second process involves the selective molecular recognition of antigens that are expressed on the surfaces of cancer cells to localize AuNPs to malignant cells or the exploitation of the membrane properties associated with malignancy [10, 11]. <\/p>\n\n\n\n<figure class=\"wp-block-image\"><img loading=\"lazy\" decoding=\"async\" width=\"920\" height=\"462\" src=\"https:\/\/materials.international\/wp-content\/uploads\/2019\/09\/XXXXYYYY11013024_1.png\" alt=\"\" class=\"wp-image-477\" srcset=\"https:\/\/materials.international\/wp-content\/uploads\/2019\/09\/XXXXYYYY11013024_1.png 920w, https:\/\/materials.international\/wp-content\/uploads\/2019\/09\/XXXXYYYY11013024_1-300x151.png 300w, https:\/\/materials.international\/wp-content\/uploads\/2019\/09\/XXXXYYYY11013024_1-768x386.png 768w, https:\/\/materials.international\/wp-content\/uploads\/2019\/09\/XXXXYYYY11013024_1-458x230.png 458w\" sizes=\"auto, (max-width: 920px) 100vw, 920px\" \/><figcaption> <strong>Figure 1.<\/strong> Applications of AuNPs in cancer diagnosis and treatment. <\/figcaption><\/figure>\n\n\n\n<p>Typically,\nAuNPs are defined as particles of 1\u2013100 nm in size, which is in the\nsub-wavelength regime of visible light [12, 13]. These nanoparticles with\ncontrolled size and shape are synthesized by various physical, chemical, and\nbiological ways [3].<\/p>\n\n\n\n<p>Physical\nmethods refer to the energy transfer that occurs in a material when it is\nirradiated using ionizing or non-ionizing radiation, which may trigger the\nreduction reactions that lead to the nucleation of metallic particles. This\nmethod includes photochemical processes, ionizing radiation and microwave\nradiation [14-16]. Ngo V.K.T. and co-workers obtained AuNPs by a low cost technique,\nmicrowave heating in order to investigate the effect of different elements\n(precursor reagents, irradiation time, and microwave radiation power) on the\nmorphology of AuNPs. It was observed that the size of AuNPs decreased and the\nsize distribution became narrower with increasing the concentration of sodium\ncitrate. Also, it has been reported that a longer reaction time and higher\nmicrowave radiation power increased the NPs size, demonstrating that microwave\nheating had a strong effect on the yield of the AuNPs [17]. Zhou Y. and\nco-workers obtained shape-controlled AuNPs by a novel ultraviolet irradiation technique\nat room temperature. It was demonstrated that, not only the concentration of Au\ncations and the irradiation time influenced the morphology of AuNPs, but also\nthe concentration and the species of the polymer capping materials play an\nimportant role. The prolongation of irradiation time facilitated the formation\nof the AuNPs with more regular shape [18]. In another study, it was\ndemonstrated that the production of hexagonal AuNPs began within seconds of\nmicrowave irradiation and the size growth increased with the microwave power\nand time [19].<\/p>\n\n\n\n<p>Chemical\nmethods utilize chemicals and solvents, like sodium borohydride (NaBH4),\nhydrazine and citrate to initiate the synthetic process and promote\nnanoparticle nucleation. It has been demonstrated that the most efficient\nreducing agents are NaBH4 and hydrazine, but these agents present the\ndisadvantage that are biologically and environmentally toxic [20-23]. Suchomel\nP. and co-workers prepared AuNPsby the reduction of tetrachloroauric acid using\nmaltose in the presence of nonionic surfactant Tween 80 at various\nconcentrations, in order to control the size of the resulting AuNPs. It was\nobserved that when the concentration of Tween 80 increased, a decrease in the\nsize of produced AuNPs was observed, which ment that the surfactant plays a key\nrole in the nanoparticles dimensions [24]. <\/p>\n\n\n\n<p>Biological\nsynthesis (plants and microorganisms mediated) is a relatively new,\neco-friendly, and promising area of research. Presently, it has been\ndemonstrating that numerous medicinal plants have shown potential to produce\nstable AuNPs [25-27]. There are some advantages using this method for making\nAuNPs, such as nontoxic biocomponents, limiting the waste formation and cutting\ndown the need for extra purification steps. This method involves mixing the\ngold salt with extracts of plant under varied reaction conditions like pH,\nincubation time and temperature to obtain specific shapes and sizes of AuNPs [18].