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Yun Y, Kim S, Lee SN, Cho HY, Choi JW. Nanomaterial-based detection of circulating tumor cells and circulating cancer stem cells for cancer immunotherapy. NANO CONVERGENCE 2024; 11:56. [PMID: 39671082 PMCID: PMC11645384 DOI: 10.1186/s40580-024-00466-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Accepted: 12/04/2024] [Indexed: 12/14/2024]
Abstract
Nanomaterials have emerged as transformative tools for detecting circulating tumor cells (CTCs) and circulating cancer stem cells (CCSCs), significantly enhancing cancer diagnostics and immunotherapy. Nanomaterials, including those composed of gold, magnetic materials, and silica, have enhanced the sensitivity, specificity, and efficiency of isolating these rare cells from blood. These developments are of paramount importance for the early detection of cancer and for providing real-time insights into metastasis and treatment resistance, which are essential for the development of personalized immunotherapies. The combination of nanomaterial-based platforms with phenotyping techniques, such as Raman spectroscopy and microfluidics, enables researchers to enhance immunotherapy protocols targeting specific CTC and CCSC markers. Nanomaterials also facilitate the targeted delivery of immunotherapeutic agents, including immune checkpoint inhibitors and therapeutic antibodies, directly to tumor cells. This synergistic approach has the potential to enhance therapeutic efficacy and mitigate the risk of metastasis and relapse. In conclusion, this review critically examines the use of nanomaterial-driven detection systems for detecting CTCs and CCSCs, their application in immunotherapy, and suggests future directions, highlighting their potential to transform the integration of diagnostics and treatment, thereby paving the way for more precise and personalized cancer therapies.
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Affiliation(s)
- Yeochan Yun
- Department of Bio and Fermentation Convergence Technology, Kookmin University, 77 Jeongneung-ro, Seongbuk-gu, Seoul, 02707, Republic of Korea
| | - Seewoo Kim
- Department of Chemical and Biomolecular Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul, 04107, Republic of Korea
| | - Sang-Nam Lee
- Uniance Gene Inc., 273, Digital-ro, Guro-gu, Seoul, 08381, Republic of Korea.
| | - Hyeon-Yeol Cho
- Department of Bio and Fermentation Convergence Technology, Kookmin University, 77 Jeongneung-ro, Seongbuk-gu, Seoul, 02707, Republic of Korea.
| | - Jeong-Woo Choi
- Department of Chemical and Biomolecular Engineering, Sogang University, 35 Baekbeom-ro, Mapo-gu, Seoul, 04107, Republic of Korea.
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Kane GI, Brassil ML, Diaz-Infante MB, Atukorale PU. Nanocarrier design for pathogen-inspired innate immune agonist delivery. Trends Immunol 2024; 45:678-692. [PMID: 39191543 PMCID: PMC11492413 DOI: 10.1016/j.it.2024.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/23/2024] [Accepted: 07/25/2024] [Indexed: 08/29/2024]
Abstract
In complex diseases such as cancer, modulating cytokine signatures of disease using innate immune agonists holds therapeutic promise. Novel multi-agonist treatments offer tunable control of the immune system because they are uniquely pathogen inspired, eliciting robust antitumor responses by promoting synergistic cytokine responses. However, the chief strategic hurdle is ensuring multi-agonist delivery to the same target cells, highlighting the importance of using nanomaterial-based carriers. Here, we place nanocarriers in center stage and review the delivery hurdles related to the varying extra- and intracellular localizations of innate immune receptors. We discuss a range of nanomaterials used for multi-agonist delivery, highlighting their respective benefits and drawbacks. Our overarching stance is that rational nanocarrier design is crucial for developing pathogen-inspired multi-agonist immunotherapies.
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Affiliation(s)
- Griffin I Kane
- Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, MA, USA; UMass Cancer Center, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Meghan L Brassil
- Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, MA, USA; UMass Cancer Center, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Miranda B Diaz-Infante
- Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, MA, USA; UMass Cancer Center, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Prabhani U Atukorale
- Department of Biomedical Engineering, University of Massachusetts Amherst, Amherst, MA, USA; Department of Molecular, Cell, and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA, USA; Division of Innate Immunity, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA; UMass Cancer Center, University of Massachusetts Chan Medical School, Worcester, MA, USA.
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Fathi-Karkan S, Sargazi S, Shojaei S, Farasati Far B, Mirinejad S, Cordani M, Khosravi A, Zarrabi A, Ghavami S. Biotin-functionalized nanoparticles: an overview of recent trends in cancer detection. NANOSCALE 2024; 16:12750-12792. [PMID: 38899396 DOI: 10.1039/d4nr00634h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/21/2024]
Abstract
Electrochemical bio-sensing is a potent and efficient method for converting various biological recognition events into voltage, current, and impedance electrical signals. Biochemical sensors are now a common part of medical applications, such as detecting blood glucose levels, detecting food pathogens, and detecting specific cancers. As an exciting feature, bio-affinity couples, such as proteins with aptamers, ligands, paired nucleotides, and antibodies with antigens, are commonly used as bio-sensitive elements in electrochemical biosensors. Biotin-avidin interactions have been utilized for various purposes in recent years, such as targeting drugs, diagnosing clinically, labeling immunologically, biotechnology, biomedical engineering, and separating or purifying biomolecular compounds. The interaction between biotin and avidin is widely regarded as one of the most robust and reliable noncovalent interactions due to its high bi-affinity and ability to remain selective and accurate under various reaction conditions and bio-molecular attachments. More recently, there have been numerous attempts to develop electrochemical sensors to sense circulating cancer cells and the measurement of intracellular levels of protein thiols, formaldehyde, vitamin-targeted polymers, huwentoxin-I, anti-human antibodies, and a variety of tumor markers (including alpha-fetoprotein, epidermal growth factor receptor, prostate-specific Ag, carcinoembryonic Ag, cancer antigen 125, cancer antigen 15-3, etc.). Still, the non-specific binding of biotin to endogenous biotin-binding proteins present in biological samples can result in false-positive signals and hinder the accurate detection of cancer biomarkers. This review summarizes various categories of biotin-functional nanoparticles designed to detect such biomarkers and highlights some challenges in using them as diagnostic tools.
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Affiliation(s)
- Sonia Fathi-Karkan
- Natural Products and Medicinal Plants Research Center, North Khorasan University of Medical Sciences, Bojnurd, 94531-55166 Iran.
- Department of Advanced Sciences and Technologies in Medicine, School of Medicine, North Khorasan University of Medical Sciences, Bojnurd 9414974877, Iran.
| | - Saman Sargazi
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran.
- Department of Clinical Biochemistry, School of Medicine, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Shirin Shojaei
- Nano Drug Delivery Research Center, Health Technology Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran.
| | - Bahareh Farasati Far
- Department of Chemistry, Iran University of Science and Technology, Tehran, Iran.
| | - Shekoufeh Mirinejad
- Cellular and Molecular Research Center, Research Institute of Cellular and Molecular Sciences in Infectious Diseases, Zahedan University of Medical Sciences, Zahedan, Iran.
| | - Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University, 28040 Madrid, Spain
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), 28040 Madrid, Spain
| | - Arezoo Khosravi
- Department of Genetics and Bioengineering, Faculty of Engineering and Natural Sciences, Istanbul Okan University, Istanbul 34959, Turkiye.
| | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul 34396, Turkiye.
- Department of Research Analytics, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai - 600 077, India
- Graduate School of Biotechnology and Bioengineering, Yuan Ze University, Taoyuan 320315, Taiwan
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3T 2N2, Canada.
