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Gold nanoparticles in image-guided cancer therapy
Inorganica Chimica Acta 393 (2012) 154–164
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Review
Gold nanoparticles in image-guided cancer therapy Dongkyu Kim a, Sangyong Jon b,⇑ a b
Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 2387 Dalgubeol-daero, Daegu 706-010, Republic of Korea Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon 305-701, Republic of Korea
a r t i c l e
i n f o
Article history: Available online 20 July 2012 Metals in Medicine Special Issue Keywords: Gold nanoparticles Computed tomography Diagnosis Therapy Cancer Molecular imaging
a b s t r a c t With advances in the syntheses of a variety of nanomaterials, including superparamagnetic iron oxide nanoparticles, quantum dots and gold nanoparticles, has come a surge of interest in the use of nanoparticles in biomedical application. Among these nanomaterials, gold nanoparticles have attracted considerable attention as imaging agents, drug-delivery vehicles and theranostic agents because of their unique physical and chemical properties, and ease of synthesis and surface modification. This review focuses on the biomedical uses of gold nanoparticles based on our research, with an emphasis on cancer applications. Ó 2012 Elsevier B.V. All rights reserved.
Dr. Dongkyu Kim is currently a senior researcher in the Laboratory Animal Center at Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF). He received his Ph.D. in the Department of Life Sciences from GIST in 2011 under supervision of Dr. Jon. His research interest lies at molecular imaging, drug delivery, and biosensor.
Dr. Sangyong Jon received his B.S. in 1993, M.S. in 1995, and Ph.D. in 1999 from the Department of Chemistry at KAIST, Korea. He had experienced his postdoc career in the Department of Chemical Engineering at M.I.T. in the United States. In 2004, he joined Gwangju Institute of Science and Technology (GIST) as an Assistant Professor of Life Sciences and promoted to a Professor in 2010. He moved to KAIST in 2012 and is currently a Professor in the Department of Biological Sciences at the institute. His research interest lies at the interface of medicine, biotechnology, nanotechnology, and biomaterials.
⇑ Corresponding author. E-mail address: [email protected] (S. Jon). 0020-1693/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ica.2012.07.001
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Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Physicochemical properties of GNPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GNPs in in vitro assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GNPs in cancer imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GNPs in cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GNP in theranostic medicine: simultaneous diagnosis and drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
1.1. Physicochemical properties of GNPs
A variety of nanoparticles has find their uses in biomedical applications, including drug delivery, molecular imaging, and/or combined therapy and diagnosis (theranosis) (Fig. 1). In particular, inorganic nanoparticles and their hybrids with organic materials possess unique optical, physical, chemical and electronic properties that distinguish them from the corresponding larger-sized particles or materials [1–7]. Inorganic nanoparticles are particularly suited for use as contrast agents for molecular imaging because they have a longer half-life in the circulation than molecular-sized conventional contrast agents. The modalities available for nanoparticle imaging include magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and ultrasound and optical imaging [8]. Additional nanoparticle-based systems are currently under investigation, and a variety of nanoparticles, including gold nanoparticles (GNPs), iron oxide nanoparticles, quantum dots, liposomes and dendrimers, have been well studied. In this paper, we review the diagnostic and therapeutic uses of GNPs based on our research, with an emphasis on cancer applications.
The past decade has seen the development of GNPs for a variety of applications, including in vitro sensing, imaging and drug delivery—an expansion of applications that reflects the advantages of such nanoparticles in terms of biocompatibility, ease of synthesis, and ability to control size and optical properties (Fig. 2). The surface plasmon resonance band of a 5-nm GNP is located at 520 nm in ethanol, but is very sensitive to particle composition, size and shape, as well as environment and interparticle distance. These factors constitute the basis for GNP applications for biological labeling, detection, diagnostics and sensing. According to the Mie theory, an electromagnetic frequency induces a resonant coherent oscillation of free electrons, called the surface plasmon resonance, at the surface of a GNP if the particle is much smaller than the light wavelength. GNPs can also be used as drug-delivery carriers because they are biocompatible and nonimmunogenic. Various GNP synthesis methods have been reported [9–11]. GNPs of various sizes, from a few to several hundred nanometers, can be easily synthesized using reducing agents, which lead to the nucleation of gold ions onto nanoparticles. Citrate-capped
Fig. 1. Applications of nanoparticle-based medicine (nanomedicine).
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Fig. 2. Advantages and biomedical applications of GNPs.
nanoparticles are stable, but the citrate ion can be replaced and functionalized with various ligands for specific applications. Because the thiol group has a high affinity for gold, most thiol-modified ligands that have been used bind to the surface of GNPs through formation of an Au–thiol bond [12–14]. 2. GNPs in in vitro assays GNPs exhibit strong surface plasmon resonance that depends on particle size and relative distance between particles. GNPs usually have an absorption in the 500–550-nm range, corresponding to the surface plasmon band. This absorption arises from the collective oscillation of the valence electrons due to resonant excitation by incident photons. Because of this property, GNPs are of interest in the rapidly developing biosensor field. Aggregation of GNPs evokes interparticle surface plasmon coupling, resulting in a significant color change from red to blue and broadening of the surface plasmon resonance band that can be readily observed by the naked
eye, obviating the need for instrumentation. Colorimetric detection based on the aggregation of GNPs has been extensively studied for the detection of a variety of targets, including metal ions [15–23], DNA [24–26], bacterial toxins [27,28] and proteins [29–32], as well as enzyme activity [33,34]. Our group has developed a simple and rapid colorimetric method that can distinguish between normal and abnormal (hypercalcemic) calcium ion (Ca2+) levels in serum using calsequestrin (CSQ)-functionalized GNPs (Fig. 3) [35]. Ca2+ is profoundly important for diverse biological functions, including skeletal mineralization, blood coagulation, neurotransmission, excitation of skeletal and cardiac muscle, and stimulus-mediated hormone secretion [36]. Because hypercalcemia can cause hyperparathyroidism, malignant tumors and hyperthyroidism, the rapid and accurate estimation of blood Ca2+ levels is very important. CSQ, the most abundant Ca2+-binding protein, undergoes a Ca2+ concentration-dependent conformational change in response to Ca2+ binding; because it has a high capacity (40–50 binding sites per molecule) and relatively low affinity for Ca2+, CSQ binds and
Fig. 3. (a) Schematic representation of the Ca2+ sensor: the aggregation of CSQ-functionalized GNPs caused by binding of Ca2+ results in a color change. (b) Colorimetric responses of CSQ–GNPs to different metal ions at concentration levels greater than those normally seen in blood: Ca2+ (5 mM), Mg2+ (5 mM), K+ (10 mM), Na+ (200 mM); Sr2+, Ba2+, Cu2+, Hg2+, Mn2+, Ni2+, Cd2+, and Zn2+ (all 100 lM). Adapted with permission from Ref. [35].
