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Application of Efficient Nanoparticles for Early Diagnosis and Treatment of Cancer Athanasios Alexiou1*, Charalampos Vairaktarakis2, Vasilis Tsiamis2 and Ghulam Md Ashraf 3 1

BiHELab, Department of Informatics, IonianUniversity, 49100 Corfu, Greece; 2Department of Computer Science and Biomedical Informatics, University of Thessaly, 35100 Lamia, Greece; 3King FahdMedicalResearchCenter, KingAbdulazizUniversity, P.O. Box 80216, Jeddah21589, Kingdom of Saudi Arabia

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Abstract: Cancer is considered as a prevalent cause of human deaths and undoubtedly, is the most complex disease with multiple cellular physiological systems involved. During the last decade, the application of nanotechnological products for cancer treatment has received considerable attention. These sophisticated tools and materials treat cancer though the early diagnosis, the prediction, the prevention and the personalized therapy. This technology enabled the development of nanoscale particles that can be conjugated with one or multiple functional molecules simultaneously. Nanoparticles have the capability to be delivered directly through blood vessels to the tumor site and interact with targeted tumor-specific proteins located inside or on the surface of cancer cells, since their size is a hundred to thousand times smaller than cancer cells. In this review, comprehensive outline of all the latest scientific and technological applications such as quantum dots and gold nanoparticles alongside with their applications in cancer diagnosis and treatment have been presented.

1. INTRODUCTION

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Keywords: Cancer diagnosis and treatment, drug delivery, gold nanoparticles, nanomedicine, quantum dots. 2. QUANTUM DOTS 2.1. Background

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QDs are almost spherical- semiconductor nanocrystals, mainly composed of elements from the periodic groups of II-VI (CdSe) or III-V (InP) [3] designed with reinforced optical and electronic properties that are nonexistent to semiconductors in bulk solids [4]. Till now, the primary interest in QDs has been focused on physical applications, such as the manufacturing of computer chips, although recent studies reveal their advanced future role in biological applications as well. QDs seemed to obtain their new potentialities as fluorescent probes in 1998 when two independent research groups reported manufacturing procedures of water-soluble QDs and conjugating them to biomolecules [5, 6]. These water-soluble QDs have been later conjugated to nucleic acids [7], peptides, polymers [8], small proteins [9], carbohydrates [10] and various biological molecules such as antibodies [11] or small molecules such as folic acid [12].

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Nanotechnology can be defined as the convergence of science and engineering in the manipulation and control of materials and equipments at the size of nanoscale [1]. It has been characterized as the next industrial revolution and the current technological tools, materials and methodologies presage a future progress in technology that verifies this conjecture. In the last decade, nanotechnology has been applied in various biomedical fields, thus introducing a new field of study; nanomedicine. The European Technology Platform on Nanomedicine (ETPN) establishes Nanomedicine through the applications of nanotechnology in health via improved materials, devices and systems at the scale of manometers. Therefore, nanomedical products have recently been reported with great potential impact on the early and reliable prevention, diagnosis and treatment of various diseases [2]. Nowadays, the application of nanomedicine in several cases like drugs delivery, in vitro/vivo imaging and diagnosis as well as regenerative medicine and implanted devices is quite common. Recently, the application of nanomedicine in cancer therapy has received considerable attention [2, 131]. Cancer nanotechnology can provide unique and integrated technological resources for diagnosis, prediction, prevention and therapy [2, 132]. The primary nanotechnological tools for cancer therapy include liposomes, nanoparticles, polymeric micelles, quantum dots, carbon nanotubes and dendrimers [130]. In this review, quantum dots (QDs) and gold nanoparticles (GNPs) have been analyzed due to their unique and novel properties, which make them very popular among alternative applications against cancer. The manufacturing methods, properties and applications in detection, imaging and therapy of cancer have also been analytically referred.

2.2. Optical Properties of QDs

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*Address correspondence to this author at Bioinformatics & Human Electrophysiology Laboratory, Department of Informatics, IonianUniversity, Plateia Tsirigoti 7, 49100 Corfu, Greece; Tel/Fax: +306944551797; E-mail: [email protected]

The comparison of QDs with other organic dyes and fluorescent proteins demonstrates unique and innovative optical and electronic properties, while biological QDs probes have been found to be 1020 times brighter in photon-limited in vivo conditions than the organic dyes, due to their very large molar extinction coefficients [5, 6]. Additionally, they have approximately a thousand times better photostability than organic fluorophores, which makes them suitable for continuous tracking studies over a period of time [11]. The fluorescence emission of the QDs is size- and composition- tunable. Quantum confinement allows the light emission of QDs at different wavelengths dependent on their core diameter and only one light source suffices to excite multiple colors of emission, leading to a large stokes shift which means large distance between excitation and emission wavelengths [13], like CdSe/Zns QDs [14]. As recent works have deduced, QDs near infrared excitation compared with

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Application of Efficient Nanoparticles

Current Drug Metabolism, 2015, Vol. 16, No. 8

cules, such as mercaptoacetic acid, phospho-alchocols and polysilanes. One end of the bifunctional molecule must contain a functional group that can interact with the metal atoms of the QDs surface, while the second end that protrudes from the QDs surface must contain a hydrophilic functional group making the whole structure extremely polar. In the second procedure, the TOPO, on the surface of the QDs, interacts with the hydrophobic part of amphiphilic molecules while the hydrophilic parts protrude from the QDs surface. Through both procedures, the hydrophobic ligands on the surface do not interact with aqueous solvents making the QDs biocompatible and in addition, capable to be conjugated to biomolecules [5, 6, 11, 24].

ultraviolet excitation of QDs, have insignificant blinking effects, deep penetration in tissue and zero auto-fluorescence [15]. The excitation of different optical emission QDs by a single wavelength allows the use of QDs in multiplexed applications, such as molecular and cellular imaging for sensitive diagnostics like in cancer biology. 2.3. Manufacturing of QDs

2.4. Targeting and Imaging of Cancer Using QDs

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Targeted delivery of the QDs in cancer cells is considered as an essential requirement for efficient cancer imaging. Targeted QDs compared to the traditional imaging probes provide several unique features and functionalities. Their optical and electronic properties are related to their size and composition and can be changed by altering these two attributes, something that allows the synthesis of a wide range of nanoparticles for multiple and simultaneous detection of cancer biomarkers. The large surface of the biocompatible QDs enables the conjugation with multiple functional groups of same or different type, which gives the opportunity to create complex nanoparticles for the application of various multimodality imaging techniques. Furthermore, recent studies have shown that macromolecules and particles in nanometer scale can be accumulated at tumor sites through the EPR effect (EnhancedPermeability-Retention). This effect is based either on the vascular endothelial growth factors that the angiogenic tumors produce or to the absence of lymphatic drainage system in tumors, which leads to subsequent macromolecule or nanoparticle accumulation [25, 26].

