Quantum Dots for Cancer Research: Current Status, Remaining Issues, and Future Perspectives
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* Min Fang
* Chun-wei Peng
* Dai-Wen Pang
* Yan Li

## Abstract

Cancer is a major threat to public health in the 21st century because it is one of the leading causes of death worldwide. The mechanisms of carcinogenesis, cancer invasion, and metastasis remain unclear. Thus, the development of a novel approach for cancer detection is urgent, and real-time monitoring is crucial in revealing its underlying biological mechanisms. With the optical and chemical advantages of quantum dots (QDs), QD-based nanotechnology is helpful in constructing a biomedical imaging platform for cancer behavior study. This review mainly focuses on the application of QD-based nanotechnology in cancer cell imaging and tumor microenvironment studies both *in vivo* and *in vitro*, as well as the remaining issues and future perspectives.

*   quantum dots
*   molecular imaging
*   multimodality probes

## Introduction

Cancer remains a global public health problem as the leading cause of death in developed countries and the second leading cause of death in developing countries[1]. It is a diverse group of diseases affecting a variety of tissues, but is generally characterized by the uncontrolled proliferation of abnormal cells, with the ability to invade surrounding tissues, and possibly metastasize. Over the past few decades, numerous studies have focused on the regulation of cell adhesion and cytoskeletal dynamics as the mechanisms of cancer invasion and progression[2–4]. However, they have largely failed to define the rate-limiting mechanisms that govern cancer invasion and progression, such as the dominant signaling pathway, receptor–ligand interactions, or protease–substrate interactions. At present, cancer invasion is regarded as a heterogeneous and adaptive process with a tumor microenvironment [5]. The tumor microenvironment, composed of tumor stromal components, host cells, and adjacent supporting tissues, is an intrinsic element because of its dynamic interactions with the tumor for continued tumor growth and progression[6,7]. Once the tumor microenvironment responds to the tumor cells, components such as fibroblasts, endothelial cells, and macrophages could be activated and could release functional factors that promote or inhibit cancer invasion[8–14]. Thus, tumor cells influence the microenvironment and vice versa, jointly driving cancer progression in a reciprocal manner[15,16]. Thus, to intensively explain the mechanism of cancer invasion and progression, understanding the biological behavior during tumor progression is necessary, and the appropriate approach for understanding the biological behavior of cancer should be established.

Nanotechnology is a promising platform in cancer molecular imaging. Quantum dots (QDs) are being intensively studied as a novel probe for biomedical imaging both *in vitro* and *in vivo* because of their unique optical and electronic characteristics. To overcome the obstacles of QDs for biomedical imaging, the physicochemical properties of QDs such as size, shape, composition, and surface features have been extensively investigated[17–23]. When conjugated with bimolecular agents such as antibodies, peptides or other small molecules, QD-based probes can be used to target cancer molecules with high specificity and sensitivity. Thus, QD-based multiplexed molecular imaging can reveal the tempo-spatial relationship among molecules by simultaneously staining several tumor biomarkers. Several studies have shown that this method is essential for deciphering the molecular mechanism of cancer invasion and is useful for the study of tumor microenvironment[20–22]. In addition to the promising application for molecular imaging *in vitro*, QD-based multifunctional probes lead to the development of anti-cancer drug and siRNA delivery[24], magnetic resonance imaging (MRI)[25,26], multiplexed molecular cancer diagnosis, and *in vivo* imaging[27–30]. In this view, QDs can be used to monitor the dynamic changes of a tumor microenvironment, which would greatly contribute in the research of cancer invasion mechanism and guide better clinical personalized therapy. Therefore, compared with conventional imaging approaches, a molecular QD-based targeted nanoplatform offers various advantages. First, hundreds, thousands or even more imaging labels or combinations of labels for different imaging modalities can be attached to a single nanoparticle, which can lead to dramatic signal amplification. Second, multiple, potentially different, targeting ligands on the nanoparticle can provide enhanced binding affinity and specificity. Third, the ability to integrate a specific biomarker to bypass biological barriers can enable enhanced targeting efficacy. Ultimately, the combination of different targeting ligands, imaging labels, therapeutic drugs, and many other agents may allow the effective and controlled delivery of therapeutic agents in patients, which can be noninvasively monitored in real time.

In this review, we summarize the major advances in the application of QD-based nanotechnology for cancer research, including the detection of primary tumor *in vitro*, tumor imaging *in vivo*, study of tumor microenvironment for invasion, and progression and multimodality biomedical molecular targeting imaging, as well as the major remaining issues and future perspectives.

## Characteristics of QDs for Biomedical Application

QDs are semiconductor nanocrystals that range from 2 nm to 10 nm in diameter and consist of elements from groups II to VI or III to V. Given their special size and surface effect, QDs are one of the most promising nanocrystals with unique optical and chemical properties. QDs offer great advantages over traditional organic fluorescent dyes and present a number of beneficial characteristics for spectroscopy, such as high fluorescence intensity, long lifetime, and good resistance to photobleaching. The brightness of QD-based multifunctional probes affords high sensitivity for simultaneous cancer molecular imaging and targeted therapy. For spectrum application, the sensitivity of QD-based molecular imaging can be two to three orders larger than that of routine fluorescent dyes[31] (Table 1). Furthermore, the fluorescence in near infrared (NIR) of NIR-QDs can be detected in deep tissues, making them suitable for *in vivo* imaging with high signaltobackground ratio[17,18,23].

View this table:
[1](http://www.cancerbiomed.org/content/9/3/151/T1)

1 
Comparison of the characteristics and applications between traditional organic fluorophores and QDs.

## Application of QD-based Nanotechnology for Cancer Research

### Detection of primary tumor *in vitro*

Since biocompatible QDs were introduced for imaging of cancer cells *in vitro* in 1998[43,44], researchers have synthesized QD-based probes conjugated with cancer specific ligands, antibodies, or peptides for cancer imaging and diagnosis *in vitro*[29,45–52]. Compared with traditional immunohistochemistry (IHC), QD-IHC is more accurate and precise at low protein expression levels[53–56] and can achieve quantitative detection which will provide much more information for personalized treatment[53]. With excellent performance on biomedical imaging, QD-based imaging has become one of the most promising technologies for early diagnosis of cancer[57,58].

### Prostate cancer

A classic example of cancer detection was demonstrated by Gao et al.[45] who labeled human prostate cancer cells based on the conjugate of QDs with an antibody for prostate specific membrane antigen (PSMA). Ruan et al.[59] showed that QD-based immunolabelling has more stable photo-intensity compared with conventional fluorescent immunolabelling. Highly sensitive QD-based probes have been reported for multicolor fluorescence imaging of cancer cells *in vivo*[42]. Shi et al.[60] showed the superior quality of QD-IHC compared with conventional IHC and also successfully realized simultaneous detection of androgen receptor and PSA in prostate cancer cells based on multiplexing QDs. The detection sensitivity of QD-based prostate cancer biomarkers can be enhanced by surface plasmon-coupled emission which has been introduced as a novel biosensing technology for detecting biosensors and biochips[61,62]. It can be a highly sensitive and efficient detection system for genomic and proteomic applications by rejecting background emission[63].

### Breast cancer (BC)

Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 25% to 30% BC patients and has an important function in cancer progression. Recent studies have validated the value of HER2 detection for BC treatment and prognosis [64, 65]. Compared with the golden standard method of fluorescence in situ hybridization (FISH), the advantages of QD-based IHC have been well documented since Wu et al.[29] labeled HER2 on human BC cells (SK-BR-3) and mouse mammary tumor sections by QD-IgG conjugates for the first time, which was much easier, cheaper, less time-consuming, and could relieve the medical burden, especially for developing countries. Various studies have reported the successful detection for BC by QD-HER2 conjugates[66]. Yezhelyev et al.[67] extended this approach to selectively label MCF-7 and BT-474 BC cells for HER2, epidermal growth factor receptor (EGFR), estrogen receptor (ER), progesterone receptor (PR), and mammalian target of rapamycin (m-TOR) by visible and NIR QDs which indicated that QD-based nanotechnology is an efficient approach to offer multiplexed cancer biomarker imaging in situ on intact tumor tissue specimens for tumor pathology study at the histological and molecular levels simultaneously[20–22]. Our group also conducted a series of studies of BC based on QD-IHC in HER2 detection and QD-based quantitative spectral analysis of HER2, ER, and PR[54–56,68]. Chen et al.[55] successfully detected BC with QD-based probes which demonstrated that lower expression of HER2 could be clearly detected by QD-IHC compared with conventional IHC (Figure 1) and could also realize multiplexed QD-based detection simultaneously[69]. The results showed that BC can be divided into 5 subtypes with different 5-year survival rate. Thus, QD-based multiplexed imaging will provide more information for the individual events of tumor, personalized diagnosis, prognosis, and treatment.

![1](http://www.cancerbiomed.org/https://www.cancerbiomed.org/content/cbm/9/3/151/F1.medium.gif)

[1](http://www.cancerbiomed.org/content/9/3/151/F1)

1 
Accurate HER2 testing by QD–IHC. A: Specimens with different HER2 IHC scores detected by QD–IHC. B: Control for (A) by conventional IHC. C: FISH positive. D: Negative. Scale bar: 100 µm for (A) and (B); 20 µm for (C) and (D). Reproduced with permission from [55].