- Faculty of Medicine in Zabrze, University of Technology in Katowice, 41-800 Zabrze, Poland
- Research Institute of Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
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Yadav A, Kumar A, Siddiqui MH. Detection of circulating tumour cells in colorectal cancer: Emerging techniques and clinical implications. World J Clin Oncol 2021; 12:1169-1181. [PMID: 35070736 PMCID: PMC8716996 DOI: 10.5306/wjco.v12.i12.1169] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 07/15/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Despite several advances in oncological management of colorectal cancer, morbidity and mortality are still high and devastating. The diagnostic evaluation by endoscopy is cumbersome, which is uncomfortable to many. Because of the intra- and inter-tumour heterogeneity and changing tumour dynamics, which is continuous in nature, the diagnostic biopsy and assessment of the pathological sample are difficult and also not adequate. Late manifestation of the disease and delayed diagnosis may lead to relapse or metastases. One of the keys to improving the outcome is early detection of cancer, ease of technology to detect with uniformity, and its therapeutic implications, which are yet to come. "Liquid biopsy" is currently the most recent area of interest in oncology, which may provide important tools regarding the characterization of the primary tumour and its metastasis as cancer cells shed into the bloodstream even at the early stages of the disease. By using this approach, clinicians may be able to find out information about the tumour at a given time. Any of the following three types of sampling of biological material can be used in the "liquid biopsy". These are circulating tumour cells (CTCs), circulating tumour DNA, and exosomes. The most commonly studied amongst the three is CTCs. CTCs with their different applications and prognostic value has been found useful in colorectal cancer detection and therapeutics. In this review, we will discuss various markers for CTCs, the core tools/techniques for detection, and also important findings of clinical studies in colorectal cancer and its clinical implications.
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Affiliation(s)
- Alka Yadav
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
| | - Ashok Kumar
- Department of Surgical Gastroenterology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow 226014, Uttar Pradesh, India
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Fabrication of Formalin-Fixed, Paraffin-Embedded (FFPE) Circulating Tumor Cell (CTC) Block Using a Hydrogel Core-Mediated Method. MICROMACHINES 2021; 12:mi12091128. [PMID: 34577771 PMCID: PMC8466852 DOI: 10.3390/mi12091128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/17/2021] [Accepted: 09/18/2021] [Indexed: 12/24/2022]
Abstract
Circulating tumor cells (CTCs) are extremely low-frequency cells in the bloodstream. As those cells have detached from the primary tumor tissues and it circulates throughout the whole body, they are considered as promising diagnostic biomarkers for clinical application. However, the analysis of CTC is often restricted due to their rarity and heterogeneity, as well as their short-term presence. Here we proposed formalin-fixed, paraffin-embedded (FFPE) CTC block method, in combination manner with the hydrogel core-mediated CTC accumulation and conventional paraffin tissue block preparation. The hydrogel core specifically captures and releases cancer cells with high efficiency with an immunoaffinity manner. An additional shell structure protects the isolated cancer cells during the FFPE CTC block preparation process. The fabricated FFPE CTC block was sectioned and cytopathologically investigated just the same way as the conventional tissue block. Our results demonstrate that rare cells such as CTCs can also be prepared for FFPE cell blocks and shows great promise for cytopathological CTC studies.
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Polymeric Lipid Hybrid Nanoparticles (PLNs) as Emerging Drug Delivery Platform-A Comprehensive Review of Their Properties, Preparation Methods, and Therapeutic Applications. Pharmaceutics 2021; 13:pharmaceutics13081291. [PMID: 34452251 PMCID: PMC8399620 DOI: 10.3390/pharmaceutics13081291] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2021] [Revised: 08/11/2021] [Accepted: 08/12/2021] [Indexed: 12/13/2022] Open
Abstract
Polymeric lipid hybrid nanoparticles (PLNs) are core–shell nanoparticles made up of a polymeric kernel and lipid/lipid–PEG shells that have the physical stability and biocompatibility of both polymeric nanoparticles and liposomes. PLNs have emerged as a highly potent and promising nanocarrier for a variety of biomedical uses, including drug delivery and biomedical imaging, owing to recent developments in nanomedicine. In contrast with other forms of drug delivery systems, PLNs have been regarded as seamless and stable because they are simple to prepare and exhibit excellent stability. Natural, semi-synthetic, and synthetic polymers have been used to make these nanocarriers. Due to their small scale, PLNs can be used in a number of applications, including anticancer therapy, gene delivery, vaccine delivery, and bioimaging. These nanoparticles are also self-assembled in a reproducible and predictable manner using a single or two-step nanoprecipitation process, making them significantly scalable. All of these positive attributes therefore make PLNs an attractive nanocarrier to study. This review delves into the fundamentals and applications of PLNs as well as their formulation parameters, several drug delivery strategies, and recent advancements in clinical trials, giving a comprehensive insight into the pharmacokinetic and biopharmaceutical aspects of these hybrid nanoparticles.
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Recent Development of Nanomaterials-Based Cytosensors for the Detection of Circulating Tumor Cells. BIOSENSORS-BASEL 2021; 11:bios11080281. [PMID: 34436082 PMCID: PMC8391755 DOI: 10.3390/bios11080281] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/13/2021] [Accepted: 08/16/2021] [Indexed: 12/12/2022]
Abstract
The accurate analysis of circulating tumor cells (CTCs) holds great promise in early diagnosis and prognosis of cancers. However, the extremely low abundance of CTCs in peripheral blood samples limits the practical utility of the traditional methods for CTCs detection. Thus, novel and powerful strategies have been proposed for sensitive detection of CTCs. In particular, nanomaterials with exceptional physical and chemical properties have been used to fabricate cytosensors for amplifying the signal and enhancing the sensitivity. In this review, we summarize the recent development of nanomaterials-based optical and electrochemical analytical techniques for CTCs detection, including fluorescence, colorimetry, surface-enhanced Raman scattering, chemiluminescence, electrochemistry, electrochemiluminescence, photoelectrochemistry and so on.
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Cho HY, Choi JH, Lim J, Lee SN, Choi JW. Microfluidic Chip-Based Cancer Diagnosis and Prediction of Relapse by Detecting Circulating Tumor Cells and Circulating Cancer Stem Cells. Cancers (Basel) 2021; 13:1385. [PMID: 33803846 PMCID: PMC8003176 DOI: 10.3390/cancers13061385] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/14/2021] [Accepted: 03/16/2021] [Indexed: 12/21/2022] Open
Abstract
Detecting circulating tumor cells (CTCs) has been considered one of the best biomarkers in liquid biopsy for early diagnosis and prognosis monitoring in cancer. A major challenge of using CTCs is detecting extremely low-concentrated targets in the presence of high noise factors such as serum and hematopoietic cells. This review provides a selective overview of the recent progress in the design of microfluidic devices with optical sensing tools and their application in the detection and analysis of CTCs and their small malignant subset, circulating cancer stem cells (CCSCs). Moreover, discussion of novel strategies to analyze the differentiation of circulating cancer stem cells will contribute to an understanding of metastatic cancer, which can help clinicians to make a better assessment. We believe that the topic discussed in this review can provide brief guideline for the development of microfluidic-based optical biosensors in cancer prognosis monitoring and clinical applications.
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Affiliation(s)
- Hyeon-Yeol Cho
- Department of Bio & Fermentation Convergence Technology, Kookmin University, Seoul 02707, Korea;
- Interdisciplinary Program for Bio-health Convergence, Kookmin University, Seoul 02707, Korea
| | - Jin-Ha Choi
- Department of Chemical and Biomolecular Engineering, Sogang University, Seoul 04107, Korea; (J.-H.C.); (J.L.)
- School of Chemical Engineering, Jeonbuk National University, Jeonju 54896, Korea
| | - Joungpyo Lim
- Department of Chemical and Biomolecular Engineering, Sogang University, Seoul 04107, Korea; (J.-H.C.); (J.L.)
| | - Sang-Nam Lee
- Uniance Gene Inc., 1107 Teilhard Hall, 35 Baekbeom-Ro, Mapo-Gu, Seoul 04107, Korea
| | - Jeong-Woo Choi
- Department of Chemical and Biomolecular Engineering, Sogang University, Seoul 04107, Korea; (J.-H.C.); (J.L.)
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Liu P, Jonkheijm P, Terstappen LWMM, Stevens M. Magnetic Particles for CTC Enrichment. Cancers (Basel) 2020; 12:cancers12123525. [PMID: 33255978 PMCID: PMC7760229 DOI: 10.3390/cancers12123525] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 11/20/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary For the enrichment of very rare cells, such as Circulating Tumor Cells (CTCs), immunomagnetic enrichment is frequently used. For this purpose, magnetic nanoparticles (MNPs) coated with specific antibodies directed against cancer cells are used. In this review, we look at the properties such a particle needs to have in order to be used successfully, and describe the different methods used in the production of such a particle as well as the methods for their separation. Additionally, an overview is given of the antibodies that could potentially be used for this purpose. Abstract Here, we review the characteristics and synthesis of magnetic nanoparticles (MNPs) and place these in the context of their usage in the immunomagnetic enrichment of Circulating Tumor Cells (CTCs). The importance of the different characteristics is explained, the need for a very specific enrichment is emphasized and different (commercial) magnetic separation techniques are shown. As the specificity of an MNP is in a large part dependent on the antibody coated onto the particle, different strategies in the coupling of specific antibodies as well as an overview of the available antibodies is given.
