Nanomaterials for Cancer Diagnosis and TherapyView this Special Issue
Application of Quantum Dots-Based Biotechnology in Cancer Diagnosis: Current Status and Future Perspectives
The semiconductor nanocrystal quantum dots (QDs) have excellent photo-physical properties, and the QDs-based probes have achieved encouraging developments in cellular and in vivo molecular imaging. More and more researches showed that QDs-based technology may become a promising approach in cancer research. In this review, we focus on recent application of QDs in cancer diagnosis and treatment, including early detection of primary tumor such as ovarian cancer, breast cancer, prostate cancer and pancreatic cancer, as well as regional lymph nodes and distant metastases. With the development of QDs synthesis and modification, the effect of QDs on tumor metastasis investigation will become more and more important in the future.
Cancer is a major public health problem in the world, and one in four deaths in the United States is due to cancer, with an estimated 1479350 new cancer cases and 562340 deaths from cancer expected in 2009 . Although progress has been made in reducing incidence and mortality rates and improving survival, cancer still accounts for more deaths than heart disease in persons younger than 85 years of age . One major challenge is how to diagnose cancer in early stage when curative treatment is possible. New technologies are required to dramatically improve the early detection and treatment of cancer, and fluorescent molecules can play a big role in this field [2, 3].
Nanotechnology is an emerging field that may have potentials to make paradigm changes in the detection, treatment, and prevention of cancer . The development of biocompatible nanoparticles for molecular targeted diagnosis and treatment is an area of considerable interest. The basic rationale is that nanoparticles have unique structural and functional properties different from those of discrete molecules or bulk materials [5, 6]. One of the most exciting advances in label technology is the development of quantum dots (QDs), a heterogeneous class of engineered nanoparticles with unique optical and chemical properties making them important nanoparticles with numerous potential applications ranging from medicine to energy [7, 8]. Used as in vitro and in vivo fluorophores, QDs are intensely studied in molecular, cellular, and in vivo imaging due to their novel optical and electronic properties [9–11]. To be different from those reviews focusing on the basic mechanisms and development of QDs, this review focuses on recent application of QDs in cancer diagnosis, including early detection of primary tumor such as ovarian cancer, breast cancer, prostate cancer, and pancreatic cancer, as well as regional lymph nodes and distant metastases.
2. QDs Properties
QDs are nanocrystals composed of a semiconductor core including group II-VI or group III-V elements encased within a shell comprised of a second semiconductor material. A typical QD has a diameter ranging from 2 to 10 nm containing roughly 200 to 10,000 atoms, with size comparable to a large protein. In comparison with organic dyes and fluorescent proteins, QDs have unique optical and electronic properties such as size- and composition-tunable light emission, improved signal brightness, resistance to photobleaching and simultaneous excitation of multiple fluorescence colors. In addition, different colors of QDs can be simultaneously excited with a single light source, with minimal spectral overlapping, which provides significant advantages for multiplexed detection of target molecules [10, 12–15] (Figure 1). However, as QDs are hydrophobic by nature, it is necessary to solubilize QDs before application by surface modification with biofunctional molecules , because QDs have large surface areas for the attachment of such molecules. When conjugated with diagnostic (e.g., optical) and therapeutic (e.g., anticancer) agents, QDs can be used for cancer diagnosis and therapy with high specificity [17–19]. Significant research efforts have been focused on cancer early diagnosis with QDs . As early as 2002, after overcoming the limitation in obtaining biocompatible nanocrystals, Dubertret  showed the potential to revolutionize biological imaging. In case of imaging probes, active targeting of cancer antigens (molecular imaging) has become an area of tremendous interest because of the potential to detect early stage cancers and their metastases [22–24]. Major recent developments in this regard are summarized in Table 1.