\nAmong various methods, chemical reduction of Au3+ ions is considered to be the\nbest method to synthesize AuNPs with controlled size and morphology [28, 29]. <\/p>\n\n\n\n<p>In\nthe last several years, these various synthesis methods to obtain AuNPs have\nbecome an attractive and potential option to explore as a tool for photothermal\ntherapy (PTT), photodynamic therapy (PDT), photoimaging, targeted drug\ndelivery, and immunoassays. Presently, various types of AuNPs, such as gold\nnanorods, nanocages, nanostarsand nanospheres, have become effective tools in\nhuman cancer [7, 30, 31].<\/p>\n\n\n\n<p>In this review, we focus on providing further new insights for exploring the AuNPs applications as a tool in cancer imaging and therapy.<\/p>\n\n\n\n<p class=\"has-text-color has-accent-1-color\">2. <strong>Gold Nanoparticles in Cancer Imaging<\/strong><\/p>\n\n\n\n<p>AuNPs\nreceived significant attention due to their high absorption coefficient,\npotential biocompatibility and relatively low toxicity. Also, it is very\nimportant for AuNPs to be synthesized under special conditions which can reduce\nconcerns regarding the potential toxicity induced by the reducing agents and\nreaction conditions [32].<\/p>\n\n\n\n<p>The main advantages of AuNPs in imaging applications are related to the fact that: <\/p>\n\n\n\n<ul class=\"wp-block-list\"><li>AuNPs\nhave long body circulation times; <\/li><li>The\nAuNPs selectively accumulate at sites of interest through the enhanced\npermeability and retention (EPR) effect or by surface modification with\nspecific coatings; <\/li><li>AuNPs\npresent a large absorption in the near-infrared window for photothermal\ntherapy; <\/li><li>Their\nsimple functionalization [33].<\/li><\/ul>\n\n\n\n<p>Due to the high rate of cancer patients around the world, the development of new techniques to diagnose early cancers is essential. The use of AuNPs offer long-time operation for optical imaging, because of the properties of these nanoparticles (i.e. photoresistance, stability). Also, these nanoparticles are efficient contrast agents in optical imaging as a result of their unique interaction process with light particles. The most important <em>in vivo<\/em> diagnostic techniques are: i) computed tomography (CT), ii) photothermal\/ photoacoustic imaging, iii) two-photon fluorescence imaging, iv) optical coherence tomography (OCT), v) Raman spectroscopy and vi) light scattering imaging &nbsp;[32]. Typically, AuNPs with dimensions between 30 and 100 nm scatter intensely and can be easily detected using a commercial microscope under dark-field illumination conditions [34]. It has been reported that the scattering cross-sections of AuNPs are 105\u2013106 times stronger than the emission from a fluorescent dye molecule [35].<\/p>\n\n\n\n<p class=\"has-text-color has-accent-1-color\">2.1. <strong>Gold Nanoparticles used in CT<\/strong><\/p>\n\n\n\n<p>Computerized\ntomography (CT) allows obtaining of 3D anatomic imaging at a high spatial\nresolution by using the difference in the absorption effect from different\nhuman tissues. Also, this technique uses an X-ray contrast agent which has the\nrole to distinguish tissues with similar or low X-ray attenuation. CT is a\nvaluable medical tool and it is used in several applications, such as diagnose,\nmonitoring of the therapy effectiveness (e.g. for cancer treatment) and blood\npool imaging [36-38].