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Fig. 4. Advantage and disadvantage of typical molecular imaging modalities.
Fig. 5. (a) A three-dimensional in vivo CT angiographic image of the heart and great vessels obtained 10 min after injection of 500 lL PEG-coated GNPs (140 mg/mL) into the tail vein of a Sprague–Dawley rat. HU values of the left ventricle (LV), aortic arch, inferior vena cava (IVC), liver and spleen before injection (pre) and at the indicated times after injection are also shown. (b) CT images obtained in a rat hepatoma model following injection of 400 lL PEG-coated GNPs (100 mg/mL) into the tail vein. Image was obtained 1 h after injection. Arrows indicate hepatoma regions. Adapted with permission from Ref. [56].
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Fig. 6. (a) A synthetic scheme for preparation of PEG-coated GIONs. Transmission electron microscopic images of (b) SPIONs (Fe3O4) and (c) PEG-coated GIONs. Scale bar = 20 nm. Adapted with permission from Ref. [65].
releases large amounts of Ca2+ [37,38]. In the absence of Ca2+, CSQ adopts an unfolded form. When the Ca2+ concentration gradually increases from 10 lM to 0.01–1 mM, the randomly coiled CSQ condenses into a compact monomer, which subsequently undergoes dimerization and then polymerization. Therefore, CSQ-functionalized GNPs undergo Ca2+-dependent CSQ polymerization, which results in a clear change in color together with precipitation. This sensing system is specific for Ca2+, and the differences between normal and disease-associated abnormal Ca2+ levels in serum can be distinguished with the naked eye. 3. GNPs in cancer imaging Molecular imaging involves characterization of biological processes in living organisms at the molecular and cellular levels. By exploiting specific molecular-imaging agents, this powerful technique can be used to visualize and characterize early-stage disease, providing a rapid method for evaluating treatment. Currently used molecular imaging modalities include MRI, CT, ultrasound, optical imaging, single-photon emission computed tomography (SPECT) and PET (Fig. 4) [39,40]. Although molecular imaging modalities, such as optical imaging, PET and SPECT, are capable of detecting molecular and cellular changes associated with diseases, they have the disadvantage of poor spatial resolution. On the other hand, MRI has good spatial resolution; however, low sensitivity of contrast agents is a major hurdle [41]. Optical imaging utilizes photons emitted from bioluminescent or fluorescent probes to study disease processes and biology in vivo. It has the advantage of being cost effective, rapid and easy to use compared to other imaging modalities. However, optical imaging suffers from poor tissue penetration due to light absorption by proteins (257–280 nm), heme groups (maximum absorbance at 60 nm) and even water (above 900 nm) [42]; a high background signal due to tissue autofluorescence is also an issue [43]. GNPs offer a number of advantages for optical imaging applications compared to other agents: their scattered light is very strong; they are much brighter than chemical fluorophores; they are resistant to photobleaching; and they can be easily detected at concentrations as low as 1016 M. Sokolov et al. have developed
an anti-EGFR (epidermal growth factor) antibody-conjugated GNP for the detection of cervical cancer [44]. Irradiation with a laser produces a single color that is close to the laser wavelength used, but when illuminated with a beam of white light, GNPs scatter light of many colors. The color of the light is determined by the absorption of the nanoparticles, which in turn depends on nanoparticle shape and size. This color-dependent scattering property makes it possible to perform imaging studies using a simple white light source. Raman spectroscopy is the most promising imaging technique for GNP-based contrast agents. GNPs have the optical property of amplifying the Raman scattering efficiencies of adsorbed molecules by as much as 1014- to 1015-fold, allowing spectroscopic detection and identification of single molecules under ambient conditions. In one such application, 60-nm GNPs were encoded with Raman reporter and stabilized with thiolated polyethylene glycol (PEG). For targeted cancer imaging, surface-enhanced Raman scattering (SERS) nanoparticles were conjugated with ScFv antibody, which is a ligand that specifically binds to the EGFR [45]. These SERS nanoparticles for active targeting of both cancer cells and tumor xenografts were more than 200-times brighter than near-infrared-emitting quantum dots, and allowed spectroscopic detection of small tumors at a penetration depth of 1–2 cm. CT, which is one of the most frequently employed and cost effective diagnostic tools used in hospitals [46–48], provides anatomical information by measuring the absorption of X-rays as they pass through tissue. Different tissues can be distinguished based on
Fig. 7. CT images and (a) T2-weighted MRI images (b) of PEG-coated GIONs at different concentrations. Adapted with permission from Ref. [65].
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Fig. 8. (a) Schematic illustration of poly(DMA-r-mPEGMA-r-MA) coating of hybrid gold–iron oxide (Au–Fe3O4) nanoparticles. (b and c) TEM images of hybrid Au–Fe3O4 nanoparticles before (b) and after (c) coating with poly(DMA-r-mPEGMA-r-MA). Scale bar = 20 nm. Adapted with permission from Ref. [66].
their distinctive degrees of X-ray attenuation, which in turn depends on the electron density of the tissue. CT contrast agents in current use are based on iodinated small compounds [49,50]. However, these agents are often associated with renal toxicity, and their low molecular weight results in a short imaging time [51,52]. Novel nanoparticle-based CT contrast agents that overcome these limitations have recently emerged [53–55]. Polymer-coated bismuth sulfide (Bi2S3) nanoparticles may be useful as CT contrast
agents and have an efficacy/safety profile in vivo that is comparable to or better than that of iodinated imaging agents [53]. Despite several favorable properties, Bi2S3 nanoparticle size and shape are difficult to control, and there is a lack of chemical methods available for modifying the surface of these nanoparticles, which may hinder their further clinical application. Recently, GNPs have been intensively investigated as noble CT contrast agents because their X-ray absorption coefficient is higher than that of iodine (5.16
Fig. 9. Serial CT (a–d) and MR (e–h) images in a mouse hepatoma model following injection of 100 lL poly(DMA-r-mPEGMA-r-MA)@Au–Fe3O4 (Au: 48 mg/kg; Fe: 36 mg/kg) into the tail vein. Images were obtained at time 0 (i.e., before injection) (a, e) and 1 h (b, f), 2 h (c, g) and 4 h (d, h) after injection. Arrows indicate hepatoma regions. Numbers in brackets are HU values of hepatomas (left) and surrounding normal liver parenchyma (right). Adapted with permission from Ref. [66].