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2.4.1. Targeting and Imaging of Cancer Cells

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QDs are typically prepared in high quality by using 300-350C pyrolysis of organometallic and chalcogenide reagents in solvents, such as trioctylphosphine oxide (TOPO) and hexadecylamine. This procedure by altering the amount of precursors and crystal growth time enables the synthesis of nanocrystals with variations on their size. For example, after rapid injection of precursors in TOPO solvent, the solution appears as light yellow and while the QDs grow bigger, the solution changes to dark ruby red [4, 16, 17]. Other researches demonstrated that organometallic precursors can be replaced with less costly and environmentally friendly reagents [18]. Recent works enabled the manufacturing of high-quality CdSe QDs with ethanol and glycerol in lower than traditional temperature (50160C) phosphine free solvent, making the whole reaction environmentally friendly [19]. The manufacturing process produces a heavy metal core with low brightness; however, the fluorescence efficiency of the QDs can be enhanced by an inorganic shell surrounding the core structure (Fig. 1). This secondary semiconductor layer must have a larger band gap energy than the core of the QDs. For example, CdSe QDs have less than 10% quantum yield, whilst the formation of a Zns cell around the CdSe core increases the quantum yield up to 85% [20-22]. This core/shell structure, nonetheless, requires further surface modification for QDs practice in biological applications, because they are neither water-soluble nor biocompatible. While most of the QDs synthesis methods use organic solvents, the surface of both core and core/shell structures is coated by hydrophobic ligands. Two different procedures have been used to solubilize QDs and render them biocompatible. In the first procedure, the surface ligands are replaced with bifunctional mole-

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Fig. (1). (A) Brightfield and true color fluorescence images of CdTe QD aqueous solutions. (B) Photoluminescence emission spectra. (C) UV-Vis absorption of CdTe QD aqueous solutions. Reprinted from The therapeutic efficacy of CdTe and CdSe quantum dots for photothermal cancer therapy, [Chu M, Pan X, Zhang D, Wu Q, Peng J, Hai W, Biomaterials 2012; 33:7071-7083], with permission from Elsevier [23].

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double-color QDs imaging was achieved through simultaneous detection of HER2 and type IV collagen on the same tissue sample by a mixture of two primary antibodies from the two species. The results showed that the increase inHER2 expression level led to a progressive decrease in type IV collagen around the cancer cell nest, and more specifically, a total destruction of type IV collagen occurred at HER2(3+) expression level while breast cancer cells showed a direct invasion into the blood vessels. Furthermore, researchers reported alternative QDs conjugates. Cai et al. [37] used QD-RGD peptide conjugate which specific target over-expressed 3 integrin. They applied these QDs successfully on targeting MDA-MB-435 human cancer cells and U87MG human glioblastoma cells; in addition, they also found that RGD peptide is equally effective for MCF-7 human breast cancer cells detection. Subsequently, Geszke et al. [38] applied ZnS:Mn/ZnS QDs – folic acid conjugate as targeted probes for two photon fluorescence imaging of MCF-7 and T47D human breast cancer cells. Prostate specific membrane antigen (PSMA) has been identified as a target for imaging and therapeutic purposes of prostate cancer. Researchers identified PSMA as a cell surface marker for neovascular endothelial cells and prostate epithelial cells [39, 40]. Gao et al. [27] reported the labeling of human C4-2 prostate cancer cells by using QDs conjugated with PSMA antibody. QDantibody conjugate efficiently labeled PSMA positive C4-2 prostate cancer cells, although did not manage to detect PSMA negative PC-3 cells. Bagalkot et al. [41] using QDs conjugated with A10RNA aptamer were able to selectively detect prostate cancer cells. In this study, researchers were successfully labeled PSMA positive LNCaP prostate cells and found that QD-aptamer conjugate can be used equally as QD-PSMA antibody conjugate for targeting and imaging prostate cancer cells. Additionally, claudin 4 and PSCA are known to be over expressed in all cases of pancreatic cancer [42]. Yong et al. [29] reported the successful use of QDs for the selective detection and imaging of human pancreatic cancer cells. For this purpose, they conjugated InP/ZnS QDs with anti-claudin 4 and anti-prostate stem cell antigen. They also achieved labeling QD bioconjugates in claudin-4 and PSCA overexpressing pancreatic cancer cells such as MiaPaCa and XPA-3. Recently, Lee et al. [43] following a similar approach conjugated QDs with three different antibodies including anti-PSCA, anti-claudin-4 and anti-mesothelin (aMSLN) for targeting and imaging human pancreatic cancer cells. Peng et al. [30] reported a QDs-based simultaneous detection and imaging of infiltrating macrophages, tumor microvessels density (MVD) and neovessels maturity in gastric cancer tissues, achieving their main purpose to reveal the spatial relationship among infiltrating macrophages, neovessels and type IV collagen in tumor stroma and the basement membrane of neo-microvessels (Fig. 3). Peng et al. used three primary antibodies for their research: mouse anti-human monoclonal antibody against macrophages, rabbit anti-human polyclonal antibody against type IV collagen for basement of neovessels and CD105 for neovessels, while secondary antibodies conjugated with QDs on the F(ab’)2 fragments, including QDs-525, QDs-585 and QDs-655, and applied on 184 tumor and 41 peritumoral tissues. The three antigens were simultaneously stained in order to identify the infiltrating macrophages, endothelial cells of neovessels and the morphological maturity of neovessels presenting the comprehensive spectra of all those stromal ingredients. Macrophages density, microvessels density and neovessels maturity were found to be associated with cancer progression and prognosis of gastric cancer, and also found that the recurrence risk of gastric cancer patients with high macrophages density was increased by 110%.