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Affiliation(s)
- Peng Liu
- Department of Medical Cell BioPhysics, University of Twente, 7522 NB Enschede, The Netherlnds; (P.L.); (L.W.M.M.T.)
- Department of Molecular Nanofabrication, University of Twente, 7522 NB Enschede, The Netherlands;
| | - Pascal Jonkheijm
- Department of Molecular Nanofabrication, University of Twente, 7522 NB Enschede, The Netherlands;
| | - Leon W. M. M. Terstappen
- Department of Medical Cell BioPhysics, University of Twente, 7522 NB Enschede, The Netherlnds; (P.L.); (L.W.M.M.T.)
| | - Michiel Stevens
- Department of Medical Cell BioPhysics, University of Twente, 7522 NB Enschede, The Netherlnds; (P.L.); (L.W.M.M.T.)
- Correspondence: ; Tel.: +31-53-489-4101
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Czaplicka M, Niciński K, Nowicka A, Szymborski T, Chmielewska I, Trzcińska-Danielewicz J, Girstun A, Kamińska A. Effect of Varying Expression of EpCAM on the Efficiency of CTCs Detection by SERS-Based Immunomagnetic Optofluidic Device. Cancers (Basel) 2020; 12:cancers12113315. [PMID: 33182636 PMCID: PMC7697545 DOI: 10.3390/cancers12113315] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2020] [Revised: 10/30/2020] [Accepted: 11/06/2020] [Indexed: 12/29/2022] Open
Abstract
Simple Summary In this work we present a magnetically supported SERS-based immunoassay based on solid SERS-active support for the detection of circulating tumor cells. The SERS response in our optofluidic device was correlated with the level of EpCAM expression. The level of EpCAM cell expression in four cell lines with relatively high (human metastatic prostate adenocarcinoma cells (LNCaP)), medium (human metastatic prostate adenocarcinoma cells (LNCaP)), weak (human metastatic prostate adenocarcinoma cells (LNCaP)), and no EpCAM expressions (cervical cancer cells (HeLa) has been estimated using Western Blot method supported by immunochemistry and correlated with responses of immunomagnetic SERS-based analysis. The capture efficiency of developed assay was investigated in metastatic lung cancer patients. The assay demonstrates the capability to detect circulating tumor cells from blood samples over a broad linear range (from 1 to 100 cells/mL) reflecting clinically relevant amount of CTCs depending on the stage of metastasis, age, applied therapy. Abstract The circulating tumor cells (CTCs) isolation and characterization has a great potential for non-invasive biopsy. In the present research, the surface–enhanced Raman spectroscopy (SERS)-based assay utilizing magnetic nanoparticles and solid SERS-active support integrated in the external field assisted microfluidic device was designed for efficient isolation of CTCs from blood samples. Magnetic nanospheres (Fe2O3) were coated with SERS-active metal and then modified with p-mercaptobenzoic acid (p-MBA) which works simultaneously as a Raman reporter and linker to an antiepithelial-cell-adhesion-molecule (anti-EpCAM) antibodies. The newly developed laser-induced SERS-active silicon substrate with a very strong enhancement factor (up to 108) and high stability and reproducibility provide the additional extra-enhancement in the sandwich plasmonic configuration of immune assay which finally leads to increase the efficiency of detection. The sensitive immune recognition of cancer cells is assisted by the introducing of the controllable external magnetic field into the microfluidic chip. Moreover, the integration of the SERS-active platform and p-MBA-labeled immuno-Ag@Fe2O3 nanostructures with microfluidic device offers less sample and analytes demand, precise operation, increase reproducibly of spectral responses, and enables miniaturization and portability of the presented approach. In this work, we have also investigated the effect of varying expression of the EpCAM established by the Western Blot method supported by immunochemistry on the efficiency of CTCs’ detection with the developed SERS method. We used four target cancer cell lines with relatively high (human metastatic prostate adenocarcinoma cells (LNCaP)), medium (human metastatic prostate adenocarcinoma cells (LNCaP)), weak (human metastatic prostate adenocarcinoma cells (LNCaP)), and no EpCAM expressions (cervical cancer cells (HeLa)) to estimate the limits of detection based on constructed calibration curves. Finally, blood samples from lung cancer patients were used to validate the efficiency of the developed method in clinical trials.
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Affiliation(s)
- Marta Czaplicka
- Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; (M.C.); (K.N.); (A.N.); (T.S.)
| | - Krzysztof Niciński
- Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; (M.C.); (K.N.); (A.N.); (T.S.)
| | - Ariadna Nowicka
- Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; (M.C.); (K.N.); (A.N.); (T.S.)
| | - Tomasz Szymborski
- Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; (M.C.); (K.N.); (A.N.); (T.S.)
| | - Izabela Chmielewska
- Department of Pneumology, Oncology and Allergology, Medical University of Lublin, Jaczewskiego 8, 20-950 Lublin, Poland;
| | - Joanna Trzcińska-Danielewicz
- Department of Molecular Biology, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland; (J.T.-D.); (A.G.)
| | - Agnieszka Girstun
- Department of Molecular Biology, Institute of Biochemistry, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096 Warsaw, Poland; (J.T.-D.); (A.G.)
| | - Agnieszka Kamińska
- Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland; (M.C.); (K.N.); (A.N.); (T.S.)
- Correspondence:
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The Significance of Circulating Tumor Cells in Patients with Hepatocellular Carcinoma: Real-Time Monitoring and Moving Targets for Cancer Therapy. Cancers (Basel) 2020; 12:cancers12071734. [PMID: 32610709 PMCID: PMC7408113 DOI: 10.3390/cancers12071734] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/26/2020] [Accepted: 06/27/2020] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is ranked as the sixth most common cancer around the world. With the emergence of the state-of-the-art modalities lately, such as liver transplantation, image-guided ablation, and chemoembolization, the death rate is still high due to high metastasis rate after therapy. Observation by biannual ultrasonography allows effective diagnosis at an early stage for candidates with no extrahepatic metastasis, but its effectiveness still remains unsatisfactory. Developing a new test with improved effectiveness and specificity is urgently needed for HCC diagnosis, especially for patients after first line therapy. Circulating tumor cells (CTCs) are a small sub-population of tumor cells in human peripheral blood, they release from the primary tumor and invade into the blood circulatory system, thereby residing into the distal tissues and survive. As CTCs have specific and aggressive properties, they can evade from immune defenses, induce gene alterations, and modulate signal transductions. Ultimately, CTCs can manipulate tumor behaviors and patient reactions to anti-tumor treatment. Given the fact that in HCC blood is present around the immediate vicinity of the tumor, which allows thousands of CTCs to release into the blood circulation daily, so CTCs are considered to be the main cause for HCC occurrence, and are also a pivotal factor for HCC prognosis. In this review, we highlight the characteristics and enrichment strategies of CTCs, and focus on the use of CTCs for tumor evaluation and management in patients with HCC.
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Wang S, Hong S, Cai S, Lei J, Chen J, Zhang N, Ai Z, Liu K, Tang M. Negative depletion mediated brightfield circulating tumour cell identification strategy on microparticle-based microfluidic chip. J Nanobiotechnology 2020; 18:70. [PMID: 32381091 PMCID: PMC7206695 DOI: 10.1186/s12951-020-00623-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 04/27/2020] [Indexed: 02/08/2023] Open
Abstract
Background The most convenient circulating tumor cells (CTCs) identification method is direct analysis of cells under bright field microscopy by which CTCs can be comprehensive studied based on morphology, phenotype or even cellular function. However, universal cell markers and a standard tumour cell map do not exist, thus limiting the clinical application of CTCs. Results This paper focuses on an automatic and convenient negative depletion strategy for circulating tumour cell identification under bright field microscopy. In this strategy, immune microparticles (IMPs) are applied to negatively label white blood cells rather than the tumour cells, such that tumour cells can be directly distinguished under brightfield of the microscopy. In this way, all of the heterogeneous tumour cells and their phenotype properties can be retained for further cancer-related studies. In addition, a wedge-shaped microfluidic chip is constructed for heterogeneous CTC pre-purification and enrichment by size, thus significantly decreasing the interference of haematological cells. Additionally, all cell treatments are processed automatically, and the tumour cells can be rapidly counted and distinguished via customized cell analytical software, showing high detection efficiency and automation. This IMPs based negative cell labelling strategy can also be combined with other classic cell identification methods, thus demonstrating its excellent compatibility. Conclusion This identification strategy features simple and harmless for tumour cells, as well as excellent accuracy and efficiency. And the low equipment demand and high automation level make it promise for extensive application in basic medical institutions.