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Fig. 10. (a) Schematic illustration of the method for preparing Dox-loaded, aptamer-conjugated GNPs. (b) PSMA aptamer and ONT sequences used to synthesize Dox-loaded, aptamer-conjugated GNPs. Adapted with permission from Ref. [81].
and 1.94 cm2/g, respectively, at 100 keV), their size and shape are easier to control and, unlike Bi2S3 nanoparticles, their surfaces can be readily modified with various functional groups. Our laboratory has developed PEG-coated GNPs as a potential CT contrast agent for in vivo imaging (Fig. 5) [56]. The simple combination of the antibiofouling property provided by PEG and the high X-ray absorption property of gold results in an efficient CT contrast agent with a long circulation time that may avoid the shortcomings of current iodine-based CT contrast agents. At the same concentration, the X-ray attenuation coefficient of PEG-coated GNPs was 1.9-times higher than that of the current iodine-based CT contrast agent. And quantitative analyses of Hounsfield unit (HU, a linear transformation of the original linear attenuation coefficient in one in which the radiodensity of distilled water is defined as zero HU) value for heart and great vessels, such as the aortic arch, aorta, interior vena cava and hepatic veins, revealed that PEG-coated GNPs circulate in the bloodstream for at least 4 h without an appreciable loss of contrast. The much longer half-life of PEGcoated GNPs in the circulation compared to the iodine-based contrast agent Ultravist (<10 min) should help improve disease diagnosis [57,58]. Furthermore, we showed that PEG-coated GNPs can be used not only as a blood pool imaging agent, but also as an agent for detecting hepatomas. Although CT is a very useful diagnostic tool in hospitals, the unavailability of targeted contrast agents has historically made it unsuitable for molecular imaging. This limitation was first surmounted by Popovtzer et al., who conjugated a UM-A9 antibody, which specifically binds to squamous cell head and neck cancer, to a gold nanoprobe, and demonstrated
exclusive association of the conjugate with targeted cancer cells and production of strong selective X-ray attenuation that was distinct from that obtained from identical, but untargeted, cancer cells or normal cells [59]. GNPs have rarely been used successfully for in vivo CT imaging of cancer, mainly because of their low stability and lack of specificity. A very recent report described in vivo tumor-targeting gold nanoprobes as contrast agents for CT/optical imaging of cancer [60]. In this study, GNPs were modified with glycol chitosan (GC) to increase physiological stability and tumor-targeting efficiency. Next, matrix metalloproteinase (MMP)activatable peptide probes were conjugated to GC-GNPs for optical imaging. MMP-GC-GNPs efficiently accumulated in the tumor tissue and their near-infrared fluorescence (NIRF), which is normally strongly quenched, was sensitively recovered by cleavage of the peptide substrates upon exposure to active MMPs, which are overexpressed in tumor tissue. This probe allowed simultaneous CT and optical imaging of the same tumor-bearing mouse model. A single imaging modality does not possess all necessary attributes for comprehensive imaging. For example, PET has high target sensitivity but low spatial resolution. On the other hand, CT has good spatial resolution, but is limited by low target sensitivity. Multimodal imaging systems that combine different modalities into a single system, thereby compensating for the deficiencies of single imaging modalities, have been extensively studied as a solution to this limitation [61–64]. Our group recently described a multimodal imaging agent consisting of a SPION core (magnetite [Fe3O4]) and a thin gold-layered shell; the resulting gold-coated iron oxide nanoparticle (GION) could be used for both MRI and
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Fig. 11. CT images (a) and HU values (b) of PBS, LNCaP and PC3 cells, and LNCaP and PC3 cells treated with PSMA-aptamer-conjugated GNPs (5 nM) or scrambled-aptamerconjugated GNPs (5 nM) for 6 h (n = 3). Adapted with permission from Ref. [81].
CT (Fig. 6) [65]. These core–shell nanoparticles showed high CT attenuation because of the presence of gold layers. However, their T2 signal intensity in MRI was much lower than that of normal SPIONs, presumably due to the embedding of SPIONs in the inner core, thus hampering the in vivo application of such nanoparticles as CT/MRI dual contrast agents (Fig. 7). To overcome this limitation, we designed a new type of hybrid nanoparticle in which several SPIONs were fused with a GNP in a dumbbell shaped (Fig. 8) [66]. This dual contrast agent, which was coated with amphiphilic polymer [Poly(DMA-r-mPEGMA-r-MA)] to impart water-dispersing and antibiofouling properties, exhibited high CT attenuation and a good MR signal because of the presence of the GNP and iron oxide nanoparticle, respectively. Intravenous injection of these hybrid nanoparticles into hepatoma-bearing mice resulted in high contrast between the hepatoma and normal hepatic parenchyma in both CT and MR images (Fig. 9). In another report, it was shown that gadolinium chelator-coated GNPs could be used as contrast agents for both in vivo X-ray and MR imaging [67]. This report showed that these nanoparticles circulated in the blood vessels without undesirable accumulation in the lung, spleen or liver. Recently, sub-50-nm multifunctional nanoparticles for fluorescence, MR and CT trimodal imaging were developed [68]. These PEGylated NaY/GdF4:Yb, Er, Tm@SiO2–Au@PEG5000 nanoparticles showed strong emissions ranging from the visible to near infrared (NIR) for fluorescence imaging, facilitated T1-weighted MRI through shorting of T1 relaxation time and served as a CT contrast agent by enhancing HU values. 4. GNPs in cancer therapy Targeted delivery of therapeutic agents to disease sites is one of most challenging research areas in pharmaceutical sciences. Nanoparticle-based drug-delivery systems provide an advantage over free drugs, improving delivery efficiency, solubility, in vivo stability and biodistribution [69,70]. Therapeutics based on nanoparti-
cles have been successfully introduced for the treatment of several pathological conditions, including cancer, pain and infectious disease. The unique properties of GNPs make these nanoparticles very promising as drug carriers, and this area of GNP applications is a rapidly expanding field. By exploiting the structural diversity made possible by ligand exchange and multifunctional monolayers, it is possible to create GNP surfaces containing targeting ligands and chemotherapeutics. CYT-6091, a PEGylated colloidal gold-TNFa nanoparticle developed by CytImmune, very recently completed Phase I clinical trials [71]. CYT6091 is a multivalent drug that is assembled on 26-nm GNP by covalently linking TNF-a and PEG-SH. CYT-6091 achieved higher concentrations within MC-38 tumors than free TNF-a, improving the efficacy of a given dose of TNF-a such that 7.5 mg of CYT6091 was as effective as 15 mg of free TNF-a in inhibiting tumor growth. Furthermore, the toxicity of CYT-6091 was lower than that of free TNF-a. Brown and colleagues also described a GNP-based strategy for delivering oxaliplatin, a platinum-based anticancer drug [72]. Although oxaliplatin has shown potential for treating colorectal tumors, its use is limited by associated neurotoxicity, nausea and vomiting. In this application, the active component of oxaliplatin, Pt(R,R-dach), was conjugated to the surface of PEGylated GNPs for improved drug delivery. In tests against various colon cancer cell lines, oxaliplatin-conjugated GNPs were up to 5.6-fold more efficacious than oxaliplatin alone, and in all cases were at least as active as free oxaliplatin. Gene therapy is a promising strategy for treating various diseases. Viral vectors are the most effective method for gene delivery, but there are safety concerns associated with their use, such as cytotoxicity and immunogenicity. Designing effective alternative vehicles for delivering plasmid DNA and siRNA is a considerable technical challenge. Such vehicles would need to provide efficient protection of nucleic acids from degradation by nucleases while allowing for the release of the nucleic acid in the cell. Nanoparticle systems are attractive candidates for the creation of nucleic acid
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Fig. 12. Confocal laser-scanning microscopic images of fluorescence, DIC and merged images of LNCaP (a, c, e) and PC3 (b, d, f) cells after treatment with Dox-loaded, aptamer-GNP conjugates. Adapted with permission from Ref. [81].