3. QDs-Based Detection of Primary Tumor
3.1. Ovarian Cancer
Ovarian cancer is the second most-common malignancy of the female genital tract and the leading cause of death from gynecological malignancies . Carbohydrate antigen 125 (CA 125) is an epithelial antigen and a useful tumor marker in the detection and therapy of ovarian cancer [34–36]. The ability to visualize native processes occurring in living organisms is invaluable for clinical diagnostic applications, yet it remains elusive in practice due to conventional imaging limitations and the availability of suitable fluorescence markers. Because of their unique photophysical properties, QDs are promising fluorophores for in vivo fluorescence imaging and can overcome many shortcomings of conventional dyes. Wang et al.  used QDs with maximum emission wavelength 605 nm (QD605) to detect CA125 in ovarian cancer specimens of different types (fixed cells, tissue sections, and xenograft tumor) with high specificity and sensitivity. Comparison between QDs and fluorescein isothiocyanate (FITC) showed that QDs labeling signals were brighter, more specific and stable than those of FITC. In another study, Nathwani  synthesized biocompatible QDs coated with a natural protein silk fibroin (SF) and used such QDs conjugates as a fluorescent label for successful bioimaging HEYA8 ovarian cancer cells. The properties of QDs have opened new possibilities for advanced molecular and cellular imaging as well as for ultrasensitive bioassays and diagnostics of ovarian cancer.
3.2. Breast Cancer
Wu et al.  explored a new technology to label HER2 (human epidermal growth factor receptor 2, HER2) on breast cancer cell membrane, which is known as c-erbB-2 or HER2/neu and overexpressed in approximately 25–30% invasive breast cancer [40, 41] and plays an important role in breast cancer prognosis and treatment selection [42–45]. After that, several studies on the detection of HER2 for breast cancer diagnosis with QDs have completed [46, 47]. Yezhelyev et al.  reported the use of multicolor QDs for quantitative and simultaneous profiling of multiple biomarkers using intact breast cancer cells and clinical specimens and the comparison between the new QDs-based molecular profiling technology with standard western blotting and fluorescence in situ hybridization (FISH). The multicolor bioconjugates were used for simultaneous detection of the five clinically significant tumor markers, including HER2 (QD-HER2), ER (QD-ER), PR (QD-PR), EGFR (QD-EGFR), and mTOR (QD-mTOR), in breast cancer cells MCF-7 and BT474. A quantitative correlation between the HER2 gene amplification and HER2 protein expression was detected using QD-Abs profiling. This study suggests the possibility of using conjugated QDs to detect low levels of HER2 protein expression, but the clinical relevance of that finding deserves further investigation. To overcome the limitation in the clinical application of those studies aforementioned, we recently used QDs conjugated with antibody for assessment of HER2 status in breast cancer . In our study, 700 patients with invasive breast cancer were enrolled, including 3 males and 697 females. The expression of HER2 in breast cancer was detected in an automated, quantitative, sensitive, and convenient way using our QDs-immunohistochemistry (QDs-IHC) analysis system. Compared with conventional IHC, the QDs-based approach is more sensitive, accurate, and economic, especially for cases of IHC (2+), which indicates that this new method may have potentials for clinical application, especially in developing countries (Figure 2).
3.3. Prostate Cancer
Adenocarcinoma of the prostate is the most common cancer for males in the West, with approximately 192,280 new cases and 27,360 deaths form this disease in 2009 in USA alone . Early diagnosis of prostate cancer is based on the prostate-specific antigen (PSA), and the introduction of PSA-based screening has revolutionized prostate cancer detection and ushered in the PSA era in which prostate cancer was detected at an earlier stage and in greater numbers than ever before [48, 49]. PSA is also an important prognostic marker of prostate cancer . Fluorescent probe conjugated with PSA provides a specific and sensitive tool for early prostate cancer imaging in vivo. With QDs probes conjugated to a PSMA monoclonal antibody (Ab), another marker for prostate cancer diagnosis and therapy, Gao et al.  have achieved sensitive and multicolor fluorescence imaging of cancer cells under in vivo conditions. Shi  showed the superior quality of QDs, in comparison to IHC, for the detection of androgen receptor (AR) and PSA in prostate cancer cells. Both of those two studies, showing the potential ability of QDs as a diagnosis technology, are good examples to demonstrate why QDs are promising nanoparticles for diagnostic applications . In another study, Gao et al.  demonstrated the potential of QDs as a new diagnosis technology for metastasis prostate cancer. Usually, antibodies conjugated to QDs are full-length antibody, which leads to dramatically reduced binding activities. Recently a study demonstrated that the use of single-chain antibody fragments (scFvs) conjugated with QDs appears to have a number of advantages, in terms of solubility, activity, ease of preparation and ease of structure-based genetic engineering, which were approved by detecting prostate cancer cells . Barua Rege  also developed a new method to identify prostate cancer cells with different phenotype by unconjugated QDs whose trafficking is cancer-cell-phenotype-dependent.