<\/p>\n\n\n\n<p>AuNPs\nhave gained recent attention as an X-ray contrast agents for CT imaging due to\nsome important features like the higher atomic number and the electron density\nof gold, but also the feasibility of AuNPs to enhance the <em>in vivo<\/em> vascular contrast in CT imaging and the capacity of AuNPs\nto selectively target tumor specific antigens [32, 34, 39-42]. AuNPs with\naverage diameter of 1.9 nm were used as contrast agent for CT to detect tumors\nin mice. It was reported that after 24 hours, the AuNPs were not detected in\nthe blood, but showed significant accumulation after 15 min in the kidney,\ntumor tissue, liver and muscle. It was reported that these nanoparticles were\ncleared by renal excretion and were not found in liver or spleen [43]. In\nanother study, PEG-coated AuNPs were used to impart antibiofouling properties\nto extend the systemic circulation half-life. These nanoparticles were injected\nintravenously into rats and their longer blood circulation time (4 h) was\nobserved by CT in case of PEG-coated AuNPs, as compared with an iodine contrast\nagent (&lt;10 min) [44]. Also, PEG-coated AuNPs injected in adult Balb\/c mice\nwhich underwent microcomputed tomography scans revealed a good biocompatibility\nwithout toxicity marks in tested mice. A stable imaging window for visualizing\nthe vasculature system, at time zero (immediately after injection and up to 24\nhours after injection) was obtained [45]. In another study,&nbsp; AuNPs obtained by encapsulating gold cores\nwithin a multilayered gadolinium chelates bound organic shell, were used as\ncontrast agents for both in vivo X-ray and MRI (Magnetic Resonance Imaging). It\nwas reported that these particles are suitable for dual modality imaging and\nfreely circulate in the blood vessels without undesirable accumulation in the\nlungs, spleen, and liver due to the fact that the contrast enhancement in MRI\nstems from the presence of gadolinium ions which are entrapped in the organic\nshell, whereas the gold core provides a strong X-ray absorption [46]. <\/p>\n\n\n\n<p>Zavaleta\nC.L. and co-workers reported a new study that consisted of a synthesis of two\ntypes of AuNPs, namely porous AuNPs (PAuNPs) and solid AuNPs (SAuNPs). The\nfirst set was prepared by reduction of a gold solution with lecithin, whereas\nthe second set was fabricated by a reflux method using lecithin as a single\nreducing agent. CT scanning revealed that PAuNPs presented a brighter contrast\n(45 HU) than SAuNPs (26 HU). <em>In vivo<\/em>\ntests were carried out on male rabbits which were intravenously injected with 1\nmg\/kg weight of PAuNPs\/SAuNPs. After 72 hours, it was observed that PAuNPs\nshowed an enhanced contrast compared to SAuNPs 6 hours after injection in\norgans scanned by CT. It was reported that IV administration of synthesized\nPAuNPs increased the levels of aspartate aminotransferase (AST), alkaline\nphosphate (ALP), serum creatinine, and blood glucose, whereas that of SAuNPs\nincreased the levels of AST, ALP, and blood glucose [47].<\/p>\n\n\n\n<p>A new study revealed that glucose-functionalized AuNPs can be used as a metabolically targeted CT contrast agent. It was reported that, due to the unique characteristics of tumor vasculatures and dissimilarities between cancer and inflammatory processes, these complexes accumulate in the tumor and not in the inflammatory lesion, thus preventing false-positive results [48]. In comparison with other techniques (such as MRI, positron-emission tomography), current X-ray imaging provides lower sensitivity and no ability for molecular imaging. So, a new and optimized X-ray contrast agent is required to give patients these benefits, AuNPs being a promising candidate [38].