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have been found to be extremely effective for the identification and imaging of human cancer cells originating from breast cancer [12], prostate cancer [27], metastatic tumor [28], pancreatic cancer [29] and gastric cancer [30]. The methods which have been developed for targeted imaging applications can be classified into antibodybased methods and ligand-based methods. QDs conjugated with primary or secondary antibodies used for the detection of specific over-expressed receptors, are ideal targets in many cancer typesand are widely used for targeting and fluorescence visualization of cancer cells. Antibodies are expensive agents, although they can be replaced by biomolecules such as folic acid, RGD peptide, tranferrin and aptamers, which similarly target specific receptors overexpressed in cancer cells. Furthermore, both of these methods can be applied in multi-targeted imaging applications by taking advantage of the multiplex capability of QDs. Many researchers reported simultaneous detection and measurement of multiple biomarkers in the same sample, highlighting the importance of QDs utility in cancer diagnostics [31]. For instance, human epidermal growth factor receptor 2 (HER2) was found to be overexpressed in approximately 25-30% of invasive breast cancer [32] and therefore, has been widely exploited for both the detection and therapy of breast cancer. Wu et al. [11] labeled SK-BR-3 human breast cancer cells by two different procedures. In the first procedure, they labeled SK-BR-3 cells by targeting cells with Herceptin and then with QD-IgG conjugates, while in the second procedure, they labeled SK-BR-3 cells using QD-streptavidin conjugate by targeting the cells with a humanized anti-HER2 antibody and then with biotinylated goat antihuman IgG [11]. In a further expansion of this approach, Yezhelyev et al. [33] labeled MCF-7 and BT-474 breast cancer cells using both visible and near infrared QDs conjugated with antibodies for HER2, epidermal growth factor receptor, progesterone receptor, estrogen receptor and mammalian target of rapamycin (m-TOR). Zhang et al. [34] found that QDs conjugated with anti-type 1 insulin-like growth factor receptor (IGF1R) can be applied for targeting and imaging of breast cancer cells, by the detection of up-regulated IGF1R in MCF-7 breast cancer cells. At the same time, Chen et al. [35] developed QDs HER2 probe kit alongside with QDs image acquisition and analysis software, which they compared with the conventional immunohistochemistry techniques. For QDs-IHC and conventional Immunohistochemistry (IHC), the CB11 clone mouse anti-human c-erbB-2 monoclonal antibody was used for HER2 targeting. QDs conjugated streptavidin (QDs-SA) probes with emission wavelengths of 605nm were used and both methods applied to 94 clinical samples of breast cancer. The expression of HER2 in breast cancer was detected with the QDs-IHC analysis system, and in comparison with the conventional IHC, the QDbased approach proved to be more sensitive, accurate and economic, especially for cases of IHC (2+). Recently, et al. [36] in order to investigate the dynamic changes of extracellular matrix (ECM) degradation during breast cancer invasion Liu et al. applied QDs-based double-color imaging technique on human breast cancer tissues for simultaneous detection of HER2 level on breast cancer cells and the type IV collagen in the tumor matrix (Fig. 2). HER2 expression status was validated by fluorescence in situ hybridization (FISH), with rabbit anti-human polyclonal antibody against type IV collagen and mouse anti-human monoclonal antibody against HER2 as the primary antibodies, while QDs probes conjugated with QDs on the F (ab)2 fragments, including QDs-525 goat F(ab)2 anti-mouse IgG conjugate and QDs-585 goat F(ab)2 antirabbit IgG conjugate served as secondary andibodies [36]. The


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Fig. (3). Multi-spectrum imaging indicates the maturity of neovessels. (A) Multiplexed imaging of neovessels (Red), type IV collagen (Yellow) and infiltrating macrophage (Green). (B) The spatial relationship between endothelial cells and type IV collagen. (C, D) Improved neovessels maturity was found in gastric cancer tissues with low macrophages density (C) compared with high macrophages density (D). (E) Immature neovessels (1), neovessels with intact type IV collagen (2) and mature neovessels (3) were showed in the same sample. Reprinted from Quantum-dots based simultaneous detection of multiple biomarkers of tumorstromal features to predict clinical outcomes in gastric cancer, Peng CW, Tian Q, Yang GF, Fang M, Zhang ZL, Peng J, Li Y, Pang DW, Biomaterials 2012; 33:5742-5752, with permission from Elsevier.

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Fig. (2). A. (A) Benign breast tumor, no HER2 expression and ECB (Red arrow). (B) Breast cancer with HER2 (+) (Red arrow), ECM becomes unsmooth and thinner (Yellow arrows). (C) HER2 (2+), moderate green fluorescence (Red arrow) while ECM becomes significantly degraded (Yellow arrow) (D) HER (3+), strong green fluorescence (Red arrow) and complete ECM degradation (Yellow arrow). B. Breast cancer invasion process of HER2 (+2). (A) The inner layer of ECM is degraded and outer layer is still intact, forming a potential invasion space between them (Red arrow). (B) ECM was completely degraded at one point (Red arrow). (C) Cancer cells “budding out” from the main cancer nest (Red arrow). (D) Integration of two cancer nests by degrading ECM at multiple points (Red arrows). Reprinted from Quantum dots-based double-color imaging of HER2 positive breast cancer invasion, Liu XL, Peng CW, Chen C, Yang XQ, Hu MB, Xia HS, Liu SP, Pang DW, Li Y, Biochemical and Biophysical Research Communications 2011; 409: 577–582, with permission from Elsevier.