delivery vectors. Mirkin and co-workers showed that protein expression could be controlled by antisense DNA-functionalized GNPs [73]. Lee et al. developed siRNA delivery vehicles using poly(b-amino esters) as delivery enhancers and GNPs as scaffolds [74]. Although poly(b-amino esters) are potential DNA delivery agents, this material is not suitable for siRNA delivery due to incomplete condensation between polymer and siRNA. However, this system does facilitate high levels of in vitro siRNA delivery—as good as or better than that achieved using the widely used transfection reagent, Lipofectamine 2000. Breunig and co-workers have shown that a heterogeneous particle system consisting of a layer-by-layer assembly on GNPs of the oppositely charged polyelectrolytes siRNA and PEI can be employed to deliver siRNA to cells [75]. 5. GNP in theranostic medicine: simultaneous diagnosis and drug delivery Nanoparticle technology holds great promise in simultaneously diagnosing disease, providing targeted drug delivery with minimal toxicity, and monitoring treatment [76–80]. Such theranostic
nanoparticles are particular promising in the emerging field of personalized medicine, because they can detect disease at an early stage in individual patients and deliver therapeutic agents over an extended period for enhanced therapeutic efficacy. Moreover, real-time, non-invasive monitoring of theranostic nanoparticles enables clinicians to rapidly decide whether a given treatment regimen is effective in an individual patient. Recently, our group developed a drug-loaded aptamer-GNP bioconjugate for combined CT imaging and therapy of prostate cancer (Fig. 10) [81]. By conjugating GNPs with a PSMA-specific aptamer, we constructed a multifunctional nanoparticle that enabled combined prostate cancer CT imaging and anticancer therapy. Aptamers are an emerging class of targeting ligands capable of also serving as biological drugs for treatment of various diseases [82– 87]. As escort molecules, aptamers are able to deliver drug or nanoparticles encapsulating drug to target cells via high-affinity, specific binding. Our group demonstrated that a PSMA-specific aptamer formed a physical complex with Dox via intercalation, and thereby delivered this anticancer drug to target prostate cancer cells [88]. However, in this system, only one Dox molecule
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could intercalate into each PSMA aptamer. To increase Dox loading efficiency, we hybridized a 21-base (CGA)7 repeating oligonucleotide (ONT), which forms a GC-rich duplex that acts as a loading site for the chemotherapeutic agent Dox, to the 30 -end of the PSMAspecific RNA aptamer. Because Dox intercalates preferentially into consecutive -CG- base pairs, fusing the (CGA)7 repeating ONT to the original PSMA aptamer significantly enhanced Dox loading capacity, providing sites for at least 6–7 Dox molecules in the extended region instead of the single Dox molecule bound by the original PSMA aptamer. The PSMA aptamer-conjugated GNPs were able to specifically bind to target prostate cancer cells that overexpressed PSMA antigen and showed more than 4-fold greater CT intensity for targeted LNCaP cells than for nontargeted PC3 cells (Fig. 11). Furthermore, after loading with Dox, PSMA aptamerconjugated GNPs were significantly more potent against targeted LNCaP cells than against nontargeted PC3 cells, suggesting targetspecific drug delivery (Fig. 12). Gold nanorods, which can easily be prepared with various aspect ratios using simple and well-established synthesis techniques, have been extensively studied as photothermal agents for cancer therapy [89]. Because they provide tunable surface plasmon absorption wavelengths in the NIR region, which can penetrate into deep tissue for photothermal therapy, gold nanorods are better potential photothermal agents than GNPs of other shapes (e.g., branched, pentagon, large prism). The heating effect of gold nanorods upon NIR absorption is a result of the electron dynamics in metallic lattices [90]. In one pioneering study, a gold nanorod (aspect ratio, 3.9) conjugated to an anti-EGFR antibody was found to specifically target malignant cells; after heating the nanorod with NIR light, malignant cells were selectively destroyed in vitro without damaging nonmalignant cells [89]. Furthermore, the strongly scattered red light from gold nanorods was clearly visible in a dark field, enabling malignant cells to be readily distinguished from nonmalignant cells. In another study, gold nanorods coated with poly(styrene-alt-maleic acid), the photosensitizer indocyanine green and anti-EGFR were developed as multifunctional nanoparticles, serving as tumor-targeting and hyperthermia agents to destroy malignant cells through photodynamic therapy (PDT), and as optical contrast agents to simultaneously monitor cells by imaging in the NIR region [91]. 6. Conclusions Because of their unique physical and chemical properties, biocompatibility, and ease of synthesis and surface modification, GNPs have received considerable research attention for use in biomedical applications. In addition to these advantages, gold has a higher X-ray absorption coefficient than iodine, encouraging us to study the feasibility of using GNPs as a CT contrast agent in vivo. We first demonstrated that PEG-coated GNPs as a new CT contrast agent could be used not only as a blood pool imaging agent but also as a hepatoma-detection agent. Then, we described hybrid amphiphilic polymer-coated Au–Fe3O4 and gold-coated iron oxide nanoparticles that compensate for the respective limitations of MRI and CT. In particular, amphiphilic polymer-coated Au–Fe3O4 can be useful as a potential dual CT/MRI contrast agent for in vivo hepatoma imaging. CT is more frequently used clinically to detect hepatomas than MRI, because MRI is relatively expensive and requires a longer scanning time. In patients with ambiguous CT findings, however, MRI may be needed to detect hepatomas. In such patients, use of the hybrid nanoparticles described here can accurately and facilely diagnose hepatoma without the need to employ the two imaging modalities separately. Furthermore, we described Dox-loaded, aptamer-conjugated GNPs for targeted molecular CT imaging and therapy of prostate cancer. We anticipate that the present GNP conjugate system could be applied to
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the design of similar multifunctional nanoparticles through the use of other disease-specific aptamers and imaging nanoprobes. We also reported a simple and rapid colorimetric method for the detection of Ca2+ with high specificity using CSQ-functionalized GNPs. This technique, which does not require specialized equipment because test results can be easily seen by the naked eye, helps to rapidly and accurately diagnose blood Ca2+ levels. As such, it may be useful in the detection or monitoring of several diseases associated with hypercalcemia, such as malignant tumors. On the basis of this research, we believe that the GNP is one of most attractive nanomaterials for in vitro diagnosis, molecular imaging, drug delivery and theranostic applications.