3.4. Pancreatic Cancer
The mean survival of pancreatic cancer is around 6 months, and less than 5% of all patients diagnosed with pancreatic cancer survive beyond 5 years [57, 58]. This dismal scenario is primarily due to the fact that most patients are diagnosed at advanced stage, due to the lack of specific symptoms and limitations in diagnostics . QDs can target the purpose of early diagnosis of pancreatic cancer , even at an early stage of development, with the help of proteins/peptides directed against overexpressed surface receptors on the cancer cells/tissues such as the transferring receptor, the antigen claudin-4 and urokinase plasminogen activator receptor (uPAR) .
Qian  used CdSe/CdS/ZnS QDs with improved photoluminescence efficiency and stability as optical agent for imaging pancreatic cancer cells using transferring and anti-Claudin-4. Pancreatic cancer specific uptake is also demonstrated using the monoclonal antibody anti-Claudin-4. This targeted QDs platform will be further modified to develop early detection imaging tool for pancreatic cancer.
Yong et al.  used non-cadmium-based QDs as highly efficient and nontoxic optical probes for imaging live pancreatic cancer cells. Further bioconjugation with pancreatic cancer specific monoclonal antibodies, such as anticlaudin 4, to the functionalized InP/ZnS QDs, allowed specific in vitro targeting of pancreatic cancer cell lines. The receptor-mediated delivery of the bioconjugates was further confirmed by the observation of poor in vitro targeting in nonpancreatic cancer cell lines without claudin-4-receptor. These observations suggest the immense potential of InP/ZnS QDs as non-cadmium-based safe and efficient optical imaging nanoprobes in diagnostic imaging.
4. QDs-Based Detection of Cancer Metastasis
Metastasis is a complex, multistep process by which primary tumor cells invade adjacent tissue, enter the systemic circulation (intravasate), translocate through the vasculature, arrest in distant capillaries, extravasate into the surrounding tissue parenchyma, and finally proliferate from microscopic growths (micrometastases) into macroscopic secondary tumors . Over the past 30 years, the study of cancer metastasis has grown exponentially, and a thorough historical review of the field by the late Leonard Weiss has been published , but the process of metastasis is still invisible. The vast majority of patients present with locally advanced or distant metastatic disease, rendering their malignancy surgically inoperable . As the origins of the invasive and metastatic phenotypes of carcinoma cells have been the subjects of intense investigation , a new model for visualizing the metastasis is needed. QDs-based technology shows advantages in detecting metastasis .
4.1. Blood-Born Metastasis to the Lungs
Most of the studies published in literature are focused on breast cancer and prostate cancer, and there is almost no report on the molecular imaging of hepatocellular carcinoma (HCC), especially HCC lung metastasis. HCC is the sixth most common cancer worldwide in terms of numbers of cases (626,000 or 5.7% of new cancer cases), but the number of deaths is almost the same (598,000) due to the very poor prognosis . Disease that is diagnosed at an advanced stage or with progression after locoregional therapy has a dismal prognosis, owing to the underlying liver disease, lack of effective treatment options and metastasis at early stage [69, 70]. It is documented that 82% of cases (and deaths) are in developing countries (55% in china alone) , but the incidence is also increasing in developed regions including Japan, West Europe, and the United States . Alpha-fetoprotein (AFP) is an important tumor marker for HCC [72–74]. In our prior study, we used CdSe/ZnS QDs with emission wavelength of 590 nm (QDs 590) linked to AFP monoclonal antibody (Ab) as a probe for fluorescence spectral analysis of HCC [75, 76]. In another study , we tested the biocompatibility, hemodynamics, tissues distribution of the QDs-AFP-Ab probes, and studied the imaging of HCC and its metastasis in vitro and in vivo. Our results indicate that such QDs-based probes have good stability, specificity and biocompatibility for ultrasensitive fluorescence imaging of molecular targets in our liver cancer model system (Figure 3).