### Ovarian cancer

QDs can also be used to detect the ovarian carcinoma marker CA125 in different types of specimens, such as fixed cells, tissue sections, and xenograft piece. Additionally, the photostability of QD signals is more specific and brighter than that of conventional organic dye[70]. Liu et al.[71] synthesized pH-sensitive photoluminescent CdSe/ZnSe/ZnS QDs in SKOV-3 human ovarian cancer cells that are pH-dependent, suggesting applications for intracellular pH sensors. Kawashima et al. successfully targeted EGFR single-molecules in human ovarian epidermal carcinoma cells (A431)[72].

### Gastrointestinal cancer

Bostick et al.[73] detected the five biomarkers on the same tissue slide by QD-based multiplexed imaging, from which more biomarkers could be measured using multiple slides each stained with the five different biomarkers. They further proposed to construct a workflow for the quantitative analysis of each biomarker. The system was both efficient and convenient, such that it only took 7 h to analyze six biomarkers, which was advantageous for clinical application.

### Pancreatic cancer

QD-based imaging probes can target pancreatic cancer at a very early stage[74,75] with the help of proteins/peptides directed against overexpressed surface receptors on cancer cells/tissues, such as the transferring receptor, antigen claudin-4, and urokinase plasminogen activator receptor[76–78]. CdSe/CdS/ZnS QDs with improved photoluminescence efficiency and stability as optical agents have been used for the imaging of pancreatic cancer cells using transferring and anti-Claudin-4[79]. Yang et al.[75] used non-cadmium-based QDs as highly efficient and non-toxic optical probes for imaging live pancreatic cancer cells. Further bioconjugation with pancreatic cancer-specific monoclonal antibodies, such as anti claudin-4, to the functionalized InP/ZnS QDs, allowed specific *in vitro* targeting of pancreatic cancer cell lines. Lee et al.[80] reported quantitative molecular profiling of biomarkers for pancreatic cancer with functionalized QDs. They obtained absolute quantitative values for the biomarker density in terms of the number of molecules per square micron on the cell surface, which is important because cancer cell populations are inherently heterogeneous. They also demonstrated highly selective targeting of molecular markers for pancreatic cancer with extremely low levels of nonspecific binding.

### *In vivo* tumor imaging

*In vivo* tumor imaging can directly demonstrate the evolution mechanism of tumor progression. More convincing evidence could be obtained from *in vivo* tumor imaging compared with *in vitro* molecular imaging. However, sensitive and specific imaging agents are urgently needed for high-quality *in vivo* tumor imaging and less biological impacts on the animal model. QD-based imaging agents can meet this demand by “enhanced permeability and retention” (EPR) or targeted molecular imaging. The principle of EPR-based tumor imaging is the leakiness of tumor blood vessels. Compared with normal tissues, tumor vasculature is quantitatively important, but irregular, leaky, dilated, and vascular endothelial cells are poorly aligned with large fenestrations[81,82]. The morphology results in increased leakage of macromolecules and nanocarriers out of the circulatory system into the tumor tissue by the EPR effect[83,84]. They finally accumulate in the tumor microenvironment because of the lack of effective lymphatic drainage. This EPR effect has inspired the development of a variety of nanotherapeutics and nanoparticulates for the imaging and treatment of cancer[83, 85–87]. Many studies have reported that non-targeted QDs can be used for cell trafficking[88], vasculature imaging[89], sentinel lymph node (SLN) mapping[30,90,91], and neural imaging[92].

SLN diagnosis contributes to operation strategy in cancer surgery. During lymph node metastasis, cancer cells first reach the SLN via lymph flow. The cancer cells should be detected with high sensitivity in the SLN connected to the tumor site to perform SLN biopsy effectively. For instance, the superiority of NIR QDs (emitting at 850 nm) has been demonstrated in SLN mapping, a common procedure in BC surgery, whereby the lymph node closest to the targeted organ is monitored for the presence of locally disseminated cancer cells. Recent studies have also reported on highly sensitive, real-time intra-operative SLN mapping of the gastrointestinal tract by NIR light and invisible fluorescent QDs[76] with high background-to-signal ratio. In these studies, NIR QDs allowed image guidance throughout the entire procedure, virtually free of any background. The SLNs and their eventual removal were imaged in real time, without the need of traditional dyes or radioactive tracers[30,93]. Hikage et al.[94] effectively detected metastatic gastrointestinal cancer cells in SLN with high sensitivity. So et al.[95] used luciferase-conjugated QDs to obtain self-illuminating QDs, which totally eliminates the issue of tissue autofluorescence. Voura et al.[49] also demonstrated that QDs can track different QD-tagged populations of cancer cells in the same animal by multiphoton laser scanning microscopy. This finding may contribute to our understanding of metastasis, which remains a fundamental barrier to the development of effective cancer therapy. Given the high sensitivity and penetration (approximately 1 cm below the skin surface) of NIR QD fluorescence, the application of QD-based SLN mapping allows the surgeon to define the tumor border accurately and minimize the size of the dissection[30,38,51,94,96]. This successful technology in preclinical studies represents a significant breakthrough, and further studies are advantageous to pave the way to clinical application.

QDs need to be effectively, specifically, and reliably directed to a specific organ or disease site without alteration to make them more beneficial for biomedical applications. Specific targeting can be achieved by attaching targeting molecules to the QD surface. After the first successful application of QDs *in vivo* by Akerman et al.[97], studies based on QDs in mouse models for cancer imaging were subsequently conducted[45,50,98,99]. Gao et al.[45] performed whole animal cancer imaging by QD-PSMA. The QD-PSMA was efficiently and uniformly distributed in the prostate tumor, indicating the potential for accurate prostate cancer diagnosis and real-time monitoring. Cai et al.[50] targeted glioblastoma with NIR QD-peptide conjugate and showed high signal-to-background ratio and long duration of signals. Arginine-glycine-aspartic acid peptide-conjugated QDs have been used to target integrin αvβ3 in a murine xenograft model specifically[50,100] because integrin αvβ3 is significantly upregulated in tumors, but not in normal tissues.

In addition, our group developed a standard protocol for in vivo imaging of liver cancer xenograft animal models[98,101–103]. We successfully achieved animal imaging by injecting human hepatocellular carcinoma cell lines (HCCLM6) that overexpress alpha-fetoprotein (AFP) with antiAFP monoclonal antibody and QD-IgG probes. HCCLM6 has increased potential for lung metastasis, so it helps in the construction of a platform for the early monitoring of liver cancer metastasis (Figure 2)[53].

![2](http://www.cancerbiomed.org/https://www.cancerbiomed.org/content/cbm/9/3/151/F2.medium.gif)

[2](http://www.cancerbiomed.org/content/9/3/151/F2)

2 
*In vivo* targeting and imaging of a lung metastasis model with QD-based nanotechnology. A: The imaging system for living animal models. B: *In vivo* targeted imaging of the subcutaneous tumor model and site-by-site spectra analysis of the tumor, which showed that the QD-labeled anti-a-fetoprotein monoclonal antibody probes per field were lower at the center than in the periphery of the tumor, indicating that tumor growth was not homogeneous and the peripheral site was more active. C: *In vivo* targeted imaging of liver cancer lung metastasis models. Reproduced with permission from [53].

However, not enough experimental evidence is available to support the conclusion that the tumor contrast observed was from active, rather than passive, targeting. Tracking the movement of a single QD-antibody conjugate (the total number of QD particles injected was approximately 1.2×1014) inside the tumor through a dorsal skinfold chamber was accomplished using a high-speed confocal microscope with a high-sensitivity camera[46]. This technique captured the specific delivery of a single QD particle that entered into circulation, extravasated into the interstitial space from the vasculature, bound to the tumor cell surface receptor, and reached the perinuclear region after it traveled on the intracellular rail protein.

Minimizing non-specific uptake of QDs by the reticuloendothelial system (RES) is necessary to maximize active targeting. Hence, proper surface modification of QDs must be designed to adjust the complicated anatomical structure and physiology in tissues and organ systems that create barriers for QDs[101,104]. For example, coating QDs with high-molecular weight poly-ethylene-glycol (PEG) molecules can reduce QD accumulation in the liver and bone marrow[105]. When using neutral methoxy-terminated PEG (mPEG) coating, results vary depending on the length of the PEG and the degree of substitution. Highly substituted QDs yield half-lives in the 3 h to 8 h range for mPEG-5000-coated QDs[106].

Although *in vivo* targeting and imaging developed quickly, these techniques are still challenging because of the relatively large overall size (typically >20 nm in hydrodynamic diameter) and short circulation half-lives of QD conjugates.