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Review
Gold nanoparticles in image-guided cancer therapy Dongkyu Kim a, Sangyong Jon b,⇑ a b
Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 2387 Dalgubeol-daero, Daegu 706-010, Republic of Korea Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Daejeon 305-701, Republic of Korea
a r t i c l e
i n f o
Article history: Available online 20 July 2012 Metals in Medicine Special Issue Keywords: Gold nanoparticles Computed tomography Diagnosis Therapy Cancer Molecular imaging
a b s t r a c t With advances in the syntheses of a variety of nanomaterials, including superparamagnetic iron oxide nanoparticles, quantum dots and gold nanoparticles, has come a surge of interest in the use of nanoparticles in biomedical application. Among these nanomaterials, gold nanoparticles have attracted considerable attention as imaging agents, drug-delivery vehicles and theranostic agents because of their unique physical and chemical properties, and ease of synthesis and surface modification. This review focuses on the biomedical uses of gold nanoparticles based on our research, with an emphasis on cancer applications. Ó 2012 Elsevier B.V. All rights reserved.
Dr. Dongkyu Kim is currently a senior researcher in the Laboratory Animal Center at Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF). He received his Ph.D. in the Department of Life Sciences from GIST in 2011 under supervision of Dr. Jon. His research interest lies at molecular imaging, drug delivery, and biosensor.
Dr. Sangyong Jon received his B.S. in 1993, M.S. in 1995, and Ph.D. in 1999 from the Department of Chemistry at KAIST, Korea. He had experienced his postdoc career in the Department of Chemical Engineering at M.I.T. in the United States. In 2004, he joined Gwangju Institute of Science and Technology (GIST) as an Assistant Professor of Life Sciences and promoted to a Professor in 2010. He moved to KAIST in 2012 and is currently a Professor in the Department of Biological Sciences at the institute. His research interest lies at the interface of medicine, biotechnology, nanotechnology, and biomaterials.
⇑ Corresponding author. E-mail address: [email protected] (S. Jon). 0020-1693/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ica.2012.07.001
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Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Physicochemical properties of GNPs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GNPs in in vitro assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GNPs in cancer imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GNPs in cancer therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . GNP in theranostic medicine: simultaneous diagnosis and drug delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
1.1. Physicochemical properties of GNPs
A variety of nanoparticles has find their uses in biomedical applications, including drug delivery, molecular imaging, and/or combined therapy and diagnosis (theranosis) (Fig. 1). In particular, inorganic nanoparticles and their hybrids with organic materials possess unique optical, physical, chemical and electronic properties that distinguish them from the corresponding larger-sized particles or materials [1–7]. Inorganic nanoparticles are particularly suited for use as contrast agents for molecular imaging because they have a longer half-life in the circulation than molecular-sized conventional contrast agents. The modalities available for nanoparticle imaging include magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography (PET), and ultrasound and optical imaging [8]. Additional nanoparticle-based systems are currently under investigation, and a variety of nanoparticles, including gold nanoparticles (GNPs), iron oxide nanoparticles, quantum dots, liposomes and dendrimers, have been well studied. In this paper, we review the diagnostic and therapeutic uses of GNPs based on our research, with an emphasis on cancer applications.
The past decade has seen the development of GNPs for a variety of applications, including in vitro sensing, imaging and drug delivery—an expansion of applications that reflects the advantages of such nanoparticles in terms of biocompatibility, ease of synthesis, and ability to control size and optical properties (Fig. 2). The surface plasmon resonance band of a 5-nm GNP is located at 520 nm in ethanol, but is very sensitive to particle composition, size and shape, as well as environment and interparticle distance. These factors constitute the basis for GNP applications for biological labeling, detection, diagnostics and sensing. According to the Mie theory, an electromagnetic frequency induces a resonant coherent oscillation of free electrons, called the surface plasmon resonance, at the surface of a GNP if the particle is much smaller than the light wavelength. GNPs can also be used as drug-delivery carriers because they are biocompatible and nonimmunogenic. Various GNP synthesis methods have been reported [9–11]. GNPs of various sizes, from a few to several hundred nanometers, can be easily synthesized using reducing agents, which lead to the nucleation of gold ions onto nanoparticles. Citrate-capped
Fig. 1. Applications of nanoparticle-based medicine (nanomedicine).
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Fig. 2. Advantages and biomedical applications of GNPs.
nanoparticles are stable, but the citrate ion can be replaced and functionalized with various ligands for specific applications. Because the thiol group has a high affinity for gold, most thiol-modified ligands that have been used bind to the surface of GNPs through formation of an Au–thiol bond [12–14]. 2. GNPs in in vitro assays GNPs exhibit strong surface plasmon resonance that depends on particle size and relative distance between particles. GNPs usually have an absorption in the 500–550-nm range, corresponding to the surface plasmon band. This absorption arises from the collective oscillation of the valence electrons due to resonant excitation by incident photons. Because of this property, GNPs are of interest in the rapidly developing biosensor field. Aggregation of GNPs evokes interparticle surface plasmon coupling, resulting in a significant color change from red to blue and broadening of the surface plasmon resonance band that can be readily observed by the naked
eye, obviating the need for instrumentation. Colorimetric detection based on the aggregation of GNPs has been extensively studied for the detection of a variety of targets, including metal ions [15–23], DNA [24–26], bacterial toxins [27,28] and proteins [29–32], as well as enzyme activity [33,34]. Our group has developed a simple and rapid colorimetric method that can distinguish between normal and abnormal (hypercalcemic) calcium ion (Ca2+) levels in serum using calsequestrin (CSQ)-functionalized GNPs (Fig. 3) [35]. Ca2+ is profoundly important for diverse biological functions, including skeletal mineralization, blood coagulation, neurotransmission, excitation of skeletal and cardiac muscle, and stimulus-mediated hormone secretion [36]. Because hypercalcemia can cause hyperparathyroidism, malignant tumors and hyperthyroidism, the rapid and accurate estimation of blood Ca2+ levels is very important. CSQ, the most abundant Ca2+-binding protein, undergoes a Ca2+ concentration-dependent conformational change in response to Ca2+ binding; because it has a high capacity (40–50 binding sites per molecule) and relatively low affinity for Ca2+, CSQ binds and
Fig. 3. (a) Schematic representation of the Ca2+ sensor: the aggregation of CSQ-functionalized GNPs caused by binding of Ca2+ results in a color change. (b) Colorimetric responses of CSQ–GNPs to different metal ions at concentration levels greater than those normally seen in blood: Ca2+ (5 mM), Mg2+ (5 mM), K+ (10 mM), Na+ (200 mM); Sr2+, Ba2+, Cu2+, Hg2+, Mn2+, Ni2+, Cd2+, and Zn2+ (all 100 lM). Adapted with permission from Ref. [35].
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Fig. 4. Advantage and disadvantage of typical molecular imaging modalities.