4.2. Lymph Node Metastasis
Lymph metastasis is a major route of cancer progression. The state of lymph node draining from the tumor is essential for the diagnosis and therapy of cancer and has major prognostic implications [78, 79]. Sentinel lymph node (SLN) is much more likely to contain metastatic tumor cells than other lymph nodes in the same region. Among the various methods for SLN diagnosis, QDs have received increasing attention as lymph node delivery agents , and Kim  was the first to detect animal model SLN as deep as 1 cm subcutaneously. Near-infrared QDs are characterized by good tissue penetration and lower background, which are suitable for lymph node metastasis diagnosis [82, 83]. Ballou et al.  demonstrated that the QDs injected into two model tumors rapidly migrate to sentinel lymph nodes. Passage from the tumor through lymphatics to adjacent nodes could be visualized dynamically through the skin, and at least two nodes could be defined. Imaging during necropsy confirmed confinement of the QDs to the lymphatic system and demonstrated easy tagging of sentinel lymph nodes for pathology. In addition, examination of the sentinel nodes showed that at least some contained metastatic tumor foci.
The axillary nodal status is the most powerful prognostic factor for early stage breast cancer [85, 86]. Breast cancer patients routinely undergo surgical staging of the axilla because other primary tumor features are inadequate in predicting the presence versus absence of nodal positivity [87, 88]. Besides identifying the SLN of breast cancer , the state of lymph node draining from esophageal cancer was diagnosed successfully with near-infrared QDs, too . Kobayashi  visualized migration of QD-labeled melanoma cells within draining lymphatics. This technique could enable better understanding of lymph node metastasis.
5. Metabolism and Toxicity
QDs are promising novel nanoparticles for in vivo biomedical application. To assess their usefulness, it is important to characterize their behavior in vivo, rather than rely on ex vivo measurements and theoretical considerations alone . One obstacle to the in vivo study of QDs is the nonspecific uptake by reticuloendothelial system (RES) including the liver, spleen and lymph system. Particle size, surface coating and PEG-gylation influence the biodistribution of QDs. Nonspecific uptake can be decreased significantly by modifying the surface of QDs with appropriate coat/polymer, which results to prolonged plasma half-self [93–95]. In another way, Jayagopal and his colleagues  increased the in vivo circulation time and targeting efficiency by synthesizing QDs incorporating PEG crosslinkers and Fc-shielding mAb fragments. Comparison of the timecourse of fluorescence from Fc-shielded and non-Fc-shielded bioconjugates indicated nonspecific uptake and increased clearance of the non-Fc-shielded QD-mAb. This combination of QD surface design elements offers a promising new in vivo approach to specifically label vascular cell and biomolecules of interest. The in vivo distribution and metabolism of QDs have been studied in some researches, which showed that QDs were generally localized in liver, kidney, spleen, and lung [97–101]. However, there was no universal conclusion about the pathway of QDs clearance and its influence factors. Chen et al.  demonstrated that the metabolic pathway of QDs were closely correlated to their aggregation states, and three metabolic pathways were disclosed after intravenous injection: (1) the QDs that maintained their original nanosize without binding in vivo can be rapidly excreted via the kidney; (2) some QDs binding to proteins were translocated to the liver and excreted with feces; (3) an even smaller fraction of the QDs aggregated to larger particles and were retained in liver tissue for long time.
The most obvious challenge to QDs clinical use is the toxicity as most QDs contained heavy metal such as Cd2+. Release of Cd2+ from QDs will result to heavy metal toxicity, which limited the use of QDs. But it is still a controversy. Cho et al.  assessed the intracellular Cd2+ concentration in human breast cancer MCF-7 cells treated with cadmium telluride (CdTe) and core/shell cadmium selenide/zinc sulfide (CdSe/ZnS) nanoparticles capped with mercaptopropuonic acid (MPA), cysteamine (Cys), or N-acetylcysteine (NAC) conjugated to cysteamine. In cells incubated with CdTe QDs, the Cd2+ concentration determined by a Cd2+ specific cellular assay ranged from 30 to 150 nm, depending on the capping molecule. A cell viability assay revealed that CdSe/ZnS QDs were nontoxic, where the CdTe QDs were cytotoxic. However, for the various CdTe QDs samples, there was no dose-dependent correlation between cell viability and intracellular [Cd2+], implying that their cytotoxicity cannot be attributed solely to the toxic effect of free Cd2+. CdTe QDs capped with small organic ligands are cytotoxic, core shell CdSe/ZnS QDs present little damaging effects to cells. Those findings conform to with the consensus that the toxicity of QDs is not only Cd-dependent, but affected by many other factors including the size, surface