<\/p>\n\n\n\n<p class=\"has-text-color has-accent-1-color\">2.2. <strong>Gold Nanoparticles used in Photothermal\/Photoacoustic Imaging<\/strong><\/p>\n\n\n\n<p>Photothermal\/photoacoustic\nimaging refers to the laser-induced heating of materials, with the former\nrelying on the direct detection of heat and the latter on the detection of\nacoustic waves generated by the thermal expansion of air surrounding the\nmaterials. In biomedicine, photoacoustic imaging is used more frequently than\nphotothermal imaging, due to the fact that the photoacoustic technique combines\nthe high contrast of optical imaging and the deep tissue penetration of\nultrasound imaging [33]. There are several key features to consider when the\nparticles are selected for hyperthermia, such as the wave-length of maximal\nabsorption, the absorption cross-section, and the size of the particle [49].<\/p>\n\n\n\n<p>AuNPs\nare the main mediators of photothermal therapy because of several advantages,\nsuch as biocompatibility, efficient light-to-heat conversion, small diameters\nthat enable tumor penetration upon systemic delivery, simple gold-thiol\nbioconjugation chemistry for the attachment of desired molecules, and the\nability to be tuned to absorb near-infrared (IR) light, which penetrates tissue\nmore deeply than other wave-lengths of light [50].<\/p>\n\n\n\n<p>Presently,\nseveral forms of gold-based nanoparticles have been developed, such as\ngold\u2013silica nanoshells, colloidal gold nanospheres, gold nanorods, and\nsmaller-diameter &nbsp;near IR (NIR) -tunable\ngold nanocages [49].<\/p>\n\n\n\n<p>Recently,\na novel photo-cross-linkable AuNP was developed. It was observed that the\nsurface plasmon resonance peak of 20.5 nm AuNPs can effectively be shifted to\nNIR regions, which makes small AuNPs not only useful for enhanced photoacoustic\nimaging, but also for effective photothermal therapy of malignant tumors [51].\nIn another study, photothermal imaging was used to detect prostate cancer by\nusing AuNPs conjugated with anti-HER2 [52]. <\/p>\n\n\n\n<p>Yang\nZ. and co-workers fabricated a complex by self-assembly of\npoly(perylenediimide) (PPDI) and PEG tethered AuNPs (Au@PPDI\/PEG). It was\nreported that the PPDI offered a greater photothermal effect and the resulted\ncomplex proved excellent therapeutic and <em>in\nvivo<\/em> biomedical imaging potential [53]. Also, AuNPs were used to observe\nthe circulation of these nanoparticles in real-time, in blood vessels in the\nneck region of a mouse injected [54]. <\/p>\n\n\n\n<p>The use of AuNPs in photothermal\/photoacoustic imaging offers a more accurate imaging of the tumor and moreover, these nanoparticles play an important role in photothermal imaging- assisted treatment modalities [55]. <\/p>\n\n\n\n<p class=\"has-text-color has-accent-1-color\">2.3. <strong>Gold Nanoparticles used in Raman spectroscopy <\/strong><\/p>\n\n\n\n<p>Raman\nspectroscopy is a sensitive method based on inelastic scattering of light by\nvibrating molecules and can provide various biochemical informations about\ncells, tissues or biofluids [56, 57]. The size and surface charge of\nsurface-enhanced Raman scattering (SERS) nanoparticles influence their <em>in vivo<\/em> biodistribution and thus, may\naffect the efficacy in raman spectroscopy. AuNPs without a passivating shell,\nalso have the tendency to aggregate <em>in\nvivo<\/em>, but several studies reported that this agglomeration can be prevented\nby applying silica or PEG coatings [58].<\/p>\n\n\n\n<p>Also, AuNPs can be used to prepare SERS nanoparticles for small animals. Raman spectroscopy and AuNPs with a silica coatings were used to separate the spectral fingerprints of up to 10 different types of SERS nanoparticles in a living mouse and to colocalize five different SERS nanoparticles within deep tissues after intravenous injection [59]. In another study, it was reported a new and facile strategy for the DNA-assisted decoration of single-walled carbon nanotubes (SWNTs) with AuNPs and their application in SERS imaging. The complex formed with SWNT-AuNPs was functionalized with synthetic DNA, in order to obtain nanocomposites with enhanced Raman signal. The big advantages of the proposed method were the presence of the free DNA overhangs around the SWNT-AuNPs which made the final nanocomposites a promising candidates in selective cancer cell labeling and imaging, or sensor developments [60]. It was reported that AuNPs-based SERS agents can improve the patient safety by highlighting the tumor margins to help ensure the complete removal of residual diseased cells and to avoid surgical injury of the normal tissues[61].