Fig. 5. (a) A three-dimensional in vivo CT angiographic image of the heart and great vessels obtained 10 min after injection of 500 lL PEG-coated GNPs (140 mg/mL) into the tail vein of a Sprague–Dawley rat. HU values of the left ventricle (LV), aortic arch, inferior vena cava (IVC), liver and spleen before injection (pre) and at the indicated times after injection are also shown. (b) CT images obtained in a rat hepatoma model following injection of 400 lL PEG-coated GNPs (100 mg/mL) into the tail vein. Image was obtained 1 h after injection. Arrows indicate hepatoma regions. Adapted with permission from Ref. [56].
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Fig. 6. (a) A synthetic scheme for preparation of PEG-coated GIONs. Transmission electron microscopic images of (b) SPIONs (Fe3O4) and (c) PEG-coated GIONs. Scale bar = 20 nm. Adapted with permission from Ref. [65].
releases large amounts of Ca2+ [37,38]. In the absence of Ca2+, CSQ adopts an unfolded form. When the Ca2+ concentration gradually increases from 10 lM to 0.01–1 mM, the randomly coiled CSQ condenses into a compact monomer, which subsequently undergoes dimerization and then polymerization. Therefore, CSQ-functionalized GNPs undergo Ca2+-dependent CSQ polymerization, which results in a clear change in color together with precipitation. This sensing system is specific for Ca2+, and the differences between normal and disease-associated abnormal Ca2+ levels in serum can be distinguished with the naked eye. 3. GNPs in cancer imaging Molecular imaging involves characterization of biological processes in living organisms at the molecular and cellular levels. By exploiting specific molecular-imaging agents, this powerful technique can be used to visualize and characterize early-stage disease, providing a rapid method for evaluating treatment. Currently used molecular imaging modalities include MRI, CT, ultrasound, optical imaging, single-photon emission computed tomography (SPECT) and PET (Fig. 4) [39,40]. Although molecular imaging modalities, such as optical imaging, PET and SPECT, are capable of detecting molecular and cellular changes associated with diseases, they have the disadvantage of poor spatial resolution. On the other hand, MRI has good spatial resolution; however, low sensitivity of contrast agents is a major hurdle [41]. Optical imaging utilizes photons emitted from bioluminescent or fluorescent probes to study disease processes and biology in vivo. It has the advantage of being cost effective, rapid and easy to use compared to other imaging modalities. However, optical imaging suffers from poor tissue penetration due to light absorption by proteins (257–280 nm), heme groups (maximum absorbance at 60 nm) and even water (above 900 nm) [42]; a high background signal due to tissue autofluorescence is also an issue [43]. GNPs offer a number of advantages for optical imaging applications compared to other agents: their scattered light is very strong; they are much brighter than chemical fluorophores; they are resistant to photobleaching; and they can be easily detected at concentrations as low as 1016 M. Sokolov et al. have developed
an anti-EGFR (epidermal growth factor) antibody-conjugated GNP for the detection of cervical cancer [44]. Irradiation with a laser produces a single color that is close to the laser wavelength used, but when illuminated with a beam of white light, GNPs scatter light of many colors. The color of the light is determined by the absorption of the nanoparticles, which in turn depends on nanoparticle shape and size. This color-dependent scattering property makes it possible to perform imaging studies using a simple white light source. Raman spectroscopy is the most promising imaging technique for GNP-based contrast agents. GNPs have the optical property of amplifying the Raman scattering efficiencies of adsorbed molecules by as much as 1014- to 1015-fold, allowing spectroscopic detection and identification of single molecules under ambient conditions. In one such application, 60-nm GNPs were encoded with Raman reporter and stabilized with thiolated polyethylene glycol (PEG). For targeted cancer imaging, surface-enhanced Raman scattering (SERS) nanoparticles were conjugated with ScFv antibody, which is a ligand that specifically binds to the EGFR [45]. These SERS nanoparticles for active targeting of both cancer cells and tumor xenografts were more than 200-times brighter than near-infrared-emitting quantum dots, and allowed spectroscopic detection of small tumors at a penetration depth of 1–2 cm. CT, which is one of the most frequently employed and cost effective diagnostic tools used in hospitals [46–48], provides anatomical information by measuring the absorption of X-rays as they pass through tissue. Different tissues can be distinguished based on
Fig. 7. CT images and (a) T2-weighted MRI images (b) of PEG-coated GIONs at different concentrations. Adapted with permission from Ref. [65].
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Fig. 8. (a) Schematic illustration of poly(DMA-r-mPEGMA-r-MA) coating of hybrid gold–iron oxide (Au–Fe3O4) nanoparticles. (b and c) TEM images of hybrid Au–Fe3O4 nanoparticles before (b) and after (c) coating with poly(DMA-r-mPEGMA-r-MA). Scale bar = 20 nm. Adapted with permission from Ref. [66].
their distinctive degrees of X-ray attenuation, which in turn depends on the electron density of the tissue. CT contrast agents in current use are based on iodinated small compounds [49,50]. However, these agents are often associated with renal toxicity, and their low molecular weight results in a short imaging time [51,52]. Novel nanoparticle-based CT contrast agents that overcome these limitations have recently emerged [53–55]. Polymer-coated bismuth sulfide (Bi2S3) nanoparticles may be useful as CT contrast
agents and have an efficacy/safety profile in vivo that is comparable to or better than that of iodinated imaging agents [53]. Despite several favorable properties, Bi2S3 nanoparticle size and shape are difficult to control, and there is a lack of chemical methods available for modifying the surface of these nanoparticles, which may hinder their further clinical application. Recently, GNPs have been intensively investigated as noble CT contrast agents because their X-ray absorption coefficient is higher than that of iodine (5.16
Fig. 9. Serial CT (a–d) and MR (e–h) images in a mouse hepatoma model following injection of 100 lL poly(DMA-r-mPEGMA-r-MA)@Au–Fe3O4 (Au: 48 mg/kg; Fe: 36 mg/kg) into the tail vein. Images were obtained at time 0 (i.e., before injection) (a, e) and 1 h (b, f), 2 h (c, g) and 4 h (d, h) after injection. Arrows indicate hepatoma regions. Numbers in brackets are HU values of hepatomas (left) and surrounding normal liver parenchyma (right). Adapted with permission from Ref. [66].