### Tumor microenvironment for invasion and progression

Cancer progression is not an entirely cell-autonomous process. The invasion is regulated by intrinsic genetic changes in cancer cells as “initiators” of carcinogenesis and by stromal cells as “promoters”. Human cancer is especially complex because it evolves over a long time course and shows a multitude of molecular, cellular, and architectural heterogeneity. Neither the studies at purely molecular and cellular levels, nor the studies at the purely clinical level can decipher the co-evolution of a cancer microenvironment. Such co-evolution of cancer microenvironment has long been underappreciated because of the lack of appropriate technology platforms to reveal the dynamic spatiotemporal processes. QDs, can be good delivery nanocarriers to tumors *in vivo* for multi-parameter imaging given their relatively large surface areas which can be conjugated with more than one targeting ligand such as novel tumor-specific antibody fragments, growth factors, peptides, and small molecules, with the ultimate goal of guiding therapy selection and predicting response to therapy. This nanoplatform approach will enable the simultaneous detection and measurement of several biomarkers, which may lead to better signal/contrast than QDs modified with only one type of targeting ligand. These properties are also very suitable for investigating the co-evolution of cancer cells and tumor microenvironment at the architectural level, a key issue in studying the mechanisms of cancer progression and in developing more specific targeting therapeutic approaches.

Since QDs were first used to detect F-actin in mouse fibroblasts[12], numerous studies have been conducted for cancer invasiveness, lymphocytes homing, and embryogenesis, confirming that QDs are potential fluorescent probes for *in vivo* imaging of lymph nodes and tumors[94]. A new approach based on multiphoton microscopy techniques and QD nanotechniques was established by Stroh et al.[51] to differentiate the tumor vessels from the perivascular cells and the matrix. With this approach, the tumor vessels can be identified from solid tumors clearly and vividly.

Our group recently confirmed the benefit of QD-based multiplexed imaging and spectrum analysis technology to study the co-evolution of cancer cells and tumor stroma by type IV collagen, tumor angiogenesis, macrophage infiltration, and tissue destructive proteolytic enzyme MMP9[107,108], which revealed the related molecular features of tumor microenvironment during cancer invasion[108] (Figure 3). Four invasive patterns with distinctive cancer cell-stroma interactions were identified, namely, washing, amoeba-like, polar, and linear patterns. Another research on QDbased doublecolor imaging of HER2 on BC cells and the type IV collagen in the ECM also showcase the dynamic processes of BC invasion (Figure 4)[69].

![3](http://www.cancerbiomed.org/https://www.cancerbiomed.org/content/cbm/9/3/151/F3.medium.gif)

[3](http://www.cancerbiomed.org/content/9/3/151/F3)

3 
The establishment of multiplexed QD imaging and spectrum analysis. A1, B1, and C1: Infiltrating macrophages (Green arrows), type IV collagen (Yellow arrows), and neovessels (Red arrows) are labeled simultaneously in gastric cancer tissues with nanoprobes QDs-525, QDs-585, and QDs-655, respectively. A2, B2, and C2: Corresponding unmixed image of A1, B1, and C1 obtained by spectrum analysis with differentiable autofluorescence (Blue arrows). D: QD emission spectra and tissue autofluorescence data used for unmixed image. Magnification: ×100 (A1 and A2), ×200 (B1 and B2), and ×400 (C1 and C2); Scale bar: 100 mm (A1 and A2), 50 mm (B1 and B2), and 20 mm (C1 and C2). Reproduced with permission from [103].

![4](http://www.cancerbiomed.org/https://www.cancerbiomed.org/content/cbm/9/3/151/F4.medium.gif)

[4](http://www.cancerbiomed.org/content/9/3/151/F4)

4 
Double-color imaging was used in BC over different levels of HER2. A: Benign breast tumor, no HER2 expression, and intact ECM (Red arrow). B: BC with HER2 (+) (Red arrow), ECM becomes unsmooth and thin (Yellow arrows). C: HER2 (2+) and moderate green fluorescence (Red arrow). ECM becomes significantly degraded (Yellow arrow). D: HER2 (3+), strong green fluorescence (Red arrow) and complete ECM degradation (Yellow arrow). (Magnification: ×, scale bar =20 µm). Reproduced with permission from [69].

In our previous *in vivo* imaging of liver cancer xenograft models[102], the heterogeneous AFP distribution was reflected by QD probes, which showed that the QD fluorescence per field was lower at the center than in the periphery of the tumor, indicating the heterogeneous proliferation in different tumor areas. This phenomenon may provide essential information on “safe” tumor margins to guide surgical resection in clinical practice. If the surgical resection is not wide enough to eradicate the tumor at the margin with strongest proliferation and invasion potentials, the clinical outcome will remain poor, although 99.99% of the cancer cells have been eliminated[109].

Doxorubicin (Dox)-conjugated QDs are used to target alveolar macrophages and inflammation. A study showed the absence of significant effects of inflammatory injury parameters (albumin leakage, proinflammatory cytokines, and neutrophil infiltration) after QD-Dox treatment compared with Dox *in vivo*, demonstrating that nanoparticle platforms provide targeted macrophage-selective therapy for the treatment of pulmonary disease[110]. Another group found that QDs impair macrophagic morphology and the ability of phagocytosis by inhibiting Rho-associated kinase signaling, which will contribute to a better understanding of the tumor microenvironment[111]. Hence, QD-based nanotechnology can reveal and detect the role and function of the tumor microenvironment and can be used for novel targeting therapy.

## Application of QD-based Multimodality Biomedical Molecular imaging

In general, molecular imaging modalities include molecular MRI, magnetic resonance spectroscopy (MRS), optical bioluminescence imaging, optical fluorescence imaging, targeted ultrasound, single-photon-emission computed tomography (SPECT), and positron emission tomography (PET). Among all the molecular imaging modalities currently available, no single modality is perfect and sufficient to obtain all the necessary information[112]. The accurate quantification of the fluorescence signals in living subjects, particularly in deep tissues, is quite difficult. MRI has high resolution, but with low sensitivity. Radionuclide-based imaging techniques have very high sensitivity, but with relatively poor resolution. The combination of multiple molecular imaging modalities can offer synergistic advantages over any modality alone. Thus, given that biomedical imaging technologies are now well-developed, cancer imaging should receive a new dimension and momentum with the design and synthesis of suitable multimodal probes based on QDs. This condition appears achievable in the context of the rapid growth in the field of QDs and the wealthy information on the molecular mechanisms of cancer.

At present, various hybrid systems that combine two or more of these imaging modalities are under active investigation[113]. With a size approximately 100 to 10,000 times smaller than human cells, QDs can offer unprecedented interactions with biomolecules on the surface of and inside cells, which may revolutionize disease diagnosis and treatment.

Nanotechnology has touched every single modality of the molecular imaging arena. Despite the great potential of optical imaging, accurately quantifying any QD signal in deep tissues based on fluorescence alone is challenging. This intrinsic limitation is now being addressed by developing QD-based probes that combine multiple molecular imaging modalities onto a single QD nanoparticle platform. Indeed, the tens to hundreds of square nanometers of surface area of QDs represent invaluable assets for surface integration of paramagnetic or radioactive agents that enable three-dimensional tomography techniques. QD-based nanoplatforms are mainly integrated with MRI and PET. For example, Mulder et al.[114,115] successfully targeted tumor angiogenesis by fluorescence and MRI imaging based on the MR-fluorescence bimodal QDs. This approach was extended to QD-based bimodal probes contained in a silica nanoparticle to improve biocompatibility[116]. It was also successfully applied in lymphatic imaging[117] or combined with other imaging modalities[118]. In another group, QD-based probes enabled PET after chelation with 64Cu[100]. Such dual-modality probes have provided unique quantitative information pertaining to tumor-targeting efficiency and *in vivo* kinetic biodistribution[119], thus helping optimize the next generation of QD probes for *in vivo* imaging. This design of QD-based imaging agents will allow simultaneous and quantitative PET detection of multiple spectrally distinct targets. Nuclear spin labels for MRI[120] or SPECT/CT contrast radionuclide could also be incorporated into the QDs. A further step could involve transmission electron microscopy imaging of the precise localization of QDs within cells and tissues [121]. Hence, QDs have the potential to provide information over a wide range of length scales (Table 2).

View this table:
[2](http://www.cancerbiomed.org/content/9/3/151/T2)

2 
Applications of QD-based multimodality imaging for tumor.

Meanwhile, due to the size and structural similarities between imaging and therapeutic nanoparticles and the multifunctionality and enormous flexibility of QDs, they can allow the integration of therapeutic components, targeting ligands, and multimodality imaging labels into one entity, termed “nanomedicine,” for the ideal target; QDs also show great potential for treating tumors in animal models[129]. Bagalkot et al.[130] reported on a ternary system composed of a QD, an aptamer, and the small molecular anticancer drug Dox with three functions integrating targeted imaging and therapy with sensing of drug release. In this system, fluorescence of QDs was quenched by Dox, and Dox was quenched by the double-stranded RNA aptamers through fluorescence resonance energy transfer. As a result, the gradual release of Dox enhanced the local anticancer effects, and the fluorescence of QDs provided a method to sense the release of the drug and a versatile nanoscale scaffold to develop multifunctional nanoparticles for siRNA delivery and imaging. Nowadays, RNA interference has broad applications, ranging from functional gene analysis to targeted therapy of cancer[131–136]. Yezhelyev et al.[137] constructed a multifunctional nanoparticle for siRNA delivery based on QDs, which showed highly effective and safe RNA interference, as well as fluorescence contrast. It can improve gene silencing activity by 10 to 20 folds, and can reduce cytotoxicity by 5 to 6 folds, compared with current siRNA delivery agents. In addition, QDs are inherently dual-modality optical and electron microscopy probes, allowing real-time tracking and ultrastructural localization during transfection.