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Affiliation(s)
- Shuibing Wang
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Engineering and Technology Research Center for Functional Fiber Fabrication and Testing, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Province Engineering Research Center for Intelligent Micro-nano Medical Equipment and Key Technologies, Wuhan, 30200, People's Republic of China
| | - Shaoli Hong
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Engineering and Technology Research Center for Functional Fiber Fabrication and Testing, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Province Engineering Research Center for Intelligent Micro-nano Medical Equipment and Key Technologies, Wuhan, 30200, People's Republic of China
| | - Shijia Cai
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China
| | - Jia Lei
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China
| | - Jinyao Chen
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China
| | - Nangang Zhang
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Engineering and Technology Research Center for Functional Fiber Fabrication and Testing, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Province Engineering Research Center for Intelligent Micro-nano Medical Equipment and Key Technologies, Wuhan, 30200, People's Republic of China
| | - Zhao Ai
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Engineering and Technology Research Center for Functional Fiber Fabrication and Testing, Wuhan Textile University, Wuhan, 430200, People's Republic of China.,Hubei Province Engineering Research Center for Intelligent Micro-nano Medical Equipment and Key Technologies, Wuhan, 30200, People's Republic of China
| | - Kan Liu
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China. .,Hubei Engineering and Technology Research Center for Functional Fiber Fabrication and Testing, Wuhan Textile University, Wuhan, 430200, People's Republic of China. .,Hubei Province Engineering Research Center for Intelligent Micro-nano Medical Equipment and Key Technologies, Wuhan, 30200, People's Republic of China.
| | - Man Tang
- School of Electronic and Electrical Engineering, Wuhan Textile University, Wuhan, 430200, People's Republic of China. .,Hubei Engineering and Technology Research Center for Functional Fiber Fabrication and Testing, Wuhan Textile University, Wuhan, 430200, People's Republic of China. .,Hubei Province Engineering Research Center for Intelligent Micro-nano Medical Equipment and Key Technologies, Wuhan, 30200, People's Republic of China.
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13
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Unni M, Zhang J, George TJ, Segal MS, Fan ZH, Rinaldi C. Engineering magnetic nanoparticles and their integration with microfluidics for cell isolation. J Colloid Interface Sci 2020; 564:204-215. [PMID: 31911225 PMCID: PMC7023483 DOI: 10.1016/j.jcis.2019.12.092] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 12/19/2019] [Accepted: 12/20/2019] [Indexed: 01/09/2023]
Abstract
Isolation of cancer cells, bacteria, and viruses from peripheral blood has important applications in cancer diagnosis, therapy monitoring, and drug development. Magnetic particles functionalized with antibodies that target receptors of cancer cells have been shown to isolate such entities using magnetic field gradients. Here, we report enhancement in capture efficiency and specificity by engineering magnetic nanoparticles and integrating them with microfluidics for the enumeration of tumor cells. Nanoparticles were made from iron oxide, coated with poly(ethylene glycol), and conjugated through avidin-biotin chemistry with antibody specifically against epithelial cell adhesion molecule (EpCAM). On exposure of targeted nanoparticles to tumor cells, specific uptake by EpCAM-expressing tumor cells (e.g., BxPC3, a pancreatic cancer cell) was observed, whereas there was negligible uptake by cells with low EpCAM expression (e.g., CCRF-CEM, a leukemia cell). Using an arrangement of magnets called a Halbach array, capture efficiency and specificity towards BxPC3 cells tagged with magnetic nanoparticles were enhanced, compared to conditions without the magnetic field gradient and/or without magnetic nanoparticles, either in buffer or in whole blood. These results illustrate that engineered magnetic nanoparticles and their integration with microfluidics have great potential for tumor cell enumeration and cancer prognosis.
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Affiliation(s)
- Mythreyi Unni
- Department of Chemical Engineering, Gainesville, FL 32611, USA
| | - Jinling Zhang
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, Gainesville, FL 32611, USA
| | - Thomas J George
- Department of Medicine, Gainesville, FL 32611, USA; University of Florida Health Cancer Center, Gainesville, FL 32611, USA
| | - Mark S Segal
- Department of Medicine, Gainesville, FL 32611, USA
| | - Z Hugh Fan
- Interdisciplinary Microsystems Group, Department of Mechanical and Aerospace Engineering, Gainesville, FL 32611, USA; J. Crayton Pruitt Family Department of Biomedical Engineering, Gainesville, FL 32611, USA; Department of Chemistry, University of Florida, Gainesville, FL 32611, USA; University of Florida Health Cancer Center, Gainesville, FL 32611, USA.
| | - Carlos Rinaldi
- Department of Chemical Engineering, Gainesville, FL 32611, USA; J. Crayton Pruitt Family Department of Biomedical Engineering, Gainesville, FL 32611, USA; University of Florida Health Cancer Center, Gainesville, FL 32611, USA.
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14
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Lin Z, Luo G, Du W, Kong T, Liu C, Liu Z. Recent Advances in Microfluidic Platforms Applied in Cancer Metastasis: Circulating Tumor Cells' (CTCs) Isolation and Tumor-On-A-Chip. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2020; 16:e1903899. [PMID: 31747120 DOI: 10.1002/smll.201903899] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 10/13/2019] [Indexed: 05/03/2023]
Abstract
Cancer remains the leading cause of death worldwide despite the enormous efforts that are made in the development of cancer biology and anticancer therapeutic treatment. Furthermore, recent studies in oncology have focused on the complex cancer metastatic process as metastatic disease contributes to more than 90% of tumor-related death. In the metastatic process, isolation and analysis of circulating tumor cells (CTCs) play a vital role in diagnosis and prognosis of cancer patients at an early stage. To obtain relevant information on cancer metastasis and progression from CTCs, reliable approaches are required for CTC detection and isolation. Additionally, experimental platforms mimicking the tumor microenvironment in vitro give a better understanding of the metastatic microenvironment and antimetastatic drugs' screening. With the advancement of microfabrication and rapid prototyping, microfluidic techniques are now increasingly being exploited to study cancer metastasis as they allow precise control of fluids in small volume and rapid sample processing at relatively low cost and with high sensitivity. Recent advancements in microfluidic platforms utilized in various methods for CTCs' isolation and tumor models recapitulating the metastatic microenvironment (tumor-on-a-chip) are comprehensively reviewed. Future perspectives on microfluidics for cancer metastasis are proposed.
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Affiliation(s)
- Zhengjie Lin
- College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, 518060, China
| | - Guanyi Luo
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Weixiang Du
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Tiantian Kong
- Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging, Department of Biomedical Engineering, School of Medicine, Shenzhen University, Shenzhen, 518060, China
| | - Changkun Liu
- College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, 518060, China
| | - Zhou Liu
- College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, 518060, China
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15
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Zhang Q, Wang W, Huang S, Yu S, Tan T, Zhang JR, Zhu JJ. Capture and selective release of multiple types of circulating tumor cells using smart DNAzyme probes. Chem Sci 2020; 11:1948-1956. [PMID: 34123289 PMCID: PMC8148068 DOI: 10.1039/c9sc04309h] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 01/06/2020] [Indexed: 12/11/2022] Open
Abstract
The effective capture, release and reanalysis of circulating tumor cells (CTCs) are of great significance to acquire tumor information and promote the progress of tumor therapy. Particularly, the selective release of multiple types of CTCs is critical to further study; however, it is still a great challenge. To meet this challenge, we designed a smart DNAzyme probe-based platform. By combining multiple targeting aptamers and multiple metal ion responsive DNAzymes, efficient capture and selective release of multiple types CTCs were realized. Sgc8c aptamer integrated Cu2+-dependent DNAzyme and TD05 aptamer integrated Mg2+-dependent DNAzyme can capture CCRF-CEM cells and Ramos cells respectively on the substrate. With the addition of Cu2+ or Mg2+, CCRF-CEM cells or Ramos cells will be released from the substrate with specific selectivity. Furthermore, our platform has been successfully demonstrated in the whole blood sample. Therefore, our capture/release platform will benefit research on the molecular analysis of CTCs after release and has great potential for cancer diagnosis and individualized treatment.