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Fig. 10. (a) Schematic illustration of the method for preparing Dox-loaded, aptamer-conjugated GNPs. (b) PSMA aptamer and ONT sequences used to synthesize Dox-loaded, aptamer-conjugated GNPs. Adapted with permission from Ref. [81].
and 1.94 cm2/g, respectively, at 100 keV), their size and shape are easier to control and, unlike Bi2S3 nanoparticles, their surfaces can be readily modified with various functional groups. Our laboratory has developed PEG-coated GNPs as a potential CT contrast agent for in vivo imaging (Fig. 5) [56]. The simple combination of the antibiofouling property provided by PEG and the high X-ray absorption property of gold results in an efficient CT contrast agent with a long circulation time that may avoid the shortcomings of current iodine-based CT contrast agents. At the same concentration, the X-ray attenuation coefficient of PEG-coated GNPs was 1.9-times higher than that of the current iodine-based CT contrast agent. And quantitative analyses of Hounsfield unit (HU, a linear transformation of the original linear attenuation coefficient in one in which the radiodensity of distilled water is defined as zero HU) value for heart and great vessels, such as the aortic arch, aorta, interior vena cava and hepatic veins, revealed that PEG-coated GNPs circulate in the bloodstream for at least 4 h without an appreciable loss of contrast. The much longer half-life of PEGcoated GNPs in the circulation compared to the iodine-based contrast agent Ultravist (<10 min) should help improve disease diagnosis [57,58]. Furthermore, we showed that PEG-coated GNPs can be used not only as a blood pool imaging agent, but also as an agent for detecting hepatomas. Although CT is a very useful diagnostic tool in hospitals, the unavailability of targeted contrast agents has historically made it unsuitable for molecular imaging. This limitation was first surmounted by Popovtzer et al., who conjugated a UM-A9 antibody, which specifically binds to squamous cell head and neck cancer, to a gold nanoprobe, and demonstrated
exclusive association of the conjugate with targeted cancer cells and production of strong selective X-ray attenuation that was distinct from that obtained from identical, but untargeted, cancer cells or normal cells [59]. GNPs have rarely been used successfully for in vivo CT imaging of cancer, mainly because of their low stability and lack of specificity. A very recent report described in vivo tumor-targeting gold nanoprobes as contrast agents for CT/optical imaging of cancer [60]. In this study, GNPs were modified with glycol chitosan (GC) to increase physiological stability and tumor-targeting efficiency. Next, matrix metalloproteinase (MMP)activatable peptide probes were conjugated to GC-GNPs for optical imaging. MMP-GC-GNPs efficiently accumulated in the tumor tissue and their near-infrared fluorescence (NIRF), which is normally strongly quenched, was sensitively recovered by cleavage of the peptide substrates upon exposure to active MMPs, which are overexpressed in tumor tissue. This probe allowed simultaneous CT and optical imaging of the same tumor-bearing mouse model. A single imaging modality does not possess all necessary attributes for comprehensive imaging. For example, PET has high target sensitivity but low spatial resolution. On the other hand, CT has good spatial resolution, but is limited by low target sensitivity. Multimodal imaging systems that combine different modalities into a single system, thereby compensating for the deficiencies of single imaging modalities, have been extensively studied as a solution to this limitation [61–64]. Our group recently described a multimodal imaging agent consisting of a SPION core (magnetite [Fe3O4]) and a thin gold-layered shell; the resulting gold-coated iron oxide nanoparticle (GION) could be used for both MRI and
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Fig. 11. CT images (a) and HU values (b) of PBS, LNCaP and PC3 cells, and LNCaP and PC3 cells treated with PSMA-aptamer-conjugated GNPs (5 nM) or scrambled-aptamerconjugated GNPs (5 nM) for 6 h (n = 3). Adapted with permission from Ref. [81].
CT (Fig. 6) [65]. These core–shell nanoparticles showed high CT attenuation because of the presence of gold layers. However, their T2 signal intensity in MRI was much lower than that of normal SPIONs, presumably due to the embedding of SPIONs in the inner core, thus hampering the in vivo application of such nanoparticles as CT/MRI dual contrast agents (Fig. 7). To overcome this limitation, we designed a new type of hybrid nanoparticle in which several SPIONs were fused with a GNP in a dumbbell shaped (Fig. 8) [66]. This dual contrast agent, which was coated with amphiphilic polymer [Poly(DMA-r-mPEGMA-r-MA)] to impart water-dispersing and antibiofouling properties, exhibited high CT attenuation and a good MR signal because of the presence of the GNP and iron oxide nanoparticle, respectively. Intravenous injection of these hybrid nanoparticles into hepatoma-bearing mice resulted in high contrast between the hepatoma and normal hepatic parenchyma in both CT and MR images (Fig. 9). In another report, it was shown that gadolinium chelator-coated GNPs could be used as contrast agents for both in vivo X-ray and MR imaging [67]. This report showed that these nanoparticles circulated in the blood vessels without undesirable accumulation in the lung, spleen or liver. Recently, sub-50-nm multifunctional nanoparticles for fluorescence, MR and CT trimodal imaging were developed [68]. These PEGylated NaY/GdF4:Yb, Er, Tm@SiO2–Au@PEG5000 nanoparticles showed strong emissions ranging from the visible to near infrared (NIR) for fluorescence imaging, facilitated T1-weighted MRI through shorting of T1 relaxation time and served as a CT contrast agent by enhancing HU values. 4. GNPs in cancer therapy Targeted delivery of therapeutic agents to disease sites is one of most challenging research areas in pharmaceutical sciences. Nanoparticle-based drug-delivery systems provide an advantage over free drugs, improving delivery efficiency, solubility, in vivo stability and biodistribution [69,70]. Therapeutics based on nanoparti-
cles have been successfully introduced for the treatment of several pathological conditions, including cancer, pain and infectious disease. The unique properties of GNPs make these nanoparticles very promising as drug carriers, and this area of GNP applications is a rapidly expanding field. By exploiting the structural diversity made possible by ligand exchange and multifunctional monolayers, it is possible to create GNP surfaces containing targeting ligands and chemotherapeutics. CYT-6091, a PEGylated colloidal gold-TNFa nanoparticle developed by CytImmune, very recently completed Phase I clinical trials [71]. CYT6091 is a multivalent drug that is assembled on 26-nm GNP by covalently linking TNF-a and PEG-SH. CYT-6091 achieved higher concentrations within MC-38 tumors than free TNF-a, improving the efficacy of a given dose of TNF-a such that 7.5 mg of CYT6091 was as effective as 15 mg of free TNF-a in inhibiting tumor growth. Furthermore, the toxicity of CYT-6091 was lower than that of free TNF-a. Brown and colleagues also described a GNP-based strategy for delivering oxaliplatin, a platinum-based anticancer drug [72]. Although oxaliplatin has shown potential for treating colorectal tumors, its use is limited by associated neurotoxicity, nausea and vomiting. In this application, the active component of oxaliplatin, Pt(R,R-dach), was conjugated to the surface of PEGylated GNPs for improved drug delivery. In tests against various colon cancer cell lines, oxaliplatin-conjugated GNPs were up to 5.6-fold more efficacious than oxaliplatin alone, and in all cases were at least as active as free oxaliplatin. Gene therapy is a promising strategy for treating various diseases. Viral vectors are the most effective method for gene delivery, but there are safety concerns associated with their use, such as cytotoxicity and immunogenicity. Designing effective alternative vehicles for delivering plasmid DNA and siRNA is a considerable technical challenge. Such vehicles would need to provide efficient protection of nucleic acids from degradation by nucleases while allowing for the release of the nucleic acid in the cell. Nanoparticle systems are attractive candidates for the creation of nucleic acid
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Fig. 12. Confocal laser-scanning microscopic images of fluorescence, DIC and merged images of LNCaP (a, c, e) and PC3 (b, d, f) cells after treatment with Dox-loaded, aptamer-GNP conjugates. Adapted with permission from Ref. [81].