Fluorescence imaging and photodynamic therapy (PDT) are used in advanced clinical trials for the efficient detection and cancer treatment. Compared with chemotherapy and radiation therapy, these methods offer selective therapy with the immune system and normal cells remaining intact. QDs are the most promising property for PDT with exceptional photostability[138,139].

## Challenges and Future Prospects

### Nanotoxicology

Although QDs have great potential for biomedical imaging and detection, toxicological and pharmacological issues mainly from heavy metal and colloidal instability limit the advancement toward the diagnosis and therapy of cancer and other diseases[140,141]. These concerns may not hinder the development of the applications *in vitro*; however, they serve as great barriers for human application for *in vivo* cancer imaging. Efforts have been exerted to generate novel QDs based on their components, sizes, surface coatings, and valences to minimize toxicity and maximize detection efficiency[36,142–148]. However, problems such as coating shell degradation caused by the modification of QDs should be considered[57]. Alternatively, nonspecific accumulation by the RES, including the liver, spleen, and lymphatic system, should also be observed[30,57,96,140]. In addition, immune response[149] and genotoxic effect[150] have been reported. Several studies have shown that QDs less than 5 nm in size can be removed by the kidney[30,141]. Thus, considering the biosafety for *in vivo* applications, long-term toxicological and pharmacokinetic investigations involving degradation, excretion, persistence, and immune response of QDs should be systematically assessed.

Considering the toxicity of Cd, Se, Zn, Te, Hg, and Pb, several low-toxicity QDs have been developed as substitutes[91,151,152]. For example, low toxicity is achieved by replacing Cd with Zn. Such QDs are also less sensitive to environmental changes, such as thermal, chemical, and photochemical disturbances. These doped QDs have color-tunability with good quantum efficiency and are promising candidates for future efforts to lower QD-based cytotoxicity. They also have narrow emission spectra (45 nm to 65 nm full width at half maximum) and can cover most of the visible spectral window. In the near future, doped QDs that emit in the NIR region will be developed. Extensive scrutiny and research on the toxicity profiles will be needed before QDs can be employed in any medical procedure. Further studies are also needed to investigate the clearance mechanism of QDs from living systems.

### Design and Generation of Biocompatible and Biodegradable Nanoparticles

QD-based *in vivo* imaging and targeting studies are limited due to nonspecific organ uptake and RES scavenging, namely, the relatively large size (15 nm to 30 nm) and short circulation half-life in the blood vascular system. Thus, various current groups attempt to prolong the circulation time of QDs by attaching passivating molecules, such as PEG, and by controlling the overall charge of the particles to prevent their adsorption to the plasma proteins[69,116,126]. Alternatively, clearance from the body is a prerequisite to the clinical use of any contrast agent. An intriguing recent finding suggests a size threshold of 5 nm to 6 nm in diameter, below which the QDs cannot escape the liver and be cleared through the kidneys[153].

### Reproducibility, Reliability, and Comparability of QDs

The present clinical applications of QDs are strongly limited by the deficient amount of data on their reproducibility and comparability, as well as on their potential for quantification. Different functionalized QDs from various sources will have different fluorescence quantum yields based on variable materials and surface chemistries. Thus, the derivation and establishment of quality criteria for these materials of different functionalized QDs is the essential initial step[154].

## Conclusions

QDs are technological marvels with characteristics that may revolutionize cancer diagnosis and treatment. Currently, QDs are widely used *in vitro*, such as in detecting cancer biomarkers in molecular pathology, revealing cancer invasion, focusing on the tumor environment, and providing a novel approach for improving tumor heterogeneity understanding, diagnosis, classification, and treatment of cancer. However, complex in vivo studies still result in the difficult identification of the dominant and compensation mechanisms of tumor invasion and microenvironment[4].

In clinical settings, optical imaging is relevant for tissues close to the surface of the skin, accessible by endoscopy, and during intraoperative visualization. The future of nanomedicine lies in the multifunctional nanoplatforms, which combine therapeutic components and multimodality imaging. The ultimate goal is for nanoplatform-based agents to allow the efficient and specific in vivo targeted delivery of drugs without systemic toxicity, and the dose delivered, as well as the therapeutic efficacy, can be accurately measured noninvasively over time. However, inefficient delivery, potential toxicity, and lack of quantification are also major roadblocks for clinical translation of QDs.

## Acknowledgements

This work is supported by the Academic Award for Excellent Ph.D. Candidates Funded by the Ministry of Education of China (No. 5052011303014), the National Natural Science Foundation of China (No. 81171396), the Science Fund for Creative Research Groups of the National Natural Science Foundation of China (Nos. 20621502 and 20921062), and the Fundamental Research Funds for the Central Universities of Ministry of Education of China (No. 4103005).

## Footnotes

*   **Conflict of interest statement** No potential conflicts of interest are disclosed.

*   Received June 11, 2012.
*   Accepted August 19, 2012.


*   Copyright: © 2012, Cancer Biology & Medicine

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## References

1.  1. Jemal A, Bray F, Center MM, et al.  Global cancer statistics. CA Cancer J Clin 2011; 61: 69–90.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.3322/caac.20107&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21296855&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000288278400004&link_type=ISI) 

2.  2. Lauffenburger DA, Horwitz AF.  Cell migration: a physically integrated molecular process. Cell 1996; 84: 359–369.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/S0092-8674(00)81280-5&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=8608589&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=A1996TV70800004&link_type=ISI) 

3.  3. Ridley AJ, Schwartz MA, Burridge K, et al.  Cell migration: integrating signals from front to back. Science 2003; 302: 1704–1709.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEzOiIzMDIvNTY1MS8xNzA0IjtzOjQ6ImF0b20iO3M6MTc6Ii9jYm0vOS8zLzE1MS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

4.  4. Sanz-Moreno V, Marshall CJ.  The plasticity of cytoskeletal dynamics underlying neoplastic cell migration. Curr Opin Cell Biol 2010; 22: 690–696.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.ceb.2010.08.020&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20829016&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

5.  5. Friedl P, Alexander S.  Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 2011; 147: 992–1009.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.cell.2011.11.016&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=22118458&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000297376600013&link_type=ISI) 

6.  6. Chaffer CL, Weinberg RA.  A perspective on cancer cell metastasis. Science 2011; 331: 1559–1564.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEzOiIzMzEvNjAyNC8xNTU5IjtzOjQ6ImF0b20iO3M6MTc6Ii9jYm0vOS8zLzE1MS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

7.  7. Joyce JA, Pollard JW.  Microenvironmental regulation of metastasis. Nat Rev Cancer 2009; 9: 239–252.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nrc2618&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19279573&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000264500800009&link_type=ISI) 

8.  8. Egeblad M, Rasch MG, Weaver VM.  Dynamic interplay between the collagen scaffold and tumor evolution. Curr Opin Cell Biol 2010; 22: 697–706.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.ceb.2010.08.015&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20822891&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

9.  9. He K, Xu T, Goldkorn A.  Cancer cells cyclically lose and regain drug-resistant highly tumorigenic features characteristic of a cancer stem-like phenotype. Mol Cancer Ther 2011; 10: 938–948.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTA6Im1vbGNhbnRoZXIiO3M6NToicmVzaWQiO3M6ODoiMTAvNi85MzgiO3M6NDoiYXRvbSI7czoxNzoiL2NibS85LzMvMTUxLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

10. 10. Picchio M, Beck R, Haubner R, et al.  Intratumoral spatial distribution of hypoxia and angiogenesis assessed by 18F-FAZA and 125I-Gluco-RGD autoradiography. J Nucl Med 2008; 49: 597–605.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam51bWVkIjtzOjU6InJlc2lkIjtzOjg6IjQ5LzQvNTk3IjtzOjQ6ImF0b20iO3M6MTc6Ii9jYm0vOS8zLzE1MS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

11. 11. Shapiro IM, Cheng AW, Flytzanis NC, et al.  An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. PLoS Genet 2011; 7: e1002218.
    