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Affiliation(s)
- Qianying Zhang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University Nanjing 210023 China
| | - Wenjing Wang
- State Key Laboratory of Agricultural Microbiology, College of Science, Huazhong Agricultural University Wuhan 430070 China
| | - Shan Huang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University Nanjing 210023 China
| | - Sha Yu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University Nanjing 210023 China
| | - Tingting Tan
- Department of Laboratory Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing 210008 China
| | - Jian-Rong Zhang
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University Nanjing 210023 China
- School of Chemistry and Life Science, Nanjing University Jinling College Nanjing 210089 China
| | - Jun-Jie Zhu
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University Nanjing 210023 China
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16
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17
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Abstract
Circulating tumor cells (CTCs) are responsible for the metastatic spread of cancer and therefore are extremely valuable not only for basic research on cancer metastasis but also as potential biomarkers in diagnosing and managing cancer in the clinic. While relatively non-invasive access to the blood tissue presents an opportunity, CTCs are mixed with approximately billion-times more-populated blood cells in circulation. Therefore, the accuracy of technologies for reliable enrichment of the rare CTC population from blood samples is critical to the success of downstream analyses. The focus of this chapter is to provide the reader an overview of significant advances made in the development of diverse CTC enrichment technologies by presenting the strengths of individual techniques in addition to specific challenges remaining to be addressed.
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18
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Li W, Wang H, Zhao Z, Gao H, Liu C, Zhu L, Wang C, Yang Y. Emerging Nanotechnologies for Liquid Biopsy: The Detection of Circulating Tumor Cells and Extracellular Vesicles. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2019; 31:e1805344. [PMID: 30589111 DOI: 10.1002/adma.201805344] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Revised: 10/29/2018] [Indexed: 05/18/2023]
Abstract
Liquid biopsy enables noninvasive and dynamic analysis of molecular or cellular biomarkers, and therefore holds great potential for the diagnosis, prognosis, monitoring of disease progress and treatment efficacy, understanding of disease mechanisms, and identification of therapeutic targets for drug development. In this review, the recent progress in nanomaterials, nanostructures, nanodevices, and nanosensors for liquid biopsy is summarized, with a focus on the detection and molecular characterization of circulating tumor cells (CTCs) and extracellular vesicles (EVs). The developments and advances of nanomaterials and nanostructures in enhancing the sensitivity, specificity, and purity for the detection of CTCs and EVs are discussed. Sensing techniques for signal transduction and amplification as well as visualization strategies are also discussed. New technologies for the reversible release of the isolated CTCs and EVs and for single-CTC/EV analysis are summarized. Emerging microfluidic platforms for the integral on-chip isolation, detection, and molecular analysis are also included. The opportunities, challenges, and prospects of these innovative materials and technologies, especially with regard to their feasibility in clinical applications, are discussed. The applications of nanotechnology-based liquid biopsy will bring new insight into the clinical practice in monitoring and treatment of tumor and other significant diseases.
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Affiliation(s)
- Wenzhe Li
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Huayi Wang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Zijian Zhao
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Houqian Gao
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Changliang Liu
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Ling Zhu
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Chen Wang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
| | - Yanlian Yang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, University of Chinese Academy of Sciences, Beijing, 100049, P. R. China
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19
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20
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Wu L, Zhu L, Huang M, Song J, Zhang H, Song Y, Wang W, Yang C. Aptamer-based microfluidics for isolation, release and analysis of circulating tumor cells. Trends Analyt Chem 2019. [DOI: 10.1016/j.trac.2019.05.003] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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21
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Gribko A, Künzel J, Wünsch D, Lu Q, Nagel SM, Knauer SK, Stauber RH, Ding GB. Is small smarter? Nanomaterial-based detection and elimination of circulating tumor cells: current knowledge and perspectives. Int J Nanomedicine 2019; 14:4187-4209. [PMID: 31289440 PMCID: PMC6560927 DOI: 10.2147/ijn.s198319] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Circulating tumor cells (CTCs) are disseminated cancer cells. The occurrence and circulation of CTCs seem key for metastasis, still the major cause of cancer-associated deaths. As such, CTCs are investigated as predictive biomarkers. However, due to their rarity and heterogeneous biology, CTCs’ practical use has not made it into the clinical routine. Clearly, methods for the effective isolation and reliable detection of CTCs are urgently needed. With the development of nanotechnology, various nanosystems for CTC isolation and enrichment and CTC-targeted cancer therapy have been designed. Here, we summarize the relationship between CTCs and tumor metastasis, and describe CTCs’ unique properties hampering their effective enrichment. We comment on nanotechnology-based systems for CTC isolation and recent achievements in microfluidics and lab-on-a-chip technologies. We discuss recent advances in CTC-targeted cancer therapy exploiting the unique properties of nanomaterials. We conclude by introducing developments in CTC-directed nanosystems and other advanced technologies currently in (pre)clinical research.
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Affiliation(s)
- Alena Gribko
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ;
| | - Julian Künzel
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ;
| | - Désirée Wünsch
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ;
| | - Qiang Lu
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ;
| | - Sophie Madeleine Nagel
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ;
| | - Shirley K Knauer
- Department of Molecular Biology II, Center for Medical Biotechnology (ZMB)/Center for Nanointegration (CENIDE), University Duisburg-Essen, Essen 45117, Germany
| | - Roland H Stauber
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ;
| | - Guo-Bin Ding
- Nanobiomedicine Department/ENT, University Medical Center Mainz, Mainz 55131, Germany, ; .,Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Shanxi University, Taiyuan 030006, People's Republic of China,
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22
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Agnoletto C, Corrà F, Minotti L, Baldassari F, Crudele F, Cook WJJ, Di Leva G, d'Adamo AP, Gasparini P, Volinia S. Heterogeneity in Circulating Tumor Cells: The Relevance of the Stem-Cell Subset. Cancers (Basel) 2019; 11:cancers11040483. [PMID: 30959764 PMCID: PMC6521045 DOI: 10.3390/cancers11040483] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 03/16/2019] [Accepted: 03/30/2019] [Indexed: 12/20/2022] Open
Abstract
The release of circulating tumor cells (CTCs) into vasculature is an early event in the metastatic process. The analysis of CTCs in patients has recently received widespread attention because of its clinical implications, particularly for precision medicine. Accumulated evidence documents a large heterogeneity in CTCs across patients. Currently, the most accepted view is that tumor cells with an intermediate phenotype between epithelial and mesenchymal have the highest plasticity. Indeed, the existence of a meta-stable or partial epithelial–mesenchymal transition (EMT) cell state, with both epithelial and mesenchymal features, can be easily reconciled with the concept of a highly plastic stem-like state. A close connection between EMT and cancer stem cells (CSC) traits, with enhanced metastatic competence and drug resistance, has also been described. Accordingly, a subset of CTCs consisting of CSC, present a stemness profile, are able to survive chemotherapy, and generate metastases after xenotransplantation in immunodeficient mice. In the present review, we discuss the current evidence connecting CTCs, EMT, and stemness. An improved understanding of the CTC/EMT/CSC connections may uncover novel therapeutic targets, irrespective of the tumor type, since most cancers seem to harbor a pool of CSCs, and disclose important mechanisms underlying tumorigenicity.
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Affiliation(s)
- Chiara Agnoletto
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy.
| | - Fabio Corrà
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy.
| | - Linda Minotti
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy.
| | - Federica Baldassari
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy.
| | - Francesca Crudele
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy.
| | | | - Gianpiero Di Leva
- School of Environment and Life Sciences, University of Salford, Salford M5 4WT, UK.
| | - Adamo Pio d'Adamo
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy.
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
| | - Paolo Gasparini
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34127 Trieste, Italy.
- Institute for Maternal and Child Health-IRCCS "Burlo Garofolo", 34137 Trieste, Italy.
| | - Stefano Volinia
- Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy.