delivery vectors. Mirkin and co-workers showed that protein expression could be controlled by antisense DNA-functionalized GNPs [73]. Lee et al. developed siRNA delivery vehicles using poly(b-amino esters) as delivery enhancers and GNPs as scaffolds [74]. Although poly(b-amino esters) are potential DNA delivery agents, this material is not suitable for siRNA delivery due to incomplete condensation between polymer and siRNA. However, this system does facilitate high levels of in vitro siRNA delivery—as good as or better than that achieved using the widely used transfection reagent, Lipofectamine 2000. Breunig and co-workers have shown that a heterogeneous particle system consisting of a layer-by-layer assembly on GNPs of the oppositely charged polyelectrolytes siRNA and PEI can be employed to deliver siRNA to cells [75]. 5. GNP in theranostic medicine: simultaneous diagnosis and drug delivery Nanoparticle technology holds great promise in simultaneously diagnosing disease, providing targeted drug delivery with minimal toxicity, and monitoring treatment [76–80]. Such theranostic
nanoparticles are particular promising in the emerging field of personalized medicine, because they can detect disease at an early stage in individual patients and deliver therapeutic agents over an extended period for enhanced therapeutic efficacy. Moreover, real-time, non-invasive monitoring of theranostic nanoparticles enables clinicians to rapidly decide whether a given treatment regimen is effective in an individual patient. Recently, our group developed a drug-loaded aptamer-GNP bioconjugate for combined CT imaging and therapy of prostate cancer (Fig. 10) [81]. By conjugating GNPs with a PSMA-specific aptamer, we constructed a multifunctional nanoparticle that enabled combined prostate cancer CT imaging and anticancer therapy. Aptamers are an emerging class of targeting ligands capable of also serving as biological drugs for treatment of various diseases [82– 87]. As escort molecules, aptamers are able to deliver drug or nanoparticles encapsulating drug to target cells via high-affinity, specific binding. Our group demonstrated that a PSMA-specific aptamer formed a physical complex with Dox via intercalation, and thereby delivered this anticancer drug to target prostate cancer cells [88]. However, in this system, only one Dox molecule
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could intercalate into each PSMA aptamer. To increase Dox loading efficiency, we hybridized a 21-base (CGA)7 repeating oligonucleotide (ONT), which forms a GC-rich duplex that acts as a loading site for the chemotherapeutic agent Dox, to the 30 -end of the PSMAspecific RNA aptamer. Because Dox intercalates preferentially into consecutive -CG- base pairs, fusing the (CGA)7 repeating ONT to the original PSMA aptamer significantly enhanced Dox loading capacity, providing sites for at least 6–7 Dox molecules in the extended region instead of the single Dox molecule bound by the original PSMA aptamer. The PSMA aptamer-conjugated GNPs were able to specifically bind to target prostate cancer cells that overexpressed PSMA antigen and showed more than 4-fold greater CT intensity for targeted LNCaP cells than for nontargeted PC3 cells (Fig. 11). Furthermore, after loading with Dox, PSMA aptamerconjugated GNPs were significantly more potent against targeted LNCaP cells than against nontargeted PC3 cells, suggesting targetspecific drug delivery (Fig. 12). Gold nanorods, which can easily be prepared with various aspect ratios using simple and well-established synthesis techniques, have been extensively studied as photothermal agents for cancer therapy [89]. Because they provide tunable surface plasmon absorption wavelengths in the NIR region, which can penetrate into deep tissue for photothermal therapy, gold nanorods are better potential photothermal agents than GNPs of other shapes (e.g., branched, pentagon, large prism). The heating effect of gold nanorods upon NIR absorption is a result of the electron dynamics in metallic lattices [90]. In one pioneering study, a gold nanorod (aspect ratio, 3.9) conjugated to an anti-EGFR antibody was found to specifically target malignant cells; after heating the nanorod with NIR light, malignant cells were selectively destroyed in vitro without damaging nonmalignant cells [89]. Furthermore, the strongly scattered red light from gold nanorods was clearly visible in a dark field, enabling malignant cells to be readily distinguished from nonmalignant cells. In another study, gold nanorods coated with poly(styrene-alt-maleic acid), the photosensitizer indocyanine green and anti-EGFR were developed as multifunctional nanoparticles, serving as tumor-targeting and hyperthermia agents to destroy malignant cells through photodynamic therapy (PDT), and as optical contrast agents to simultaneously monitor cells by imaging in the NIR region [91]. 6. Conclusions Because of their unique physical and chemical properties, biocompatibility, and ease of synthesis and surface modification, GNPs have received considerable research attention for use in biomedical applications. In addition to these advantages, gold has a higher X-ray absorption coefficient than iodine, encouraging us to study the feasibility of using GNPs as a CT contrast agent in vivo. We first demonstrated that PEG-coated GNPs as a new CT contrast agent could be used not only as a blood pool imaging agent but also as a hepatoma-detection agent. Then, we described hybrid amphiphilic polymer-coated Au–Fe3O4 and gold-coated iron oxide nanoparticles that compensate for the respective limitations of MRI and CT. In particular, amphiphilic polymer-coated Au–Fe3O4 can be useful as a potential dual CT/MRI contrast agent for in vivo hepatoma imaging. CT is more frequently used clinically to detect hepatomas than MRI, because MRI is relatively expensive and requires a longer scanning time. In patients with ambiguous CT findings, however, MRI may be needed to detect hepatomas. In such patients, use of the hybrid nanoparticles described here can accurately and facilely diagnose hepatoma without the need to employ the two imaging modalities separately. Furthermore, we described Dox-loaded, aptamer-conjugated GNPs for targeted molecular CT imaging and therapy of prostate cancer. We anticipate that the present GNP conjugate system could be applied to
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the design of similar multifunctional nanoparticles through the use of other disease-specific aptamers and imaging nanoprobes. We also reported a simple and rapid colorimetric method for the detection of Ca2+ with high specificity using CSQ-functionalized GNPs. This technique, which does not require specialized equipment because test results can be easily seen by the naked eye, helps to rapidly and accurately diagnose blood Ca2+ levels. As such, it may be useful in the detection or monitoring of several diseases associated with hypercalcemia, such as malignant tumors. On the basis of this research, we believe that the GNP is one of most attractive nanomaterials for in vitro diagnosis, molecular imaging, drug delivery and theranostic applications.
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