    

12. 12. Alexander S, Friedl P.  Cancer invasion and resistance: interconnected processes of disease progression and therapy failure. Trends Mol Med 2012; 18: 13–26.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.molmed.2011.11.003&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=22177734&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

13. 13. Sansing HA, Sarkeshik A, Yates JR, et al.  Integrin alphabeta1, alphavbeta, alpha6beta effectors p130Cas, Src and talin regulate carcinoma invasion and chemoresistance. Biochem Biophys Res Commun 2011; 406: 171–176.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.bbrc.2011.01.109&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21291860&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

14. 14. Yao H, Zeng ZZ, Fay KS, et al.  Role of alpha(5)beta(1) Integrin Up-regulation in Radiation-Induced Invasion by Human Pancreatic Cancer Cells. Transl Oncol 2011; 4: 282–292.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1593/tlo.11133&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21966545&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

15. 15. Nelson CM, Khauv D, Bissell MJ, et al.  Change in cell shape is required for matrix metalloproteinase-induced epithelial-mesenchymal transition of mammary epithelial cells. J Cell Biochem 2008; 105: 25–33.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1002/jcb.21821&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18506791&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

16. 16. Xu R, Boudreau A, Bissell MJ.  Tissue architecture and function: dynamic reciprocity via extra- and intra-cellular matrices. Cancer Metastasis Rev 2009; 28: 167–176.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1007/s10555-008-9178-z&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19160017&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000264476600014&link_type=ISI) 

17. 17. Bentolila LA, Ebenstein Y, Weiss S.  Quantum dots for in vivo small-animal imaging. J Nucl Med 2009; 50: 493–496.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam51bWVkIjtzOjU6InJlc2lkIjtzOjg6IjUwLzQvNDkzIjtzOjQ6ImF0b20iO3M6MTc6Ii9jYm0vOS8zLzE1MS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

18. 18. Hilderbrand SA, Weissleder R.  Near-infrared fluorescence: application to in vivo molecular imaging. Curr Opin Chem Biol 2010; 14: 71–79.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.cbpa.2009.09.029&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19879798&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

19. 19. Wang Y, Chen L.  Quantum dots, lighting up the research and development of nanomedicine. Nanomedicine 2011; 7: 385–402.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.nano.2010.12.006&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21215327&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

20. 20. Tholouli E, Sweeney E, Barrow E, et al.  Quantum dots light up pathology. J Pathol 2008; 216: 275–285.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1002/path.2421&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18814189&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

21. 21. Byers RJ, Hitchman ER.  Quantum dots brighten biological imaging. Prog Histochem Cytochem 2011; 45: 201–237.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21196026&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

22. 22. True LD, Gao X.  Quantum dots for molecular pathology: their time has arrived. J Mol Diagn 2007; 9: 7–11.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.2353/jmoldx.2007.060186&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17251330&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

23. 23. He X, Gao J, Gambhir SS, et al.  Near-infrared fluorescent nanoprobes for cancer molecular imaging: status and challenges. Trends Mol Med 2010; 16: 574–583.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.molmed.2010.08.006&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20870460&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000285727200004&link_type=ISI) 

24. 24. Medarova Z, Pham W, Farrar C, et al.  In vivo imaging of siRNA delivery and silencing in tumors. Nat Med 2007; 13: 372–377.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nm1486&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17322898&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000244715700052&link_type=ISI) 

25. 25. McCarthy JR, Kelly KA, Sun EY, et al.  Targeted delivery of multifunctional magnetic nanoparticles. Nanomedicine (Lond) 2007; 2: 153–167.
    
    

26. 26. Harisinghani MG, Barentsz J, Hahn PF, et al.  Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003; 348: 2491–2499.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1056/NEJMoa022749&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=12815134&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000183577200003&link_type=ISI) 

27. 27. Rhyner MN, Smith AM, Gao X, et al.  Quantum dots and multifunctional nanoparticles: new contrast agents for tumor imaging. Nanomedicine (Lond) 2006; 1: 209–217.
    
    

28. 28. Xing Y, Chaudry Q, Shen C, et al.  Bioconjugated quantum dots for multiplexed and quantitative immunohistochemistry. Nat Protoc 2007; 2: 1152–1165.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nprot.2007.107&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17546006&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000253138700013&link_type=ISI) 

29. 29. Wu X, Liu H, Liu J, et al.  Immunofluorescent labeling of cancer marker Her2 and other cellular targets with semiconductor quantum dots. Nat Biotechnol 2003; 21: 41–46.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nbt764&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=12459735&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000180209200022&link_type=ISI) 

30. 30. Kim S, Lim YT, Soltesz EG, et al.  Near-infrared fluorescent type II quantum dots for sentinel lymph node mapping. Nat Biotechnol 2004; 22: 93–97.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nbt920&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=14661026&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000187745400032&link_type=ISI) 

31. 31. Alivisatos AP, Gu W, Larabell C.  Quantum dots as cellular probes. Annu Rev Biomed Eng 2005; 7: 55–76.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1146/annurev.bioeng.7.060804.100432&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=16004566&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000231513200003&link_type=ISI) 

32. 32. Tavares AJ, Chong L, Petryayeva E, et al.  Quantum dots as contrast agents for in vivo tumor imaging: progress and issues. Anal Bioanal Chem 2011; 399: 2331–2342.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20658228&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

33. 33. Miyawaki A, Sawano AKogure T.  Lighting up cells: labelling proteins with fluorophores. Nat Cell Biol 2003;Suppl:S1-7.
    
    

34. 34. Johnson I.  Fluorescent probes for living cells. Histochem J 1998; 30: 123–140.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1023/A:1003287101868&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=10188922&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000072597700002&link_type=ISI) 

35. 35. Emptage NJ.  Fluorescent imaging in living systems. Curr Opin Pharmacol 2001; 1: 521–525.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/S1471-4892(01)00090-X&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=11764779&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

36. 36. Michalet X, Pinaud FF, Bentolila LA, et al.  Quantum dots for live cells, in vivo imaging, and diagnostics. Science 2005; 307: 538–544.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIzMDcvNTcwOS81MzgiO3M6NDoiYXRvbSI7czoxNzoiL2NibS85LzMvMTUxLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

37. 37. Wang X, Ren X, Kahen K, et al.  Non-blinking semiconductor nanocrystals. Nature 2009; 459: 686–689.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nature08072&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19430463&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000266608600040&link_type=ISI) 

38. 38. Larson DR, Zipfel WR, Williams RM, et al.  Water-soluble quantum dots for multiphoton fluorescence imaging in vivo. Science 2003; 300: 1434–1436.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEzOiIzMDAvNTYyNC8xNDM0IjtzOjQ6ImF0b20iO3M6MTc6Ii9jYm0vOS8zLzE1MS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

39. 39. Dahan M, Laurence T, Pinaud F, et al.  Time-gated biological imaging by use of colloidal quantum dots. Opt Lett 2001; 26: 825–827.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1364/OL.26.000825&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18040463&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000168924200023&link_type=ISI) 

40. 40. Alivisatos P.  The use of nanocrystals in biological detection. Nat Biotechnol 2004; 22: 47–52.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nbt927&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=14704706&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000187745400025&link_type=ISI) 

41. 41. Murphy CJ.  Materials science. Nanocubes and nanoboxes. Science 2002; 298: 2139–2141.
    
    

42. 42. Medintz IL, Uyeda HT, Goldman ER, et al.  Quantum dot bioconjugates for imaging, labelling and sensing. Nat Mater 2005; 4: 435–446.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nmat1390&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=15928695&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000229502700008&link_type=ISI) 

43. 43. Chan WC, Nie S.  Quantum dot bioconjugates for ultrasensitive nonisotopic detection. Science 1998; 281: 2016–2018.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEzOiIyODEvNTM4NS8yMDE2IjtzOjQ6ImF0b20iO3M6MTc6Ii9jYm0vOS8zLzE1MS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

44. 44. Bruchez M, Jr., Moronne M, Gin P, et al.  Semiconductor nanocrystals as fluorescent biological labels. Science 1998; 281: 2013–2016.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEzOiIyODEvNTM4NS8yMDEzIjtzOjQ6ImF0b20iO3M6MTc6Ii9jYm0vOS8zLzE1MS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

45. 45. Gao X, Cui Y, Levenson RM, et al.  In vivo cancer targeting and imaging with semiconductor quantum dots. Nat Biotechnol 2004; 22: 969–976.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nbt994&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=15258594&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000223039500025&link_type=ISI) 

46. 46. Tada H, Higuchi H, Wanatabe TM, et al.  In vivo real-time tracking of single quantum dots conjugated with monoclonal anti-HER2 antibody in tumors of mice. Cancer Res 2007; 67: 1138–1144.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiY2FucmVzIjtzOjU6InJlc2lkIjtzOjk6IjY3LzMvMTEzOCI7czo0OiJhdG9tIjtzOjE3OiIvY2JtLzkvMy8xNTEuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

47. 47. Zhang H, Sachdev D, Wang C, et al.  Detection and downregulation of type I IGF receptor expression by antibody-conjugated quantum dots in breast cancer cells. Breast Cancer Res Treat 2009; 114: 277–285.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1007/s10549-008-0014-5&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18418709&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

48. 48. Yong KT, Ding H, Roy I, et al.  Imaging pancreatic cancer using bioconjugated InP quantum dots. ACS Nano 2009; 3: 502–510.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/nn8008933&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19243145&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000264535200005&link_type=ISI) 

49. 49. Voura EB, Jaiswal JK, Mattoussi H, et al.  Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning microscopy. Nat Med 2004; 10: 993–998.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nm1096&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=15334072&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000223658400038&link_type=ISI) 

50. 50. Cai W, Shin DW, Chen K, et al.  Peptide-labeled near-infrared quantum dots for imaging tumor vasculature in living subjects. Nano Lett 2006; 6: 669–676.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/nl052405t&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=16608262&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000236916200015&link_type=ISI) 

51. 51. Stroh M, Zimmer JP, Duda DG, et al.  Quantum dots spectrally distinguish multiple species within the tumor milieu in vivo. Nat Med 2005; 11: 678–682.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nm1247&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=15880117&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000229589800036&link_type=ISI) 

52. 52. Li Z, Wang K, Tan W, et al.  Immunofluorescent labeling of cancer cells with quantum dots synthesized in aqueous solution. Anal Biochem 2006; 354: 169–174.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=16729957&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

53. 53. Chen C, Peng J, Sun SR, et al.  Tapping the potential of quantum dots for personalized oncology: current status and future perspectives. Nanomedicine (Lond) 2012; 7: 411–428.
    