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23
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Cho H, Kim J, Song H, Sohn KY, Jeon M, Han KH. Microfluidic technologies for circulating tumor cell isolation. Analyst 2019; 143:2936-2970. [PMID: 29796523 DOI: 10.1039/c7an01979c] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Metastasis is the main cause of tumor-related death, and the dispersal of tumor cells through the circulatory system is a critical step in the metastatic process. Early detection and analysis of circulating tumor cells (CTCs) is therefore important for early diagnosis, prognosis, and effective treatment of cancer, enabling favorable clinical outcomes in cancer patients. Accurate and reliable methods for isolating and detecting CTCs are necessary to obtain this clinical information. Over the past two decades, microfluidic technologies have demonstrated great potential for isolating and detecting CTCs from blood. The present paper reviews current advanced microfluidic technologies for isolating CTCs based on various biological and physical principles, and discusses their fundamental advantages and drawbacks for subsequent cellular and molecular assays. Owing to significant genetic heterogeneity among CTCs, microfluidic technologies for isolating individual CTCs have recently been developed. We discuss these single-cell isolation methods, as well as approaches to overcoming the limitations of current microfluidic CTC isolation technologies. Finally, we provide an overview of future innovative microfluidic platforms.
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Affiliation(s)
- Hyungseok Cho
- Department of Nanoscience and Engineering, Center for Nano Manufacturing, Inje University, Gimhae 621-749, Republic of Korea.
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24
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Wu LL, Tang M, Zhang ZL, Qi CB, Hu J, Ma XY, Pang DW. Chip-Assisted Single-Cell Biomarker Profiling of Heterogeneous Circulating Tumor Cells Using Multifunctional Nanospheres. Anal Chem 2018; 90:10518-10526. [DOI: 10.1021/acs.analchem.8b02585] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Affiliation(s)
- Ling-Ling Wu
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, The Institute for Advanced Studies, and Wuhan Institute of Biotechnology, Wuhan University, Wuhan 430072, PR China
| | - Man Tang
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, The Institute for Advanced Studies, and Wuhan Institute of Biotechnology, Wuhan University, Wuhan 430072, PR China
| | - Zhi-Ling Zhang
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, The Institute for Advanced Studies, and Wuhan Institute of Biotechnology, Wuhan University, Wuhan 430072, PR China
| | - Chu-Bo Qi
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, The Institute for Advanced Studies, and Wuhan Institute of Biotechnology, Wuhan University, Wuhan 430072, PR China
| | - Jiao Hu
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, The Institute for Advanced Studies, and Wuhan Institute of Biotechnology, Wuhan University, Wuhan 430072, PR China
| | - Xu-Yan Ma
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, The Institute for Advanced Studies, and Wuhan Institute of Biotechnology, Wuhan University, Wuhan 430072, PR China
| | - Dai-Wen Pang
- Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education), College of Chemistry and Molecular Sciences, State Key Laboratory of Virology, The Institute for Advanced Studies, and Wuhan Institute of Biotechnology, Wuhan University, Wuhan 430072, PR China
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25
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Kim KJ, Cho HY, Lee WJ, Choi JW. Subtyping of Magnetically Isolated Breast Cancer Cells Using Magnetic Force Microscopy. Biotechnol J 2018; 13:e1700625. [DOI: 10.1002/biot.201700625] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 03/23/2018] [Indexed: 01/02/2023]
Affiliation(s)
- Kyeong-Jun Kim
- Department of Chemical and Biomolecular Engineering, Sogang University; Seoul Republic of Korea
| | - Hyeon-Yeol Cho
- Department of Chemical and Biomolecular Engineering, Sogang University; Seoul Republic of Korea
- Department of Chemistry and Chemical Biology, Rutgers, The State University of New Jersey; Piscataway NJ USA
| | - Won-Jun Lee
- Department of Chemical and Biomolecular Engineering, Sogang University; Seoul Republic of Korea
| | - Jeong-Woo Choi
- Department of Chemical and Biomolecular Engineering, Sogang University; Seoul Republic of Korea
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26
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Zhang Y, Wang Z, Wu L, Zong S, Yun B, Cui Y. Combining Multiplex SERS Nanovectors and Multivariate Analysis for In Situ Profiling of Circulating Tumor Cell Phenotype Using a Microfluidic Chip. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2018; 14:e1704433. [PMID: 29665274 DOI: 10.1002/smll.201704433] [Citation(s) in RCA: 66] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/20/2017] [Revised: 02/17/2018] [Indexed: 05/22/2023]
Abstract
Isolating and in situ profiling the heterogeneous molecular phenotype of circulating tumor cells are of great significance for clinical cancer diagnosis and personalized therapy. Herein, an on-chip strategy is proposed that combines size-based microfluidic cell isolation with multiple spectrally orthogonal surface-enhanced Raman spectroscopy (SERS) analysis for in situ profiling of cell membrane proteins and identification of cancer subpopulations. With the developed microfluidic chip, tumor cells are sieved from blood on the basis of size discrepancy. To enable multiplex phenotypic analysis, three kinds of spectrally orthogonal SERS aptamer nanovectors are designed, providing individual cells with composite spectral signatures in accordance with surface protein expression. Next, to statistically demultiplex the complex SERS signature and profile the cellular proteomic phenotype, a revised classic least square algorithm is employed to obtain the 3D phenotypic information at single-cell resolution. Combined with categorization algorithm partial least square discriminate analysis, cells from different human breast cancer subtypes can be reliably classified with high sensitivity and selectivity. The results demonstrate that this platform can identify cancer subtypes with the spectral information correlated to the clinically relevant surface receptors, which holds great potential for clinical cancer diagnosis and precision medicine.
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Affiliation(s)
- Yizhi Zhang
- Advanced Photonics Center, Southeast University, Nanjing, 210096, China
| | - Zhuyuan Wang
- Advanced Photonics Center, Southeast University, Nanjing, 210096, China
| | - Lei Wu
- Advanced Photonics Center, Southeast University, Nanjing, 210096, China
| | - Shenfei Zong
- Advanced Photonics Center, Southeast University, Nanjing, 210096, China
| | - Binfeng Yun
- Advanced Photonics Center, Southeast University, Nanjing, 210096, China
| | - Yiping Cui
- Advanced Photonics Center, Southeast University, Nanjing, 210096, China
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27
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Cho HY, Hossain MK, Lee JH, Han J, Lee HJ, Kim KJ, Kim JH, Lee KB, Choi JW. Selective isolation and noninvasive analysis of circulating cancer stem cells through Raman imaging. Biosens Bioelectron 2018; 102:372-382. [DOI: 10.1016/j.bios.2017.11.049] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 11/13/2017] [Accepted: 11/15/2017] [Indexed: 01/06/2023]
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El-Said WA, Yoon J, Choi JW. Nanostructured surfaces for analysis of anticancer drug and cell diagnosis based on electrochemical and SERS tools. NANO CONVERGENCE 2018; 5:11. [PMID: 29721403 PMCID: PMC5913382 DOI: 10.1186/s40580-018-0143-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/25/2018] [Accepted: 04/12/2018] [Indexed: 05/22/2023]
Abstract
Discovering new anticancer drugs and screening their efficacy requires a huge amount of resources and time-consuming processes. The development of fast, sensitive, and nondestructive methods for the in vitro and in vivo detection of anticancer drugs' effects and action mechanisms have been done to reduce the time and resources required to discover new anticancer drugs. For the in vitro and in vivo detection of the efficiency, distribution, and action mechanism of anticancer drugs, the applications of electrochemical techniques such as electrochemical cell chips and optical techniques such as surface-enhanced Raman spectroscopy (SERS) have been developed based on the nanostructured surface. Research focused on electrochemical cell chips and the SERS technique have been reviewed here; electrochemical cell chips based on nanostructured surfaces have been developed for the in vitro detection of cell viability and the evaluation of the effects of anticancer drugs, which showed the high capability to evaluate the cytotoxic effects of several chemicals at low concentrations. SERS technique based on the nanostructured surface have been used as label-free, simple, and nondestructive techniques for the in vitro and in vivo monitoring of the distribution, mechanism, and metabolism of different anticancer drugs at the cellular level. The use of electrochemical cell chips and the SERS technique based on the nanostructured surface should be good tools to detect the effects and action mechanisms of anticancer drugs.