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2.4.2. In vivo Targeting and Imaging of Cancer

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2.4.2.1. Imaging of Tumor Vasculature and Mapping of Sentinel Lymph Nodes In the treatment of breast cancer, the axillary lymph node status is the major prognostic factor for the lymphatic drainage and the level of metastasis of the primary tumor [44]. The QDs successfully applied in vivo conditions as contrast agents for both cardiovascular system and the lymphatic system. Ballou et al. [45] demonstrated that PEG-coated QDs can stay in blood circulation for a longer period of time than organic dyes, after they injected PEG-coated QDs into the mouse blood stream. Larson et al. [46] found that CdSe/Zns QDs with green light emission remained fluorescent and detectable in capillaries of adipose tissue and skin of living mice. During the last research, Larson et al. achieved the visualization of capillaries in the adipose tissue and skin through near infrared

excitation of two-photon fluorescence. PEG-coated QDs were found to be able to remain in blood circulation for a long time, although, they are large enough to avoid renal filtration or in other cases, nanoparticles are too large and remain at the injection point [47]. These conclusion led researchers to improve the tissue penetration by applying near infrared emitting QDs. Zimmer et al. [48] injected 16-19nm near-infrared QDs in mice and pigs and found that QDs gathered to sentinel lymph nodes due to the passive flow in lymphatic vessels and the active migration of the dendritic cells that engulfed the QDs. It was also found that further migration could be achieved in the lymphatic system if the probes were smaller. Soltesz et al. [49] around the same period developed a near infrared fluorescence imaging system which exhibits simultaneous NIR images and color video of the surgical field. For their research, 12 Yorkshire pigs were injected with 200pmol of NIR QDs of 15nm into lobar parenchyma succeeding accurate mapping and real time imaging of lymphatic drainage and the sentinel lymph node. It is widely accepted that lymph node mapping during operations is


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not efficient in light tissue penetration. QDs overcome these problems and have been used in vivo imaging of living animals. Akerman et al. [8] firstly reported in vivo tumor targeting by injecting CdSe/Zns QDs coated with peptides into the tail vein in mouse, discovering that the injected QDs preferentially distribute in endothelial cells in the blood vessels of lungs. Few years later, Gao et al. [52] worked on the manufacturing of multifunctional QDs probes for simultaneous targeting and imaging in vivo conditions. They conjugated QDs with an amphiphilic triblock copolymer for protection in vivo, targeting ligands for the recognition of the tumor antigens and multiple PEG molecules for biocompatibility and circulation improvisation. The results showed that tumor fluorescence was greater as compared to nonconjugated QDs, while QDs-antibody conjugates were efficiently and uniformly distributed in prostate cancer cells. Yu et al. [53] conjugated QDs with an antibody against alpha-fetoprotein (anti-AFP) and by using similar methods enabled targeted imaging of human liver cancer into mice. Kim et al. [54] imaged sentinel lymph nodes by direct injection of near-infrared (NIR) QDs (emission peak of 850nm) deep in tissues. In a more recent application of NIR QDs in vivo conditions, Shi et al. [55] reported the visualization of human prostate cancer cells in the mouse bone using NIR QDs of emission peak of 800 nm. QDs conjugated with a prostate-specific membrane antigen monoclonal antibody (aJ591) recognizing a human cancer cellsurface antigen (PSMA), detected C4-2B prostate cancer cells but not PC3 cells. Yang et al. [56] explored the competence of NIR QDs for visual in vivo imaging on oral carcinoma BcaCD885 cells. NIR QDspeptide conjugate with an emission wavelength of 800 nm was injected in the dorsum subcutaneous, back muscle and under the cheek oral mucosa of nude mice, in order to label BcaCD885 cells by endocytosis. The average depth of the injection points in these three areas were 0, 96±0, 12 mm, 1, 53±mm and 3, 42±0, 39 mm, respectively. The minimum counts of BcaCD885 cells detected were 10. 000 in dorsum subcutaneous, back muscle and under the cheek oral mucosa. This finding proved that QDs-based imaging increases the sensitivity of the early diagnosis of cancer by more than 100-fold, in comparison with traditional methods like CT and MRI. Recently, a new class of nanoparticle probes called MQQ has been developed for in vivo multimodality tumor imaging. Maa et al. [57] designed a multilayered nanoprobe based on magnetic nanoparticles (MNPs) and QDs, which contains Fe3O4 MNPs, visible-fluorescent CdSe/ZnS QDs and NIRfluorescent CdSeTe/CdS QDs in multiple silica layers. The fabrication of the MQQ-probe involves the synthesis of a primer Fe3O4 MNPs/SiO2 core by a revenge micro-emulsion method. The MQQprobes can be applied both as fluorescence probe and as contrast

2.4.2.2. Targeting and Imaging of Tumor in vivo

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highly significant for many surgeries against cancer. Si et al. [50] compared the effectiveness of NIR QDs and methylene blue in intraoperative lymph node mapping (Fig. 4). Twelve SpragueDawley rats were separated into two groups of six each. The QDs probes of average size 3. 5 ± 0. 3 nm and methylene blue were injected into the plantar metatarsal regions of the rats and observed directly as well as with a near-infrared imaging system. Blue stained lymph nodes remained dyed for 2 hours, while QDs retained their fluorescence up to one day after injection. Methylene blue was difficult to be identified in deep tissues and the lymph nodes beyond the sentinel lymph node. Si et al. found an ideal lymphatic drainage model; two level drainage pathways were identified including peripheral drainage (popliteal LNs, inguinal LNs and axillary LNs) and central drainage (popliteal LN, iliac LN and renal LN), and demonstrated the superiority of QDs as intraoperative probes compared to methylene blue. Li et al. [51] recently demonstrated the successful application of NIR-II Ag2S QDs in vivo realtime visualization of circulatory system and tumor angiogenesis. Compared to visible emission CdSe/ZnS QDs with emission peak at 635 and NIR-I indocyacine green (ICG) with emission peak at 835 nm, NIR-II Ag2S QDs (emission peak at 1200 nm) found to be less auto-fluorescent and appropriate for deeper tissue penetration, while their spatial and temporal resolution in the NIR-II window was higher too. The fact that NIR-II Ag2S QDs have lower tissue phantom and deeper tissue penetration in comparison with CdSe/ZnS QDs allows the acquisition of higher-resolution images of deep structures and more accurate imaging of sentinel lymph nodes, which can be applied as an intraoperative guidance. During the last research, PEGylated NIR-II Ag2S QDs were injected intravenously as probes into mice blood circulation. As a result, the clear visualization of whole vascular network of the animals and the tracking of QDs circulation in real time were achieved (high fluorescence remained in blood flow for more than 9 hours). High-order branches of blood vessels were defined and even small vessels of 100 m diameter were able to be observed without using any device.