<\/p>\n\n\n\n<p class=\"has-text-color has-accent-1-color\">2.4. <strong>Gold Nanoparticles in Cancer Therapy<\/strong><\/p>\n\n\n\n<p>AuNPs\nhave been gaining popularity in medical applications for several reasons. One\nreason is given by their potential to be relatively non-reactive in biological\nenvironment, character which makes them suitable for <em>in vivo<\/em> applications. Moreover, &nbsp;properties like strong optical behaviour, easy\ncontrollable surface chemistry enabling versatility in adding surface\nfunctional groups and ease in control over particle size and shape during\nsynthesis contribute to AuNPs esteem. Due to these reasons, AuNPs are\nconsidered to be fully multifunctional and offer the possibility of combining\ndifferent desired functionalities in one molecular-sized package [62-64]. <\/p>\n\n\n\n<p class=\"has-text-color has-accent-1-color\">2.5. <strong>Gold Nanoparticles as drug delivery agents targeted to cancer cells<\/strong><\/p>\n\n\n\n<p>Presently, chemotherapy is the most used method for the treatment of cancer, even if it presents many limitations, mainly due to the numerous side effects resulting from non-specific interactions of drugs with cells and tissues, and low solubility. So, because of these important disadvantages, it is very important to improve the existing therapies. One method refers to the use of drug delivery systems which could provide efficient targeted transport and overcome &nbsp;limitations of standard anticancer therapy. These systems have to be capable of stocking an adequate amount of drug, bypassing mechanisms of drug resistance, improving biodistribution and preventing fast removal of the drug from the body. Also, these systems should be performed with prolonged biological half-life, tumor accumulation, efficient cellular uptake and controlled release patterns. In several studies, it has been reported that AuNPs present the ability to meet almost all of the above requirements [34, 62, 65-68].<\/p>\n\n\n\n<p style=\"text-align:center\"><strong>Table 1.<\/strong> Drugs conjugated with AuNPs.<strong> <\/strong><\/p>\n\n\n\n<table class=\"wp-block-table\"><thead><tr><td>\n   <strong>Nanoparticle<\/strong>\n   <\/td><td>\n   <strong>Nanoparticle\n   Size (nm)<\/strong>\n   <\/td><td>\n   <strong>Cell Lines<\/strong>\n   <\/td><td>\n   <strong>Remarks<\/strong>\n   <\/td><td>\n   <strong>Ref.<\/strong>\n   <\/td><\/tr><\/thead><tbody><tr><td>\n  DOX@PVP-AuNP\n  <\/td><td>\n  12\n  <\/td><td>\n  A549, H460, and H520 human lung cancer cells\n  <\/td><td>\n  Induction of early apoptosis in lung cancer cells and\n  upregulation of tumor suppression genes.\n  <\/td><td>   [70]   <\/td><\/tr><tr><td>\n  DOX-Hyd@AuNP\n  <\/td><td>\n  30\n  <\/td><td>\n  MCF-7\/ADR cancer cells\n  <\/td><td>\n  Enhanced toxicity against multi drug resistant cancer cells.\n  <\/td><td>   [71]   <\/td><\/tr><tr><td>\n  DOX-BLM-PEG-AuNP\n  <\/td><td>\n  10\n  <\/td><td>\n  HeLa Cells\n  <\/td><td>\n  Enhanced half-maximal effective drug concentration.\n  <\/td><td>   [72]   <\/td><\/tr><tr><td>\n  CPP-DOX-AuNP\n  <\/td><td>\n  25\n  <\/td><td>\n  HeLa cells and A549 cells\n  <\/td><td>\n  Higher cell death.\n  <\/td><td>   [73]   <\/td><\/tr><tr><td>\n  DOX-PEG-AuNP\n  <\/td><td>\n  12\n  <\/td><td>\n  KB cellsand A549 cells\n  <\/td><td>\n  Higher cytotoxic effect as compared to free DOX.\n  <\/td><td>   [74]   <\/td><\/tr><tr><td>\n  MTX-AuNP\n  <\/td><td>\n  8-80\n  <\/td><td>\n  LL2 cells\n  <\/td><td>\n  Higher cytotoxicity towards numerous cell lines as compared\n  to free MTX.