    

54. 54. Chen C, Peng J, Xia H, et al.  Quantum-dot-based immunofluorescent imaging of HER2 and ER provides new insights into breast cancer heterogeneity. Nanotechnology 2010; 21: 095101.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20110584&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

55. 55. Chen C, Peng J, Xia HS, et al.  Quantum dots-based immunofluorescence technology for the quantitative determination of HER2 expression in breast cancer. Biomaterials 2009; 30: 2912–2918.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.biomaterials.2009.02.010&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19251316&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

56. 56. Chen C, Sun SR, Gong YP, et al.  Quantum dots-based molecular classification of breast cancer by quantitative spectroanalysis of hormone receptors and HER2. Biomaterials 2011; 32: 7592–7599.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.biomaterials.2011.06.029&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21745686&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

57. 57. Smith AM, Duan H, Mohs AM, et al.  Bioconjugated quantum dots for in vivo molecular and cellular imaging. Adv Drug Deliv Rev 2008; 60: 1226–1240.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.addr.2008.03.015&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18495291&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000258313900002&link_type=ISI) 

58. 58. Zhang H, Yee D, Wang C.  Quantum dots for cancer diagnosis and therapy: biological and clinical perspectives. Nanomedicine (Lond) 2008; 3: 83–91.
    
    

59. 59. Ruan Y, Yu W, Cheng F, et al.  Comparison of quantum-dots-and fluorescein-isothiocyanate-based technology for detecting prostate-specific antigen expression in human prostate cancer. IET Nanobiotechnol 2011; 5: 47.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21495780&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

60. 60. Shi C, Zhou G, Zhu Y, et al.  Quantum dots-based multiplexed immunohistochemistry of protein expression in human prostate cancer cells. Eur J Histochem 2008; 52: 127–134.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18591159&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

61. 61. Jin LH, Li SM, Cho YH.  Enhanced detection sensitivity of pegylated CdSe/ZnS quantum dots-based prostate cancer biomarkers by surface plasmon-coupled emission. Biosens Bioelectron 2012; 33: 284–287.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=22310156&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

62. 62. Huang C, Stakenborg T, Cheng Y, et al.  Label-free genosensor based on immobilized DNA hairpins on gold surface. Biosens Bioelectron 2011; 26: 3121–3126.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21208795&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

63. 63. Yuk JS, MacCraith BD, McDonagh C.  Signal enhancement of surface plasmon-coupled emission (SPCE) with the evanescent field of surface plasmons on a bimetallic paraboloid biochip. Biosens Bioelectron 2011; 26: 3213–3218.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21256731&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

64. 64. Goldhirsch A, Glick JH, Gelber RD, et al.  Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005; 16: 1569–1583.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1093/annonc/mdi326&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=16148022&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000232597700003&link_type=ISI) 

65. 65. Moasser MM.  The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene 2007; 26: 6469–6487.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/sj.onc.1210477&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17471238&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000249919800001&link_type=ISI) 

66. 66. Xiao Y, Gao X, Gannot G, et al.  Quantitation of HER2 and telomerase biomarkers in solid tumors with IgY antibodies and nanocrystal detection. Int J Cancer 2008; 122: 2178–2186.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1002/ijc.23320&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18214859&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000254983100002&link_type=ISI) 

67. 67. O'Connor AE, Gallagher WM, Byrne AT.  Porphyrin and nonporphyrin photosensitizers in oncology: preclinical and clinical advances in photodynamic therapy. Photochem Photobiol 2009; 85: 1053–1074.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1111/j.1751-1097.2009.00585.x&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19682322&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000269463700002&link_type=ISI) 

68. 68. Chen C, Xia HS, Gong YP, et al.  The quantitative detection of total HER2 load by quantum dots and the identification of a new subtype of breast cancer with different 5-year prognosis. Biomaterials 2010; 31: 8818–8825.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.biomaterials.2010.07.091&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20723971&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

69. 69. Liu XL, Peng CW, Chen C, et al.  Quantum dots-based double-color imaging of HER2 positive breast cancer invasion. Biochem Biophys Res Commun 2011; 409: 577–582.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.bbrc.2011.05.052&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21609713&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

70. 70. Wang HZ, Wang HY, Liang RQ, et al.  Detection of tumor marker CA125 in ovarian carcinoma using quantum dots. Acta Biochim Biophys Sin (Shanghai) 2004; 36: 681–686.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1093/abbs/36.10.681&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=15483748&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

71. 71. Liu YS, Sun Y, Vernier PT, et al.  pH-sensitive Photoluminescence of CdSe/ZnSe/ZnS Quantum Dots in Human Ovarian Cancer Cells. J Phys Chem C Nanomater Interfaces 2007; 111: 2872–2878.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18985164&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

72. 72. Kawashima N, Nakayama K, Itoh K, et al.  Reversible dimerization of EGFR revealed by single-molecule fluorescence imaging using quantum dots. Chemistry 2010; 16: 1186–1192.
    
    

73. 73. Bostick RM, Kong KY, Ahearn TU, et al.  Detecting and quantifying biomarkers of risk for colorectal cancer using quantum dots and novel image analysis algorithms. Conf Proc IEEE Eng Med Biol Soc 2006; 1: 3313–3316.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17947019&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

74. 74. Montet X, Weissleder R, Josephson L.  Imaging pancreatic cancer with a peptide-nanoparticle conjugate targeted to normal pancreas. Bioconjug Chem 2006; 17: 905–911.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/bc060035+&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=16848396&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

75. 75. Yang L, Mao H, Cao Z, et al.  Molecular imaging of pancreatic cancer in an animal model using targeted multifunctional nanoparticles. Gastroenterology 2009; 136: 1514–1525 e1512.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1053/j.gastro.2009.01.006&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19208341&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

76. 76. Soltesz EG, Kim S, Kim SW, et al.  Sentinel lymph node mapping of the gastrointestinal tract by using invisible light. Ann Surg Oncol 2006; 13: 386–396.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1245/ASO.2006.04.025&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=16485157&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000235449700017&link_type=ISI) 

77. 77. Yong KT.  Anti-claudin-4-conjugated highly luminescent nanoparticles as biological labels for pancreatic cancer sensing. Methods Mol Biol 2011; 762: 427–438.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21717374&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

78. 78. Yong KT.  Biophotonics and biotechnology in pancreatic cancer: cyclic RGD-peptide-conjugated type II quantum dots for in vivo imaging. Pancreatology 2010; 10: 553–564.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1159/000283577&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20975319&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

79. 79. Qian J, Yong KT, Roy I, et al.  Imaging pancreatic cancer using surface-functionalized quantum dots. J Phys Chem B 2007; 111: 6969–6972.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17552555&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

80. 80. Lee KH, Galloway JF, Park J, et al.  Quantitative molecular profiling of biomarkers for pancreatic cancer with functionalized quantum dots. Nanomedicine: Nanotechnology, Biology and Medicine 2012.
    
    

81. 81. Baban DF, Seymour LW.  Control of tumour vascular permeability. Adv Drug Deliv Rev 1998; 34: 109–119.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/S0169-409X(98)00003-9&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=10837673&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000077175900008&link_type=ISI) 

82. 82. Konerding MA, Fait E, Gaumann A.  3D microvascular architecture of pre-cancerous lesions and invasive carcinomas of the colon. Br J Cancer 2001; 84: 1354–1362.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1054/bjoc.2001.1809&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=11355947&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000169042800013&link_type=ISI) 

83. 83. Matsumura Y, Maeda H.  A new concept for macromolecular therapeutics in cancer chemotherapy: mechanism of tumoritropic accumulation of proteins and the antitumor agent smancs. Cancer Res 1986; 46: 6387–6392.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiY2FucmVzIjtzOjU6InJlc2lkIjtzOjE3OiI0Ni8xMl9QYXJ0XzEvNjM4NyI7czo0OiJhdG9tIjtzOjE3OiIvY2JtLzkvMy8xNTEuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

84. 84. Fang J, Nakamura H, Maeda H.  The EPR effect: Unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 2011; 63: 136–151.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.addr.2010.04.009&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20441782&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

85. 85. Jain RK.  Transport of molecules, particles, and cells in solid tumors. Annu Rev Biomed Eng 1999; 1: 241–263.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1146/annurev.bioeng.1.1.241&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=11701489&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000087705700010&link_type=ISI) 

86. 86. Jain RK.  Delivery of molecular medicine to solid tumors: lessons from in vivo imaging of gene expression and function. J Control Release 2001; 74: 7–25.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/S0168-3659(01)00306-6&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=11489479&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000170603600003&link_type=ISI) 

87. 87. Maeda H, Wu J, Sawa T, et al.  Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Control Release 2000; 65: 271–284.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/S0168-3659(99)00248-5&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=10699287&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000085933700025&link_type=ISI) 

88. 88. Dubertret B, Skourides P, Norris DJ, et al.  In vivo imaging of quantum dots encapsulated in phospholipid micelles. Science 2002; 298: 1759–1762.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEzOiIyOTgvNTU5OS8xNzU5IjtzOjQ6ImF0b20iO3M6MTc6Ii9jYm0vOS8zLzE1MS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