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Methods like Positron emission tomography–computed tomography (PET/CT) enable the characterization of the molecular status of tumors in depth, within living animals, although, radioactivity-based methods lack low spatial resolution and multiplex capability. Other methods like multiphoton microscopy are even capable of 3D imaging of high sensitivity and high spatial and temporal resolution, but

Fig. (4). The anatomy of LNs. (A.) (A,B,C) Periferal system. (D) Central System. a: Popliteal LN, b: Inguinal LNs , c: Axillary LNs, d: Iliac LN (stained), e: Para-aortic LN (stained), f: Renal LN (stained), g: Iliac LN (unstained),h: Para-aortic LN (unstained). Reprinted from In Vivo Lymph Node Mapping by CdTe Quantum Dots in Rats, Si C, Zhang Y, Lv X, Yang W, Ran Z, Sun P, Journal of Surgical Research 2014; doi: 10.1016/j.jss.2014.07.028, with permission from Elsevier.



2.4.2.3. In vivo Toxicity

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2.5. Therapy of Cancer

2.5.1. Quantum Dots as Photosensitizers

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Photodynamic therapy (PDT) or photochemotherapy is a form of phototherapy that involves the administration of a photosensitizer that is preferably localized in a target tissue and is exposed to

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In vivo toxicity is a factor that can likely determine whether QDs could be approved for human clinical applications. Due to this reason, the potential toxicity of semiconductor QDs became a very important subject for assiduous studies and discussions. Many researchers reported that QDs probes can be injected into the circulation of living animals or cells without any negative effect on the viability, morphology or function of the cells. Akerman et al. [8] injected QDs conjugated with GFE or peptidases F3, demonstrating expected differential binding with no toxicity. Ballou et al. [45] also confirmed the non-toxic behavior of stably protected QDs. However, these studies were conducted to determine the utility of QDs for imaging rather than toxicity. Derfus et al. [58] demonstrated that photolysis or oxidation may adversely affect the stability of QDs. These researchers showed that CdSe QDs are highly toxic to cultured cells under UV illumination for extended periods of time. Semiconductors found to be dissolved under the UV illumination releasing toxic cadmium ions in the culture medium. Yang et al. [59] reported that after the injection of cadmium-based QDs in blood circulation, the concentration of cadmium in the liver and kidneys gradually increased and reached eventually upto 10% and 40% of the dose respectively. However, it was not clear if the cadmium was in the form of free ion or in nano-crystalline form. Cadmium ions can be released via oxidative degradation of the QDs and later bind to sulfhydryl groups of intracellular proteins, thus, changing the functionality in many intracellular organelles [60]. For this purpose, many studies were focused on the intracellular release and quantification of free cadmium ions from QDs [61]. Stern et al. [62] focused on the differences between the cytotoxic mechanisms

of two QDs with similar size and surface composition and different core materials. The core structure of the first QD was composed by cadmium selenide (CdSe), while the second one was composed by the less toxic indium gallium phosphide (InGaP). In a recent study, Tang et al. [63] examined the effects of surface chemistry and surface charge on in vivo biodistribution and toxicity of CdSe/ZnS QDs. For their research, they used positive, negative or PEG coated QDs for in vivo evaluation in mouse model. QDs with different surface coatings displayed dramatically different biodistribution and in vivo toxicity. They found that QDs coated with cationic polydiallyldimethylammonium chloride (PDDA) preferred to deposit in the lung than in the liver. On the other hand, negative and PEGylated QDs accumulated preferentially in the liver. The positive QDs acute toxicity especially in higher doses was found to be related to the coating material polydiallyldimethylammonium chloride. All the QDs despite their different surface coatings caused chronic injuries in the liver, spleen, lung and kidney after acute and long exposure, while the degree of the injuries was reported to be dependent on their surface composition. The chronic injuries remained in all the mice for a period of 15 weeks. Liu et al. [64] used two different types of CdTe QDs, one with emission peak at 530 nm and the other with emission peak at 720 nm. They examined the toxicity of these QDs on hematopoiesis in Bombyxmori. They found that a large amount of reactive oxygen species (ROS) which is toxic induced by QDs exposure in the hemopoietic organs, before the serious impairment of hematopoiesis. The ROS were found to be different after the exposure to QDs530 and QDs720. Two types of QDs with different diameters had extremely different impact on the growth and hematopoiesis of hemopoietic organs.

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reagent of magnetic resonance imaging. In this research [57] about cancer tumor imaging, they conjugated anti-HER2 antibody on the surface of the MQQ-probe, and successfully targeted human breast cancer cells (KLP-4), using NIR fluorescence and T2-weighted magnetic resonance (Fig. 5).

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Fig. (5). (A) In vivo NIR fluorescence imaging of a HER2-MQQ-probe injected mice bearing human breast tumors: (A, B) 0.1 hours and (C,D) 48 hours after injection of the HER2-MQQ-probe. The color mapping images of (B) and (D) show the fluorescence intensity at 830 nm. (B) Ex vivo NIR fluorescence imaging of tumors and major organs. Images were taken 48 hours after injection of (A) HER2-MQQ-probe and (B) BSA-MQQ-probe. Reprinted from Multilayered, core/shell nanoprobes based on magnetic ferric oxide particles and quantum dots for multimodality imaging of breast cancer tumors, Maa Q, Nakane Y, Mori Y, Hasegawa M, Yoshioka Y, Watanabe TM, Gonda K, Ohuchi N, Jin T, Biomaterials 2012; 33:8486-8494, with permission from Elsevier.