\n  <\/td><td>   [75]   <\/td><\/tr><tr><td>\n  3-MPA-AuNP\n  <\/td><td>\n  5\n  <\/td><td>\n  K562\/ADM cells\n  <\/td><td>\n  Higher cell death.\n  <\/td><td>   [76]   <\/td><\/tr><tr><td>\n  TAM-PEG-AuNP\n  <\/td><td>\n  25\n  <\/td><td>\n  MCF-7 and HSC-3\n  <\/td><td>\n  Higher cell death.\n  <\/td><td>   [77]   <\/td><\/tr><tr><td>\n  FA-BHC-AuNP\n  <\/td><td>\n  20-60\n  <\/td><td>\n  Vero and HeLa\n  <\/td><td>\n  Increased efficacy of BHC against cancer cells.\n  <\/td><td>   [78]   <\/td><\/tr><tr><td>\n  Gem-C225-AuNP\n  <\/td><td>\n  5\n  <\/td><td>\n  PANC-1, AsPC-1, and MIA Paca2\n  <\/td><td>\n  Significant inhibition of pancreatic tumor cell\n  proliferation.\n  <\/td><td>   [79]   <\/td><\/tr><tr><td>\n  DOD-AuNP\n  <\/td><td>\n  3-6\n  <\/td><td>\n  EAC\n  <\/td><td>\n  Anti-tumour activity of the prepared surfactant was enhanced\n  with the presences of the AuNPs.\n  <\/td><td>   [80]   <\/td><\/tr><\/tbody><\/table>\n\n\n\n<p>It\nhas been reported that AuNPs present the following advantages as drug delivery\nsystems: <\/p>\n\n\n\n<ul class=\"wp-block-list\"><li>Large\nsurface area- they offers high loading capacity of drug, improving the drug hydrophilicity and stability (AuNPs can\nbe synthetized in a large board of sizes, from 1 to 150 nm); <\/li><li>Easy\nsurface modification, with targeting ligands to enhance the tumor selective\naccumulation (the presence of a negative charge on the surface of AuNPs makes\nthem easy to be modified, they can be functionalized easily by the addition of\nvarious biomolecules such as drugs, targeting ligands, and genes); <\/li><li>Passive\ntargeting ability to tumor site, due to their leaky neo-vessels (EPR effect); <\/li><li>Controlled\nrelease of drugs, in the case of internal or external stimulus [7].<\/li><\/ul>\n\n\n\n<p>Over the last several years, AuNPs have been conjugated to a variety of antitumor substances, either hydrophobic or hydrophilic. For example, 5-Fuorouracil was attached to AuNPs with terminal carboxylic acid groups from the capping agent, in order to investigate their potential anticancer effect. Ma X. and co-workers synthesized SM5-1 (humanized mouse monoclonal antibody)- conjugated AuNPs and investigated their anticancer efficacy in hepatocellular carcinoma (HCC) both <em>in vitro<\/em> and <em>in vivo<\/em>. The studies proved that conjugation of SM5-1 and AuNPs efficiently increased the tumor growth inhibition rates in HCC. In addition, the bioluminescent images showed that AuNPs- SM5-1 can achieve considerable antitumor efficacy in HCC, providing a potential therapy approach for HCC [69]. Other drugs conjugated with AuNPs are summarized in Table 1.<\/p>\n\n\n\n<p class=\"has-text-color has-accent-1-color\">3. <strong>Biodistribution and Toxicity Aspects of Gold Nanoparticles<\/strong><\/p>\n\n\n\n<p>AuNPs\nhave been extensively explored in biomedical applications, especially as drug\ncarriers or contrast agents. However, AuNP can exhibit a cytotoxic profile,\nwhen the size of the nanoparticles is below 2 nm (ultrasmall AuNP) or when the\nstabilizing ligands determine a direct interaction with biomolecules or for\ncatalytic activity of the unshielded gold surface. It has been reported that\nthese ultrasmall AuNPs exhibit significantly different biodistribution and\nenhanced circulation times compared to larger AuNPs [81-85].<\/p>\n\n\n\n<p>Also,\nin several studies it has been reported that anticancer drugs conjugated with\nAuNPs exhibited higher cytotoxicity towards numerous tumor cell lines, compared\nwith the equivalent free anticancer drug. For example, MTX was used to treat\ncancer for decades, but upon conjugation with AuNPs displayed higher\ncytotoxicity towards numerous tumor cell lines as compared to that of free MTX.