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Affiliation(s)
- Waleed A. El-Said
- Department of Chemical and Biomolecular Engineering, Sogang University, 35 Baekbeom-Ro, Mapo-Gu, Seoul, 04375 Republic of Korea
- Department of Chemistry, Faculty of Science, Assiut University, Assiut, 71516 Egypt
| | - Jinho Yoon
- Department of Chemical and Biomolecular Engineering, Sogang University, 35 Baekbeom-Ro, Mapo-Gu, Seoul, 04375 Republic of Korea
| | - Jeong-Woo Choi
- Department of Chemical and Biomolecular Engineering, Sogang University, 35 Baekbeom-Ro, Mapo-Gu, Seoul, 04375 Republic of Korea
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Huang Q, Wang Y, Chen X, Wang Y, Li Z, Du S, Wang L, Chen S. Nanotechnology-Based Strategies for Early Cancer Diagnosis Using Circulating Tumor Cells as a Liquid Biopsy. Nanotheranostics 2018; 2:21-41. [PMID: 29291161 PMCID: PMC5743836 DOI: 10.7150/ntno.22091] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 10/10/2017] [Indexed: 12/11/2022] Open
Abstract
Circulating tumor cells (CTCs) are cancer cells that shed from a primary tumor and circulate in the bloodstream. As a form of “tumor liquid biopsy”, CTCs provide important information for the mechanistic investigation of cancer metastasis and the measurement of tumor genotype evolution during treatment and disease progression. However, the extremely low abundance of CTCs in the peripheral blood and the heterogeneity of CTCs make their isolation and characterization major technological challenges. Recently, nanotechnologies have been developed for sensitive CTC detection; such technologies will enable better cell and molecular characterization and open up a wide range of clinical applications, including early disease detection and evaluation of treatment response and disease progression. In this review, we summarize the nanotechnology-based strategies for CTC isolation, including representative nanomaterials (such as magnetic nanoparticles, gold nanoparticles, silicon nanopillars, nanowires, nanopillars, carbon nanotubes, dendrimers, quantum dots, and graphene oxide) and microfluidic chip technologies that incorporate nanoroughened surfaces and discuss their key challenges and perspectives in CTC downstream analyses, such as protein expression and genetic mutations that may reflect tumor aggressiveness and patient outcome.
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Affiliation(s)
- Qinqin Huang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Yin Wang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Xingxiang Chen
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Yimeng Wang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Zhiqiang Li
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Shiming Du
- Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, 442000, China
| | - Lianrong Wang
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
| | - Shi Chen
- Key Laboratory of Combinatorial Biosynthesis and Drug Discovery of Ministry of Education, School of Pharmaceutical Sciences, and Brain Center, Zhongnan Hospital, and Medical Research Institute, Wuhan University, Wuhan 430072, China
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Kang YT, Kim YJ, Bu J, Cho YH, Han SW, Moon BI. High-purity capture and release of circulating exosomes using an exosome-specific dual-patterned immunofiltration (ExoDIF) device. NANOSCALE 2017; 9:13495-13505. [PMID: 28862274 DOI: 10.1039/c7nr04557c] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
We present a microfluidic device for the capture and release of circulating exosomes from human blood. The exosome-specific dual-patterned immunofiltration (ExoDIF) device is composed of two distinct immuno-patterned layers, and is capable of enhancing the chance of binding between the antibody and exosomes by generating mechanical whirling, thus achieving high-throughput exosome isolation with high specificity. Moreover, follow-up recovery after the immuno-affinity based isolation, via cleavage of a linker, enables further downstream analysis. We verified the performance of the present device using MCF-7 secreted exosomes and found that both the concentration and proportion of exosome-sized vesicles were higher than in the samples obtained from the conventional exosome isolation kit. We then isolated exosomes from the human blood samples with our device to compare the exosome level between cancer patients and healthy donors. Cancer patients show a significantly higher exosome level with higher selectivity when validating the exosome-sized vesicles using both electron microscopy and nanoparticle tracking analysis. The captured exosomes from cancer patients also express abundant cancer-associated antigens, the epithelial cell adhesion molecule (EpCAM) on their surface. Our simple and rapid exosome recovery technique has huge potential to elucidate the function of exosomes in cancer patients and can thus be applied for various exosome-based cancer research studies.
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Affiliation(s)
- Yoon-Tae Kang
- Cell Bench Research Center, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
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31
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Wu LL, Wen CY, Hu J, Tang M, Qi CB, Li N, Liu C, Chen L, Pang DW, Zhang ZL. Nanosphere-based one-step strategy for efficient and nondestructive detection of circulating tumor cells. Biosens Bioelectron 2017; 94:219-226. [DOI: 10.1016/j.bios.2017.03.009] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 02/21/2017] [Accepted: 03/06/2017] [Indexed: 12/26/2022]
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Abstract
Circulating tumor cells are a hallmark of cancer metastasis which accounts for approximately 90% of all cancer-related deaths. Their detection and characterization have significant implications in cancer biology and clinical practice. However, CTCs are rare cells and consist of heterogeneous subpopulations, requiring highly sensitive and specific techniques to identify and isolate them with high efficiency. Nanomaterials, with unique structural and functional properties, have shown strong promise to meet the challenging demands. In this review, we discuss CTC capture and therapeutic targeting, emphasizing the significance of the nanomaterials being used for this purpose. The next generation of therapy for metastatic cancer may well involve capturing and even directly neutralizing CTCs using nanomaterials.
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Affiliation(s)
- Zhenjiang Zhang
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235 USA
| | - Michael R. King
- Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37235 USA
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Rawal S, Yang YP, Cote R, Agarwal A. Identification and Quantitation of Circulating Tumor Cells. ANNUAL REVIEW OF ANALYTICAL CHEMISTRY (PALO ALTO, CALIF.) 2017; 10:321-343. [PMID: 28301753 DOI: 10.1146/annurev-anchem-061516-045405] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Circulating tumor cells (CTCs) are shed from the primary tumor into the circulatory system and act as seeds that initiate cancer metastasis to distant sites. CTC enumeration has been shown to have a significant prognostic value as a surrogate marker in various cancers. The widespread clinical utility of CTC tests, however, is still limited due to the inherent rarity and heterogeneity of CTCs, which necessitate robust techniques for their efficient enrichment and detection. Significant recent advances have resulted in technologies with the ability to improve yield and purity of CTC enrichment as well as detection sensitivity. Current efforts are largely focused on the translation and standardization of assays to fully realize the clinical utility of CTCs. In this review, we aim to provide a comprehensive overview of CTC enrichment and detection techniques with an emphasis on novel approaches for rapid quantification of CTCs.
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Affiliation(s)
- Siddarth Rawal
- Department of Pathology, DJTMF Biomedical Nanotechnology Institute, University of Miami, Coral Gables, Florida 33146
| | - Yu-Ping Yang
- Department of Pathology, DJTMF Biomedical Nanotechnology Institute, University of Miami, Coral Gables, Florida 33146
- Department of Biochemistry and Molecular Biology, University of Miami, Coral Gables, Florida 33146
| | - Richard Cote
- Department of Pathology, DJTMF Biomedical Nanotechnology Institute, University of Miami, Coral Gables, Florida 33146
- Department of Biochemistry and Molecular Biology, University of Miami, Coral Gables, Florida 33146
| | - Ashutosh Agarwal
- Department of Pathology, DJTMF Biomedical Nanotechnology Institute, University of Miami, Coral Gables, Florida 33146
- Department of Biomedical Engineering, University of Miami, Coral Gables, Florida 33146;
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Zhao Y, Xu D, Tan W. Aptamer-functionalized nano/micro-materials for clinical diagnosis: isolation, release and bioanalysis of circulating tumor cells. Integr Biol (Camb) 2017; 9:188-205. [PMID: 28144664 DOI: 10.1039/c6ib00239k] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Detection of rare circulating tumor cells (CTCs) in peripheral blood is a challenging, but necessary, task in order to diagnose early onset of metastatic cancer and to monitor treatment efficacy. Over the last decade, step-up produced aptamers have attracted great attention in clinical diagnosis. They have offered great promise for a broader range of cell-specific recognition and isolation. In particular, aptamer-functionalized magnetic particles for selective extraction of target CTCs have shown reduced damage to cells and relatively simple operation. Also, efforts to develop aptamer-functionalized microchannel/microstructures able to efficiently isolate target CTCs are continuing, and these efforts have brought more advanced geometrically designed substrates. Various aptamer-mediated cell release techniques are being developed to enable subsequent biological studies. This article reviews some of these advances in aptamer-functionalized nano/micro-materials for CTCs isolation and methods for releasing captured CTCs from aptamer-functionalized surfaces. Biological studies of CTCs after release are also discussed.