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which were exploited in FRET for activating photoporphyrin (PpIX) to generate reactive oxygen in oxygen saturated water and in cultivations with E. Coli. Additionally, Hsu et al. [72] suggested renilla luciferase-immobilized QDs-655 (QD-RLuc8) for bioluminescence resonance energy transfer (BRET) - mediated PDT to overcome these problems. The QD-RLuc8 conjugate exhibited selfillumination at 655nm by the addition of coelenterazine, which activated the photosensitizer Foscan-loaded micelles for PDT. Hsu et al. [72] demonstrated that BRET-mediated PDT by the participation of QD-RLuc8 and coelenterazine successfully generated ROS (40, 8%), killed approximately 50% of the A549 cells at 2 g/ml equivalent Foscan in vitro and notably delayed the in vivo tumor growth without obvious weight loss (Fig. 6). Furthermore, it was shown that the proliferating cell nuclear antigen (PCNA)-antigen area of tumor sections after BRET-mediated PDT was obviously increased without any external light source. 2.5.2. Drug Delivery Using Quantum Dots Several applications based on nanoparticles can facilitate accurate drug delivery to tumors with reduced toxic side effects. Nanoparticle-based drug carriers provide long blood circulation and highly protection of their cargo, their large surface enables the conjugation with multiple targeting molecules and they possess large capacity for drug loading. In addition, QDs provide the possibility of traceable drug delivery and real-time monitoring. Liu et al. [73] developed a multifunctional system for targeting, imaging and therapy. Cancer cells for specific folic acid targeting ligand, QDs as imaging agents and silica nanoparticles loaded with hydrophobic drug (Docetaxel), were used for this purpose. Docetaxel was covalently attached to the nanocarriers through an acid-sensitive linker. This delivery system was found to provide high drug loading capacity, controlled drug release and stable drug preservation. In other similar studies, QDs have been used to trace nanocarriers based on liposomes or micelles, attached on their surface or loaded inside the nanocarriers. Weng et al. [74] conjugated hydrophilic QDs and HER-2 ligands with PEG-phospholipids which were attached on the

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visible light. In PDT, cells located in a tissue are chemically targeted by a photosensitizing agent, usually a porphyrin dye. Subsequently, the tissue is illuminated and the photosensitizer generates signet oxygen which is cytotoxic for the cells leading to cellular death. The photosensitizer is not cytotoxic before illumination exposure and only the cells around photosensitizer are affected, which can be applied for cancer cells targeting. QDs conjugated with photosensitizing agents, may have some advantages due to size- and composition-tunable optical properties. Samia et al. [65] demonstrated that the QDs conjugated with photosensitizing agents allow the use of excitation wavelength that the agents do not absorb alone. For their study, CdSe QD-based-Förster resonance energy transfer (FRET) was used to help the excitation of phthalocyanine photosensitizer, which generates reactive singlet oxygen with about 43% quantum yield. The FRET measurement efficiency was found to be 77%, although, the wave length that was used to excite the QDs (488nm) was not able to penetrate deep into the tissue. Ma et al. [66] reported the conjugation of CdTe QDs with aluminiumtetrasulfophthalocyanine (AISPc) and the generation of singlet oxygen with quantum yield about 15%, as well the FRET efficiency of the conjugate was found to be around 58% [67]. Many studies examined the generation of singlet oxygen by using QDs with organic dye. Tsay et al. [68] composited CdSe/CdS/ZnS QDs with Chlorin e6 in both covalent and non-covalent ways and found that the luminescence lifetime of the QDs was decreased due to the energy transfer from QDs to Chlorin e6. Although Dayal et al. [69] demonstrated that the energy transfer efficiency between QDs and Chlorin e6 was increased by the increment of the number of Chlorin e6 molecules conjugated with the QD. They also found that QD composed of Chlorin e6 generated singlet oxygen at 31% efficiency. Shi et al. [70] worked on the nanocomposition of CdTe QDs with meso-tetra (4-sulfonatophenyl)porphinedihydrochloride (TSPP) as an organic dye. They found that the excitation of the TSPP moiety led to generation of singlet oxygen with a quantum yield of 43%. More recently, Duong et al. [71] used CdSe/Zns QDs with two kinds of charges and emission wavelengths of 550 nm and 580 nm,

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offered great accuracy as tumor-targeted drug delivery vehicles and a great assistant role in the treatment of cancer. 3. GOLD NANOPARTICLES 3.1. Background

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By taken into consideration global historical evidences and literature, gold has been already reported as a health adjuvant. More specifically, over 5000 years ago, mainly Chinese and Indian cultures reported the use of gold compounds in the form of combined elements (called ‘SwarnaBhasma’ where ‘Swarna’ means gold and‘Bhasma’ means ash) for the treatment of various health issues [78-80], a treatment that is still used in India. The Egyptians also ingested gold for mental, bodily and spiritual purification while the Greeks used ground gold to color glasses, giving them a rich ruby red color. Nowadays, gold seems to be an important and attractive element for the researchers of Nanoengineering, mainly due to its unique properties and the rapid progress in chemical synthesis techniques [81]. It is worth saying that several scientific groups in the past few years have demonstrated that GNPs possess the power to improve the efficacy of cancer treatment [82, 83].

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surface of the nanoparticle in order to label targeted liposomes. It was found that HER-2 liposomes accurately and specifically targeted tumor cells with a 900-1800 fold increase in cellular uptake in comparison with non-targeted liposomes and via in vivo fluorescence imaging observed accumulation in tumors and good circulation for about 3 hours. Bagalkot et al. [75] developed a QDaptamer-doxorubicin (Dox) conjugate as a targeted cancer imaging, therapy and sensing system. The surface of QDs functionalized with A10 RNA aptamer, which is able to detect prostate specific membrane antigen (PSMA). These functionalized QDs are capable for prostate cancer cells imaging that express the PSMA protein. In this study, A10 RNAaptamer was incubated with Dox resulting in a targeted QD-Aptamer (Dox) conjugate with reversible selfquenching properties based on Bi-FRET mechanism. FRET between QDs and Dox as well as between Dox and aptamer quenched both Dox and QDs signals due to Dox fluorescence, which rendered the nanoparticle in off-state when Dox was bound. Furthermore, the simultaneous increase of fluorescence in both QDs and Dox helped the visualization of intracellular release of Dox. This study demonstrated the capabilities of QDs as fluorescent probes for the localization of nanoparticles and as sensors for drug release. QDs can not only trace drug nanocarriers but also are able to monitor in realtime the drug release kinetics. In another similar study, QDs were conjugated with mucin 1 aptamer (MUC1) in order to actively target ovarian carcinoma and release drug inside the acidic environment of cancer cells, where QD-MUC1-Dox conjugate found to have higher cytotoxicity than free Dox [76]. More recently, Chen et al. [77] conjugated ZnO QDs with GNPs as the core of a multifunctional nanocarrier and amphiphilichyperbranched block copolymer used as shell for this structure in order to demonstrate targeted anticancer drug delivery (Fig. 7). During the last study UVvisible spectra, FT-IR spectra, X-ray diffraction (XRD), fluorescence spectroscopy and TEM analyses were used for the characterization and determination of the structure and properties of their multifunctional nanocarriers. Researchers reported that camptothecin (CPT) release from nanocarriers at pH 7. 4 was greater than the release at pH 5. 3 and both of these blank and CPT-loaded nanocarriers provide high anticancer activity against Hela cells, which