\nMTX was observed to accumulate in the tumor cells at a faster rate and to a\nhigher level when conjugated with AuNPs [75]. Also, DOX bounded to AuNPs via an\nacid labile linker, showed enhanced toxicity against the multi drug resistant\nMCF-7\/ADR breast cancer cell line, thus overcoming the multi drug resistance to\nsome extent due to the enhanced uptake of the AuNPs-tethered drug followed by\nits responsive release within the cell [71].<\/p>\n\n\n\n<p>The\n<em>in vivo<\/em> biodistribution of AuNPs was intensively\nstudied. For example, Le Q. L. and co-workers evaluated the <em>in vivo<\/em> distribution of AuNPs (20 nm)\nafter intravenous administration in mice. It was observed that after 1 hour of\nadministration, the nanoparticles were mainly accumulated in blood (41.56%),\nliver (51.60%), lungs (6.16%) and kidneys (0.53%). After 6 hours of\nadministration, the nanoparticles were mainly accumulated in liver (76.33%),\nlungs (11.86%) and kidneys (2.23%) [86].<\/p>\n\n\n\n<p>Table\n2, presents the biodistribution of AuNPs at 24 hours after IV administration in\nrats and can be observed that in the case of ultrasmall AuNPs, a very high\nconcentration was present in liver, compared to AuNPs with higher dimensions.\nAlso, the lung represents the primary entry route for airborne particles into\nthe human body. It has been reported that, aerosolic NPs tend to aggregate and\nform structures of several hundred nm in diameter, changing the\nphysico-chemical properties and interaction with cells. For example, Durantie\nE. and co-workers compared single AuNPs with aggregated AuNPs with hydrodynamic\ndiameter of 32 and 106 nm, respectively. A 3D lung model was used and exposures\nwere performed by aerosolization of the particles. No apparently harmful effects\nof single and aggregated AuNPs were observed using lactate dehydrogenase assay;\nalso, the cell layer integrity was not impaired. The bio-distribution revealed\nthat the majority of the AuNPs, single or aggregated, were inside the cells,\nand only a minor fraction (less than 5%) was found on the basolateral side. In\nthe case of translocation rate, no significant difference was observed.\nHowever, aggregated AuNPs showed a significantly faster cellular uptake than\nsingle AuNPs at the first time point &#8211; 4 h [87].<\/p>\n\n\n\n<p style=\"text-align:center\"><strong>Table 2.<\/strong> Biodistribution of AuNPs at 24 h after IV administration to rats, expressed as % of the given dose [88, 89].<\/p>\n\n\n\n<div class=\"wp-block-image\"><figure class=\"aligncenter\"><img loading=\"lazy\" decoding=\"async\" width=\"528\" height=\"462\" src=\"https:\/\/materials.international\/wp-content\/uploads\/2019\/09\/XXXXYYYY11013024_T_2.png\" alt=\"\" class=\"wp-image-478\" srcset=\"https:\/\/materials.international\/wp-content\/uploads\/2019\/09\/XXXXYYYY11013024_T_2.png 528w, https:\/\/materials.international\/wp-content\/uploads\/2019\/09\/XXXXYYYY11013024_T_2-300x263.png 300w, https:\/\/materials.international\/wp-content\/uploads\/2019\/09\/XXXXYYYY11013024_T_2-400x350.png 400w\" sizes=\"auto, (max-width: 528px) 100vw, 528px\" \/><\/figure><\/div>\n\n\n\n<p class=\"has-text-color has-accent-1-color\">4. <strong>Conclusions and Perspectives<\/strong><\/p>\n\n\n\n<p>AuNPs can be synthesized in a variety of shapes and sizes, can be conjugated with various coating agents to tailor their properties, and can also be used as core or shell for hybrid nanoparticles, to obtain different types of nanosystems with various applications. In the case of biomedical imaging, AuNPs are preferred because of their advantages such as large absorption in the near-infrared window for photothermal therapy and selective accumulation at sites of interest through the EPR effect. Due to these properties, along with their biocompatibility and low toxicity, AuNPs have led to an excellent performance in recent <em>in vivo<\/em> studies and clinical trials. Also, side effects of conventional drugs have been minimized by conjugation with AuNPs. <\/p>\n\n\n\n<p>Future studies tend to focus in demonstrating the idea that AuNPs could be used as next generation theranostic agents. The concept of theranostics with multifunctional AuNPs has a great potential to enhance the medical area towards personalized medicine [90]. Also, another new dimension in the field of medicine refers to the AuNPs used as antiangiogenic agents in cancer therapy [91, 92].