charge, concentration, coat, oxidation, photo-degradation of QDs [104–107]. When injected into Xenopus embryos, the QDs were stable, and embryos displayed an unaltered phenotype and their health was similar to that of uninjected embryos ( QDs/cell). At higher injection concentration ( QDs/cell), abnormalities became apparent which may result from changes in the osmotic equilibrium of the cell . Lovric et al.  founded out that the size of QDs contributes to their subcellular distribution and pretreatment of cells with the antioxidant N-acetylcysteine and with bovine serum albumin, but not Trolox, significantly reduced the QD-induced cell death. QDs induce cell death via mechanisms involving both Cd2+ and reactive oxygen species (ROS) accompanied by lysosomal enlargement and intracellular redistribution . Other mechanisms of cell death induced by QDs have been revealed. In a study focused on the cellular calcium homeostasis dysregulation caused by QDs , it was found that unmodified QDs can induce neuron death dose dependently, via two possible mechanisms: (a) elevated cytoplasmic calcium levels for an extended period by QDs treatment, due to both extracellular calcium influx and internal calcium release from endoplasmic reticulum; and (b) QDs treatment enhanced activation and inactivation of I-Na, prolonged the time course of activation, slowed I-Na recovery, and reduced the fraction of available voltage-gated sodium channel (VGSC). Therefore, although QDs provide potential invaluable benefit, there are still biosafety considerations for in vivo imaging clinically.
6. Future Perspectives
It is clear that as biocompatible QDs are developed they will make powerful basic probes and research tools, and the delivery of QDs/QD biocomjugates is strongly affected by the nature of both the QDs conjugates and the cell types utilized . A lot of techniques about QDs have been improved with the development of new QDs, major issues need to be resolved in the near future. (1) As surface and function modification endue QDs more advantages, QDs become too large for medical imaging with the diameter up to 100 nm; (2) For the stereospecific blockade effect, it is not clear how many functional molecules can conjugate to one QD, which hold back the quantification in molecular detection. (3) FRET is based on individual QDs for QDs deep in aggregation cannot be acting as energy donor, how to avoid the aggregation of QDs in vivo is an important practical issue; (4) More studies on the toxicity of QDs are needed [53, 112–115]. (5) For the ethics reason, there is no clinical trail of QDs with large samples. Though it is revealed that QDs are stable in animal [98, 102, 116], more research about kinetics and toxicity of QDs in human are needed before extensive application for clinical diagnosis and therapy .
Since the first report about the application of QDs in biology in 1998, there has been no doubt about the advantages of QDs for long fluorescence time and photo-stability . QDs offer a powerful new tool for illuminating the complex labyrinth of signal transduction pathways and uncovering the intricacies of biomolecular interaction within cells. Remarkably, QDs-base intracellular probes have advantages concurrently with superresolution optical imaging techniques, a combination of the two techniques promises to reveal the mysteries of cellular biology in unprecedented detail [17, 118, 119]. As much technologies based on QDs such as FISH, FRET, and BRET will provide an opportunity for optimizing the treatment of cancer. Cancer therapy will be influenced by QDs significantly. The National Institutes Health (NIH) and the National Nanotechnology Initiative (NNI) are investing into nanomedicine in general and resolving QD toxicity issues for medical applications in particular [120–122]. The NIH expects that over half of the biomedical advances by 2010 will be in the nanotechnology sector, and by that time, the projected market growth for molecular imaging is $45 billion . The most promising applications of QDs in cancer are tumor detection, tissue imaging, intracellular imaging, immunohistochemistry, multiplexed diagnostics, and fluoroimmunoassays. All in all, the potential of QDs is immense and would shed a new light on various medical applications.
In summary, the use of QDs in cancer investigations has increased dramatically due to their unique size-dependent optical properties. Bioconjugated near-infrared QDs probes are highly sensitive molecular imaging tools for in vivo study. Further development of QDs might enable their application in detecting and localizing metastasis, quantitative measurement of molecular targets to facilitate targeted therapy, tracking drug delivery, and monitoring the efficacy of therapeutics noninvasively in real time.
This research was supported by the grants from the New-Century Excellent Talents Supporting Program of the Ministry of Education of China (no. NCET-04-0669), the Natural Science Foundation of China (no. 20675058), the Science Fund for Creative Research Groups of the National Natural Science Foundation of China (no. 20621502).
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