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Inorganic nanoparticles offer great flexibility and efficacy upon their application in various fields. There can be adjustments for example in the shape, size, at the number of deliverable drugs, or even in the biocompatibility of the particle as well as their optoelectronic properties increasing their potential functionalities and applications in biomedicine. The reasons that GNPs are nowadays considered as highly suitable for biomedical applications including their brilliant color, the high atomic number and a strong surface plasmon resonance (SPR) bandthat make them an ideal imaging contrast agent [84, 85, 114, 127-129]. Referring to the SPR phenomenon when GNPs are exposed to light, the oscillating electromagnetic field of light induces free electrons at the NP’s surface on a contiguous oscillation. SPR is the frequency where the amplitude of the oscillation reaches maximum and during that state, the parti-

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ee e ee Fig. (8). Origin of surface plasmon resonance (SPR) due to interaction of the electrons. Reprinted from Huang X, El-Sayed MA. Gold nanoparticles: Optical properties and implementations in cancer diagnosis and photothermal therapy. Journal of Advanced Research 2010; 1:13-28, with permission from Elsevier.

confirmed that GNPs structures were not greatly influenced by this functionalization. Lima et al. [112] successfully fabricated anticatenin/GNPs and anti-E-cadherin/GNPs that were applied for imaging colorectal cancer cells. UV-results showed that the conjugates are stable in solutions that resemble the physiological medium. The fluorescence results indicated maximum adsorption of antibodies onto the surface of the GNPs having low antibody concentrations. The above method compared with a standard one has the advantage of reduced overall analysis time from 27h to only 1h, making it ideal for routine imaging of colorectal cancer cells. In a similar study Kim et al. [113] produced PEGylatedGNPs in aqueous dissolvable microneedles for controlled drug delivery into hamster oral tissue in vivo, proving that oral cancer can be detected at an early stage by OCT signals of GNPs. In another study, a theranostic core/shell nanoparticle of Au@PB has been developed for CT/PA bimodal imaging guide photothermal therapy of cancer [107]. The particle could operate as an excellent CT contrast agent in order to locate the tumor in vivo with great accuracy due to the high absorption of X-ray. In addition, Au@PB upon exposure to NIR laser pulses could generate a strong photoacoustic signal which was related to the concentration of the specific nanoparticles. The increased concentration of Au@PB NPs led to increase PA signal, a fact that showed high PA contrast potential to acquire the detailed structure of tumor region. The method was tested in HT-29 tumorbearing nude mice and results showed that the tumor was completely eliminated within 6 days, without re-growth over the therapeutic period of 18 days (Fig. 9).

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According to recent studies, molecular imaging likes MRI, CT, ultrasound, optical imaging, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) involves characterization of biological processes in living organisms at the molecular and cellular levels in order to visualize and typify early-stage disease, providing simultaneously a rapid method for evaluating treatment [109-111]. As shown in the previous section, GNPs scatter strongly and their scattering properties depend on the size, shape and structure of the nanoparticles. Infact, the scattering of nanoparticles with diameter between 30-100nm is intense and can be detected simply with a commercial microscope under darkfield illumination conditions [97]. For nanoparticles with 40nm, GNPs can be detected by focusing on a particle concentration of 1014M. The high scattering cross-sections of GNPs together with their superior photostability, unique physical properties, and adaptable absorption and emission properties make them extremely promising for cellular imaging [98-102] and early detection of life threatening diseases like cancer. Due to their small size, NPs can be considered as the smarter choice for passively targeting tumor cells in the intracellular level or providing gene therapy and thus can be monitored and visualized with the help of latest emerging imaging techniques which were described above [83, 104-108].

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It is well known and proved that GNPs possess an excellent mechanical and chemical stability that makes them a significant factor in the advancement of theragnostic nanomedicine (therapeutic and diagnostic) [92-95], while, on the contrary, it can be easily reduced and stabilized by chemical agents like ascorbic acid or citrate. Nevertheless, aggregation of nanostructures in a surfactantfree reaction is a common phenomenon leading to difficulties as far as the studies of their applications and properties are concerned. Recently, researchers have also proved the key role of negatively charged heparin molecules end-grafted onto the surface of GNPs in promoting their aqueous dispersion stability via an electro-repulsive mechanism [96].

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cle possesses strong absorption with respect to the incident light [84]. Optical behavior of GNPs and nanorods can be adjusted to near infrared (IR) region by synthesizing gold nanoshells [87-91]. Another optical property that makes GNPs a fascinating material for researchers is the surface plasmon scattering and absorption, an attribute that makes us realize how many choices can be offered, concerning the various applications of GNPs in biomedicine. While the ratio of scattering to absorption depends on particle’s [84, 86] (Fig. 8) it seems that particles with larger diameter will be preferred for imaging by the time the scatter efficiency is higher while smaller particles are considered to be more efficient for photothermal therapy.