<\/p>\n\n\n\n<p class=\"has-text-color has-accent-1-color\"><strong>Funding<\/strong><\/p>\n\n\n\n<p>This research\nreceived no external funding.<\/p>\n\n\n\n<p class=\"has-text-color has-accent-1-color\"><strong>Conflicts of Interest<\/strong><\/p>\n\n\n\n<p>The authors declare\nno conflict of interest.<\/p>\n\n\n\n<p class=\"has-text-color has-accent-1-color\"><strong>Acknowledgments<\/strong><\/p>\n\n\n\n<p>The authors declare no acknowledgments.<\/p>\n\n\n\n<p class=\"has-text-color has-accent-1-color\"><strong>References<\/strong><\/p>\n\n\n\n<p>1.&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Grigore, M.E.; Biscu,\nE.; Holban, A.; Gestal, M.; Grumezescu, A. 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Antiangiogenic properties of nanoparticles: a systematic review. <em>Int J Nanomedicine<\/em>, <strong>2019<\/strong>, <em>Volume 14<\/em>, pp.5135. <a href=\"https:\/\/doi.org\/10.2147\/IJN.S199974\">https:\/\/doi.org\/10.2147\/IJN.S199974<\/a>. <\/p>\n","protected":false},"excerpt":{"rendered":"<p>Materials International, 2019, 1, 1, 0013-0024, https:\/\/doi.org\/10.33263\/Materials11.013024 M\u0103d\u0103lina Elena David1,*, Alexandru Mihai Grumezescu2 National Research &amp; Development Institute for Chemistry and Petrochemistry\u2013ICECHIM, 202 Splaiul Independentei, Sector 6, Bucharest 060021, Romania Department of Science and Engineering of Oxide Materials and Nanomaterials, Faculty of Applied Chemistry and Materials Science, Politehnica University of Bucharest, 060042 Bucharest, Romania *&nbsp; Correspondence: madalina.e.david@gmail.com Abstract: In recent years, nanomedicine focused on the development of functional AuNPs for biomedical imaging, attributed to the intriguing optical properties of these nanoparticles, which are discussed in this review. Moreover, are presented the most important in vivo diagnostic techniques which have benefited &hellip;<\/p>\n","protected":false},"author":1,"featured_media":477,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"pagelayer_contact_templates":[],"_pagelayer_content":"","footnotes":""},"categories":[4],"tags":[],"class_list":["post-474","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-review"],"_links":{"self":[{"href":"https:\/\/materials.international\/index.php?rest_route=\/wp\/v2\/posts\/474","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/materials.international\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/materials.international\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/materials.international\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/materials.international\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=474"}],"version-history":[{"count":7,"href":"https:\/\/materials.international\/index.php?rest_route=\/wp\/v2\/posts\/474\/revisions"}],"predecessor-version":[{"id":500,"href":"https:\/\/materials.international\/index.php?rest_route=\/wp\/v2\/posts\/474\/revisions\/500"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/materials.international\/index.php?rest_route=\/wp\/v2\/media\/477"}],"wp:attachment":[{"href":"https:\/\/materials.international\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=474"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/materials.international\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=474"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/materials.international\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=474"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}