89. 89. Smith JD, Fisher GW, Waggoner AS, et al.  The use of quantum dots for analysis of chick CAM vasculature. Microvasc Res 2007; 73: 75–83.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17070560&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

90. 90. Zimmer JP, Kim SW, Ohnishi S, et al.  Size series of small indium arsenide-zinc selenide core-shell nanocrystals and their application to in vivo imaging. J Am Chem Soc 2006; 128: 2526–2527.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/ja0579816&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=16492023&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000235787200012&link_type=ISI) 

91. 91. Kim SW, Zimmer JP, Ohnishi S, et al.  Engineering InAs(x)P(1-x)/InP/ZnSe III-V alloyed core/shell quantum dots for the near-infrared. J Am Chem Soc 2005; 127: 10526–10532.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/ja0434331&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=16045339&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000230831600030&link_type=ISI) 

92. 92. Thorne RG, Nicholson C.  In vivo diffusion analysis with quantum dots and dextrans predicts the width of brain extracellular space. Proc Natl Acad Sci U S A 2006; 103: 5567–5572.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoicG5hcyI7czo1OiJyZXNpZCI7czoxMToiMTAzLzE0LzU1NjciO3M6NDoiYXRvbSI7czoxNzoiL2NibS85LzMvMTUxLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

93. 93. Frangioni JV, Kim SW, Ohnishi S, et al.  Sentinel lymph node mapping with type-II quantum dots. Methods Mol Biol 2007; 374: 147–159.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.jmb.2007.09.019&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17237537&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

94. 94. Hikage M, Gonda K, Takeda M, et al.  Nano-imaging of the lymph network structure with quantum dots. Nanotechnology 2010; 21: 185103.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1088/0957-4484/21/18/185103&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20388975&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

95. 95. So MK, Xu C, Loening AM, et al.  Self-illuminating quantum dot conjugates for in vivo imaging. Nat Biotechnol 2006; 24: 339–343.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nbt1188&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=16501578&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000235868600037&link_type=ISI) 

96. 96. Ballou B, Ernst LA, Andreko S, et al.  Sentinel lymph node imaging using quantum dots in mouse tumor models. Bioconjug Chem 2007; 18: 389–396.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/bc060261j&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17263568&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000245041500016&link_type=ISI) 

97. 97. Akerman ME, Chan WC, Laakkonen P, et al.  Nanocrystal targeting in vivo. Proc Natl Acad Sci U SA 2002; 99: 12617–12621.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoicG5hcyI7czo1OiJyZXNpZCI7czoxMToiOTkvMjAvMTI2MTciO3M6NDoiYXRvbSI7czoxNzoiL2NibS85LzMvMTUxLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

98. 98. Yu X, Chen L, Li K, et al.  Immunofluorescence detection with quantum dot bioconjugates for hepatoma in vivo. J Biomed Opt 2007; 12: 014008.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17343483&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

99. 99. Weng KC, Noble CO, Papahadjopoulos-Sternberg B, et al.  Targeted tumor cell internalization and imaging of multifunctional quantum dot-conjugated immunoliposomes in vitro and in vivo. Nano Lett 2008; 8: 2851–2857.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/nl801488u&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18712930&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000259140200043&link_type=ISI) 

100.100. Cai W, Chen K, Li ZB, et al.  Dual-function probe for PET and near-infrared fluorescence imaging of tumor vasculature. J Nucl Med 2007; 48: 1862–1870.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam51bWVkIjtzOjU6InJlc2lkIjtzOjEwOiI0OC8xMS8xODYyIjtzOjQ6ImF0b20iO3M6MTc6Ii9jYm0vOS8zLzE1MS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

101.101. Chen LD, Liu J, Yu XF, et al.  The biocompatibility of quantum dot probes used for the targeted imaging of hepatocellular carcinoma metastasis. Biomaterials 2008; 29: 4170–4176.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.biomaterials.2008.07.025&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18691751&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000259960600004&link_type=ISI) 

102.102. Chen LD, Liu J, Yu XF, et al.  In-vivo targeted imaging of hepatocellular carcinoma in nude mice using quantum dot probes. Zhonghua Bing Li Xue Za Zhi 2007; 36: 394–399 (in Chinese).
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17822625&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

103.103. Yu X, Chen L, Deng Y, et al.  Fluorescence analysis with quantum dot probes for hepatoma under one- and two-photon excitation. J Fluoresc 2007; 17: 243–247.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17279333&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

104.104. Pons T, Pic E, Lequeux N, et al.  Cadmium-free CuInS2/ZnS quantum dots for sentinel lymph node imaging with reduced toxicity. ACS Nano 2010; 4: 2531–2538.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/nn901421v&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20387796&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000277976900007&link_type=ISI) 

105.105. Ballou B, Lagerholm BC, Ernst LA, et al.  Noninvasive imaging of quantum dots in mice. Bioconjug Chem 2004; 15: 79–86.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/bc034153y&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=14733586&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000188393200011&link_type=ISI) 

106.106. Ballou B.  Quantum dot surfaces for use in vivo and in vitro. Curr Top Dev Biol 2005; 70: 103–120.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=16338339&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

107.107. Peng CW, Liu XL, Liu X, et al.  Co-evolution of cancer microenvironment reveals distinctive patterns of gastric cancer invasion: laboratory evidence and clinical significance. J Transl Med 2010; 8: 101.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20950454&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

108.108. Peng CW, Liu XL, Chen C, et al.  Patterns of cancer invasion revealed by QDs-based quantitative multiplexed imaging of tumor microenvironment. Biomaterials 2011; 32: 2907–2917.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.biomaterials.2010.12.053&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21262536&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

109.109. Cance WG.  Society of surgical oncology presidential address: the war on cancer--shifting from disappointment to new hope. Ann Surg Oncol 2010; 17: 1971–1978.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20180028&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

110.110. Chakravarthy KV, Davidson BA, Helinski JD, et al.  Doxorubicin-conjugated quantum dots to target alveolar macrophages and inflammation. Nanomedicine 2011; 7: 88–96.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.nano.2010.09.001&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20887813&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

111.111. Qu G, Zhang C, Yuan L, et al.  Quantum dots impair macrophagic morphology and the ability of phagocytosis by inhibiting the Rho-associated kinase signaling. Nanoscale 2012; 4: 2239–2244.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=22395807&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

112.112. Massoud TF, Gambhir SS.  Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev 2003; 17: 545–580.
    
    [FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6ODoiZ2VuZXNkZXYiO3M6NToicmVzaWQiO3M6ODoiMTcvNS81NDUiO3M6NDoiYXRvbSI7czoxNzoiL2NibS85LzMvMTUxLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

113.113. Catana C, Wu Y, Judenhofer MS, et al.  Simultaneous acquisition of multislice PET and MR images: initial results with a MR-compatible PET scanner. J Nucl Med 2006; 47: 1968–1976.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam51bWVkIjtzOjU6InJlc2lkIjtzOjEwOiI0Ny8xMi8xOTY4IjtzOjQ6ImF0b20iO3M6MTc6Ii9jYm0vOS8zLzE1MS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

114.114. Mulder WJ, Koole R, Brandwijk RJ, et al.  Quantum dots with a paramagnetic coating as a bimodal molecular imaging probe. Nano Lett 2006; 6: 1–6.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/nl051935m&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=16402777&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000235532400001&link_type=ISI) 

115.115. Mulder WJ, Castermans K, van Beijnum JR, et al.  Molecular imaging of tumor angiogenesis using alphavbeta3-integrin targeted multimodal quantum dots. Angiogenesis 2009; 12: 17–24.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1007/s10456-008-9124-2&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19067197&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

116.116. Koole R, van Schooneveld MM, Hilhorst J, et al.  Paramagnetic lipid-coated silica nanoparticles with a fluorescent quantum dot core: a new contrast agent platform for multimodality imaging. Bioconjug Chem 2008; 19: 2471–2479.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/bc800368x&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19035793&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

117.117. Kobayashi H, Koyama Y, Barrett T, et al.  Multimodal nanoprobes for radionuclide and five-color near-infrared optical lymphatic imaging. ACS Nano 2007; 1: 258–264.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19079788&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

118.118. Duconge F, Pons T, Pestourie C, et al.  Fluorine-18-labeled phospholipid quantum dot micelles for in vivo multimodal imaging from whole body to cellular scales. Bioconjug Chem 2008; 19: 1921–1926.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18754572&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

119.119. Schipper ML, Iyer G, Koh AL, et al.  Particle size, surface coating, and PEGylation influence the biodistribution of quantum dots in living mice. Small 2009; 5: 126–134.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1002/smll.200800003&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19051182&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000262895300019&link_type=ISI) 

120.120. Jin T, Yoshioka Y, Fujii F, et al.  Gd3+-functionalized near-infrared quantum dots for in vivo dual modal (fluorescence/magnetic resonance) imaging. Chem Commun (Camb) 2008; 5764–5766.
    