Lee et al. [96] fabricated GNP-H Hepnanoprobes for optically detecting metastatic cancer cells that over-express heparinase/ heparanase. Results showed that heparin immobilized GNPs had high potentials for optical imaging and apoptotic death of cancer cells. Additionally, Ai et al. [105] designed multifunctional fluorescent GNPs for further targeted cell imaging and photodynamic therapy by functionalizing the GNPs with AS1411 aptamereven though UV and transmission electron microscopy (TEM) techniques

3.4. GNPs and Their Applications in Cancer Therapy Targeted delivery of nanodrugs is one of the most emerging research fields in pharmaceutical sciences. Nowadays, treatments based on nanoparticles have been successfully applied in several cases including cancer, pain or even infectious diseases, in an effort to reduce traditional strategies like surgery, chemotherapy, and radiation therapy [121]. 3.4.1. GNPs in Photothermal Cancer Therapy According to the related literature, most of the clinical studies that emphasize at cancer therapy via nanotechnology, used photothermal therapy (PTT) for the damage of cancer cells or tumor’s tissue. While ‘the optical transparency window’ of bio-tissues corresponds to the near infrared (NIR) region, Maksimova et al. [115] presented that in order to achieve an effective photothermal therapy in cancer cells, a combination of three factors has to be ensured: the laser wavelength, the maximal absorbance of the gold nanostructures being used as selective labels, and the spectral transmittance of the bio tissues treated by laser pulses. A pioneering experiment



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Photodynamic therapy (PDT) is a medical tool developed over the last century and after the regulatory approval for the treatment of various lethal diseases, it is now rapidly expanding its medical usage and importance. The method is based on the photochemical reactions between light and tumor tissues with exogenous photosensitizing agents (PS) [124], where the delivery of a photosensitizing drug is followed by the irradiation of light, finally resulting in the production of reactive oxygen species and cells apoptosis or necrosis [124]. Recently, Vankayala et al. [125] instead of simply delivering PDT drugs, suggested the formation of that singlet oxygen, by delivering 22nm GNPs directly without organic photosensitizers with only one drawback, and that is the low quantum yield of GNPs. Even if the quantum yield is low, the satisfying stability and the high molar extinction coefficient of GNPs counterbalance that shortcoming and making them a new generation of PDT reagents for cancer treatment. In another interesting study [116], nanorods were serving as tumor-targeting and hyperthermia agents in order to destroy malignant cells through PDT, and simultaneously as optical contrast agents to monitor cells by imaging in the NIR region.

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Fig. (10). (A) Photograph of a mouse with a tumor during photothermal therapy. Thermographic images of nanocage injected (B-E) and saline injected (F-I) tumor bearing mice at different times (from top to bottom: 1,3,5 and 10 min). (J) Average tumor temperature as a function of exposure time. All scale bars are 1cm. Reprinted from [Chen JY, Glaus C, Laforest R, Zhang Q, Yang MX, Gidding M, Welch MJ, Xia YN. Gold Nanocages as Photothermal Transducers for Cancer Treatment. Small 2010; 6:811-817], with permission from John Wiley and Sons [120].

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performed by Huang et al. [117] also indicated the true advantages of nanotechnology against cancer. In this study, a gold nanorods conjugated to an anti-EGFR antibody has been heated with NIR light, causing the destruction of all the malignant cells without damaging the nonmalignant cells. In a similar way, Maksimova et al. [119] achieved a successful destruction of cancer cells in the ears, mouth and skin by local injection of plasmon resonant nanoshells followed by semiconductor laser irradiation. In 2007, Xia et al. [118, 119] reported the use of antibody conjugated goldnanocages to kill SK-BR-3 breast cancer cells with NIR PTT treatment in vitro, also observing the decrease of the tumor’s metabolic activity by 70% after 24h of treatment (Fig. 10). Vankayala et al. [123] demonstrated in their recent experiment the same efficient results with PTT against tumor tissue with other well-known methods (use of doxorubicin) but they specifically used ultra-low laser doses (28-150mW/cm2) of NIR light instead of ultra-high doses (148W/cm2). At the same time, all the gold nanoshells were exerting bimodal NmPDT and NmPTT effects upon NIR light excitation, emitting plasmonic luminescence showing that AuNS (gold nanoshells) can serve as multi-functional theranostic nanomaterials, against tumors and under ultra-low laser power conditions.

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Fig. (9). Fluorescence image of a tumor-bearing mouse 1 minute after the injection of Au NP-Pc 4 conjugates. [Reprinted from Cheng Y et al. Highly Efficient Drug Delivery with Gold Nanoparticle Vectors for in Vivo Photodynamic Therapy of Cancer. Chem. Soc. 2008; 130(32): 10643-10647], with permission from the American Chemical Society [122].

Huang et al. [126] mentioned the construction of a chlorine 6conjugated silica-coated gold nanocluster (AuNCs@SiO2–Ce6) for the improvement of fluorescence imaging-guided PDT. Thus, after measuring the tumor growth rates, AuNCs@SiO2–Ce6 was indicated as a highly capable imaging particle suitable for NIR fluorescence imaging-guided PDT treatment. CONCLUSION Trying to establish the future of nanotechnology in biomedicine, there are several hybrid and combined solutions that scientists and industries can apply, in order to deliver more efficient medications with decreased side-effects. Among all these solutions, we focus on highlighting the properties and the efficiency of QDs and GNPs applications in cancer diagnosis and treatment. QDs compared with traditional probes including organic dyes and fluorophores have been found to be 10-20 times brighter in photon limited in vivo conditions and have a thousand times better photostability. Moreover, QDs have deeper penetration in tissues and zero autofluorescence while the specific probe can remain for longer period


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Declared none.

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The authors confirm that this article content has no conflict of interest.

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of time in blood circulation. Compared to other imaging methods, GNPS and QDs overcome the main problems concerning spatial resolution, light tissue penetration and multiplex capability. Their large surface, which enables simultaneous conjugation with multiple functional groups and their unique photostability, render these particles capable for multiplexed imaging applications, continuous tracking studies over period of time, simultaneous detection of cancer biomarkers in the same sample and finally improvement in the possibility of traceable drug delivery and real-time monitoring. It is widely known that cancer is a disease with high heterogeneity, thus, the proposed targeted treatments may not be effective in all the cases. It is imperative that the conduction of a crossover and essential research is necessary in both cancer biology and nanotechnology fields in order to identify new and unique biomarkers/targets related to cancer cells and their environment. Conclusively, while the majority of nanomedical applications are nowadays enriched with the potentials of quantum biophysics, biochemistry microgravity and fractal analysis [133], the usage of these elements is closely related to nanoethical considerations and legal aspects that have to be discussed and clarified to their target groups [103, 134, 135].

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