    

121.121. Giepmans BN, Deerinck TJ, Smarr BL, et al.  Correlated light and electron microscopic imaging of multiple endogenous proteins using Quantum dots. Nat Methods 2005; 2: 743–749.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nmeth791&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=16179920&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000232998600013&link_type=ISI) 

122.122. Chen K, Li ZB, Wang H, et al.  Dual-modality optical and positron emission tomography imaging of vascular endothelial growth factor receptor on tumor vasculature using quantum dots. Eur J Nucl Med Mol Imaging 2008; 35: 2235–2244.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1007/s00259-008-0860-8&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18566815&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000261654000011&link_type=ISI) 

123.123. Leung K.  64Cu-Tetraazacyclododecane-N, N', N'', N'''-tetraacetic acid-quantum dot-c(Arg-Gly-Asp-D-Tyr-Lys), in Molecular Imaging and Contrast Agent Database (MICAD). 2004: Bethesda (MD).
    
    

124.124. Schipper ML, Cheng Z, Lee SW, et al.  microPET-based biodistribution of quantum dots in living mice. J Nucl Med 2007; 48: 1511–1518.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam51bWVkIjtzOjU6InJlc2lkIjtzOjk6IjQ4LzkvMTUxMSI7czo0OiJhdG9tIjtzOjE3OiIvY2JtLzkvMy8xNTEuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

125.125. Jin T, Fujii F, Komai Y, et al.  Preparation and characterization of highly fluorescent, glutathione-coated near infrared quantum dots for in vivo fluorescence imaging. Int J Mol Sci 2008; 9: 2044–2061.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.3390/ijms9102044&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19325735&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

126.126. Park JH, von Maltzahn G, Ruoslahti E, et al.  Micellar hybrid nanoparticles for simultaneous magnetofluorescent imaging and drug delivery. Angew Chem Int Ed Engl 2008; 47: 7284–7288.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1002/anie.200801810&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18696519&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

127.127. Bakalova R, Zhelev Z, Aoki I, et al.  Multimodal silica-shelled quantum dots: direct intracellular delivery, photosensitization, toxic, and microcirculation effects. Bioconjug Chem 2008; 19: 1135–1142.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18494515&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

128.128. Yong KT, Hu R, Roy I, et al.  Tumor targeting and imaging in live animals with functionalized semiconductor quantum rods. ACS Appl Mater Interfaces 2009; 1: 710–719.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20160901&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

129.129. Cai W, Chen X.  Nanoplatforms for targeted molecular imaging in living subjects. Small 2007; 3: 1840–1854.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1002/smll.200700351&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17943716&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000251038800001&link_type=ISI) 

130.130. Bagalkot V, Zhang L, Levy-Nissenbaum E, et al.  Quantum dot-aptamer conjugates for synchronous cancer imaging, therapy, and sensing of drug delivery based on bi-fluorescence resonance energy transfer. Nano Lett 2007; 7: 3065–3070.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/nl071546n&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17854227&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000250143400023&link_type=ISI) 

131.131. Bumcrot D, Manoharan M, Koteliansky V, et al.  RNAi therapeutics: a potential new class of pharmaceutical drugs. Nat Chem Biol 2006; 2: 711–719.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nchembio839&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17108989&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000242168800015&link_type=ISI) 

132.132. Dykxhoorn DM, Lieberman J.  The silent revolution: RNA interference as basic biology, research tool, and therapeutic. Annu Rev Med 2005; 56: 401–423.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1146/annurev.med.56.082103.104606&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=15660519&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000227504100022&link_type=ISI) 

133.133. Kim DHRossi JJ.  Strategies for silencing human disease using RNA interference. Nat Rev Genet 2007; 8: 173–184.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nrg2006&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17304245&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000244274400011&link_type=ISI) 

134.134. Meister G, Tuschl T.  Mechanisms of gene silencing by double-stranded RNA. Nature 2004; 431: 343–349.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nature02873&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=15372041&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000223864000050&link_type=ISI) 

135.135. Rana TM.  Illuminating the silence: understanding the structure and function of small RNAs. Nat Rev Mol Cell Biol 2007; 8: 23–36.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nrm2085&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17183358&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000243005100012&link_type=ISI) 

136.136. Petrocca F, Lieberman J.  Promise and challenge of RNA interference-based therapy for cancer. J Clin Oncol 2011; 29: 747–754.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiamNvIjtzOjU6InJlc2lkIjtzOjg6IjI5LzYvNzQ3IjtzOjQ6ImF0b20iO3M6MTc6Ii9jYm0vOS8zLzE1MS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

137.137. Yezhelyev MV, Qi L, O'Regan RM, et al.  Proton-sponge coated quantum dots for siRNA delivery and intracellular imaging. J Am Chem Soc 2008; 130: 9006–9012.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/ja800086u&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18570415&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000257507400030&link_type=ISI) 

138.138. Triesscheijn M, Baas P, Schellens JH, et al.  Photodynamic therapy in oncology. Oncologist 2006; 11: 1034–1044.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTM6InRoZW9uY29sb2dpc3QiO3M6NToicmVzaWQiO3M6OToiMTEvOS8xMDM0IjtzOjQ6ImF0b20iO3M6MTc6Ii9jYm0vOS8zLzE1MS5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

139.139. Samia AC, Chen X, Burda C.  Semiconductor quantum dots for photodynamic therapy. J Am Chem Soc 2003; 125: 15736–15737.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/ja0386905&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=14677951&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

140.140. Hardman R.  A toxicologic review of quantum dots: toxicity depends on physicochemical and environmental factors. Environ Health Perspect 2006; 114: 165–172.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1289/ehp.8284&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=16451849&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000235226300032&link_type=ISI) 

141.141. Rzigalinski BA, Strobl JS.  Cadmium-containing nanoparticles: perspectives on pharmacology and toxicology of quantum dots. Toxicol Appl Pharmacol 2009; 238: 280–288.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1016/j.taap.2009.04.010&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19379767&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

142.142. Choi HS, Liu W, Liu F, et al.  Design considerations for tumour-targeted nanoparticles. Nat Nanotechnol 2010; 5: 42–47.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nnano.2009.314&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19893516&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000274652200014&link_type=ISI) 

143.143. Howarth M, Liu W, Puthenveetil S, et al.  Monovalent, reduced-size quantum dots for imaging receptors on living cells. Nat Methods 2008; 5: 397–399.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nmeth.1206&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18425138&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000255411700013&link_type=ISI) 

144.144. Shiohara A, Hanada S, Prabakar S, et al.  Chemical reactions on surface molecules attached to silicon quantum dots. J Am Chem Soc 2010; 132: 248–253.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/ja906501v&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20000400&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000275084400057&link_type=ISI) 

145.145. Smith AM, Nie S.  Next-generation quantum dots. Nat Biotechnol 2009; 27: 732–733.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nbt0809-732&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=19668181&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000268774500022&link_type=ISI) 

146.146. Warner JH, Hoshino A, Yamamoto K, et al.  Water-soluble photoluminescent silicon quantum dots. Angew Chem Int Ed Engl 2005; 44: 4550–4554.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1002/anie.200501256&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=15973756&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

147.147. Erogbogbo F, Tien CA, Chang CW, et al.  Bioconjugation of luminescent silicon quantum dots for selective uptake by cancer cells. Bioconjug Chem 2011; 22: 1081–1088.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/bc100552p&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21473652&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

148.148. Bottrill M, Green M.  Some aspects of quantum dot toxicity. Chem Commun (Camb) 2011; 47: 7039–7050.
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=21475767&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

149.149. Dobrovolskaia MA, McNeil SE.  Immunological properties of engineered nanomaterials. Nat Nanotechnol 2007; 2: 469–478.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nnano.2007.223&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=18654343&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000249062900010&link_type=ISI) 

150.150. Choi AO, Brown SE, Szyf M, et al.  Quantum dot-induced epigenetic and genotoxic changes in human breast cancer cells. J Mol Med (Berl) 2008; 86: 291–302.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1007/s00109-007-0274-2&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17965848&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

151.151. Landin L, Miller MS, Pistol M, et al.  Optical studies of individual InAs quantum dots in GaAs: few-particle effects. Science 1998; 280: 262–264.
    
    [Abstract/FREE Full Text](http://www.cancerbiomed.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Mzoic2NpIjtzOjU6InJlc2lkIjtzOjEyOiIyODAvNTM2MS8yNjIiO3M6NDoiYXRvbSI7czoxNzoiL2NibS85LzMvMTUxLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

152.152. Pradhan N, Battaglia DM, Liu Y, et al.  Efficient, stable, small, and water-soluble doped ZnSe nanocrystal emitters as non-cadmium biomedical labels. Nano Lett 2007; 7: 312–317.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1021/nl062336y&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17297994&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 

153.153. Choi HS, Liu W, Misra P, et al.  Renal clearance of quantum dots. Nat Biotechnol 2007; 25: 1165–1170.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1038/nbt1340&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=17891134&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom) 
    
    [Web of Science](http://www.cancerbiomed.org/lookup/external-ref?access_num=000250226600028&link_type=ISI) 

154.154. Xu H, Chen C, Peng J, et al.  Evaluation of the bioconjugation efficiency of different quantum dots as probes for immunostaining tumor-marker proteins. Appl Spectrosc 2010; 64: 847–852.
    
    [CrossRef](http://www.cancerbiomed.org/lookup/external-ref?access_num=10.1366/000370210792081154&link_type=DOI) 
    
    [PubMed](http://www.cancerbiomed.org/lookup/external-ref?access_num=20719046&link_type=MED&atom=%2Fcbm%2F9%2F3%2F151.atom)