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Affiliation(s)
- Yaju Zhao
- State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
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35
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Bu J, Kang YT, Kim YJ, Cho YH, Chang HJ, Kim H, Moon BI, Kim HG. Dual-patterned immunofiltration (DIF) device for the rapid efficient negative selection of heterogeneous circulating tumor cells. LAB ON A CHIP 2016; 16:4759-4769. [PMID: 27858042 DOI: 10.1039/c6lc01179a] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
The analysis of circulating tumor cells (CTCs) is an emerging field for estimating the metastatic relapse and tumor burden of cancer patients. However, the isolation of CTCs is still challenging due to their ambiguity, rarity, and heterogeneity. Here, we present an anti-CD45 antibody based dual-patterned immunofiltration (DIF) device for the enrichment of heterogeneous CTC subtypes by effective elimination of leukocytes. Our uniquely designed dual-patterned layers significantly enhance the binding chance between immuno-patterns and leukocytes due to the fluidic whirling and the increased binding sites, thus achieving superior negative selection in terms of high-throughput and high purity. From the experiments using lung cancer cells, 97.07 ± 2.79% of leukocytes were eliminated with less than 10% loss of cancerous cells at the flow rate of 1 mL h-1. To verify the device as a potential diagnostic tool, CTCs were collected from 11 cancer patients' blood and an average of 283.3 CTC-like cells were identified while less than 1 CTC-like cells were found from healthy donors. The samples were also analyzed by immunohistochemistry and the reverse transcription polymerase chain reaction to identify their heterogeneous characteristics. These remarkable results demonstrate that the present device could help to understand the unknown properties or undiscovered roles of CTCs with a non-biased view.
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Affiliation(s)
- Jiyoon Bu
- Cell Bench Research Center, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
| | - Yoon-Tae Kang
- Cell Bench Research Center, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
| | - Young Jun Kim
- Cell Bench Research Center, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
| | - Young-Ho Cho
- Cell Bench Research Center, Korea Advanced Institute of Science and Technology (KAIST), 291 Daehak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
| | - Hee Jin Chang
- Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 10408, Republic of Korea
| | - Hojoong Kim
- Sungkyunkwan University School of Medicine, Samsung Medical Center, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
| | - Byung-In Moon
- College of Medicine, Ewha Womans University and Ewha Medical Research Institute, 911-1, MokDong, YangCheon-Ku, Seoul, 07985, Republic of Korea
| | - Ho Gak Kim
- Catholic University of Daegu School of Medicine, 33, Duryugongwon-ro 17-gil, Nam-gu, Daegu, 42472, Republic of Korea
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36
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Li R, Liu B, Gao J. The application of nanoparticles in diagnosis and theranostics of gastric cancer. Cancer Lett 2016; 386:123-130. [PMID: 27845158 DOI: 10.1016/j.canlet.2016.10.032] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 10/12/2016] [Accepted: 10/22/2016] [Indexed: 02/07/2023]
Abstract
Gastric cancer is the fourth most common cancer and the second leading cause of cancer related death worldwide. For the diagnosis of gastric cancer, apart from regular systemic imaging, the locoregional imaging is also of great importance. Moreover, there are still other ways for the detecting of gastric cancer, including the early detection of gastric cancer by endoscopy, the detection of gastric-cancer related biomarkers and the detection of circulating tumor cells (CTCs) of gastric cancer. However, conventional diagnostic methods are usually lack of specificity and sensitivity. Nanoparticles provide many benefits in the diagnosis of gastric cancer. Besides, nanoparticles are capable of integrating the functions of diagnosis and treatment together (theranostics). In this paper, we reviewed the applications of nanoparticles in diagnosis and theranostics of gastric cancer in the above mentioned aspects.
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Affiliation(s)
- Rutian Li
- The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, PR China; Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, PR China
| | - Baorui Liu
- The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, PR China.
| | - Jiahui Gao
- The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, PR China; Nanjing Drum Tower Hospital, Clinical College of Nanjing Medical University, Nanjing, PR China
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37
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Hassan EM, Willmore WG, DeRosa MC. Aptamers: Promising Tools for the Detection of Circulating Tumor Cells. Nucleic Acid Ther 2016; 26:335-347. [PMID: 27736306 DOI: 10.1089/nat.2016.0632] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Circulating tumor cells (CTCs) are cells that shed from a primary tumor and freely circulate in the blood, retaining the ability to initiate metastasis and form a secondary tumor in distant organs in the body. CTCs reflect the molecular profile of the primary tumor, therefore studying CTCs can allow for an understanding of the mechanism of metastasis, and an opportunity to monitor the prognosis of cancer. Unfortunately, the detection of CTCs is a considerable challenge due to their low abundance in the bloodstream and the lack of consistent markers present to recognize these cells. The aim of this review is to summarize some of the aptamer-based affinity methods for the detection of CTCs. The basic biological concept of how metastasis occurs and the role of CTCs in this process are presented. Some methods of CTC detection employing antibodies or peptides are mentioned here for comparison. The review of present literature suggests that aptamers are emerging as competitive technology in the detection of CTCs, especially due to their unique properties, but there still remain several challenges to be met, including the need to improve the throughput and sensitivity of such methods.
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Affiliation(s)
- Eman M Hassan
- 1 Institut National de la Recherche Scientifique-Energie, Materiaux Telecommunication , Quebec, Canada .,2 Department of Chemistry, Carleton University , Ottawa, Canada
| | | | - Maria C DeRosa
- 2 Department of Chemistry, Carleton University , Ottawa, Canada .,3 Institute of Biochemistry, Carleton University , Ottawa, Canada
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38
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Bhana S, Wang Y, Huang X. Nanotechnology for enrichment and detection of circulating tumor cells. Nanomedicine (Lond) 2016; 10:1973-90. [PMID: 26139129 DOI: 10.2217/nnm.15.32] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Circulating tumor cells (CTCs) are a hallmark of invasive behavior of cancer, responsible for the development of metastasis. Their detection and analysis have significant impacts in cancer biology and clinical practice. However, CTCs are rare events and contain heterogeneous subpopulations, requiring highly sensitive and specific techniques to identify and capture CTCs with high efficiency. Nanotechnology shows strong promises for CTC enrichment and detection owning to the unique structural and functional properties of nanoscale materials. In this review, we discuss the CTC enrichment and detection technologies based on a variety of functional nanosystems and nanostructured substrates, with the goal to highlight the role of nanotechnology in the advancement of basic and clinical CTC research.
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Affiliation(s)
- Saheel Bhana
- Department of Chemistry, The University of Memphis, Memphis, TN 38152, USA
| | - Yongmei Wang
- Department of Chemistry, The University of Memphis, Memphis, TN 38152, USA
| | - Xiaohua Huang
- Department of Chemistry, The University of Memphis, Memphis, TN 38152, USA
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39
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Hossain MK, Cho HY, Kim KJ, Choi JW. In situ monitoring of doxorubicin release from biohybrid nanoparticles modified with antibody and cell-penetrating peptides in breast cancer cells using surface-enhanced Raman spectroscopy. Biosens Bioelectron 2015; 71:300-305. [DOI: 10.1016/j.bios.2015.04.053] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2015] [Revised: 04/09/2015] [Accepted: 04/17/2015] [Indexed: 01/09/2023]
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40
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Myung JH, Tam KA, Park SJ, Cha A, Hong S. Recent advances in nanotechnology-based detection and separation of circulating tumor cells. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2015; 8:223-39. [PMID: 26296639 DOI: 10.1002/wnan.1360] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Revised: 06/05/2015] [Accepted: 06/16/2015] [Indexed: 01/09/2023]
Abstract
Although circulating tumor cells (CTCs) in blood have been widely investigated as a potential biomarker for diagnosis and prognosis of metastatic cancer, their inherent rarity and heterogeneity bring tremendous challenges to develop a CTC detection method with clinically significant specificity and sensitivity. With advances in nanotechnology, a series of new methods that are highly promising have emerged to enable or enhance detection and separation of CTCs from blood. In this review, we systematically categorize nanomaterials, such as gold nanoparticles, magnetic nanoparticles, quantum dots, graphenes/graphene oxides, and dendrimers and stimuli-responsive polymers, used in the newly developed CTC detection methods. This will provide a comprehensive overview of recent advances in the CTC detection achieved through application of nanotechnology as well as the challenges that these existing technologies must overcome to be directly impactful on human health.
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Affiliation(s)
- Ja Hye Myung
- Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL, USA
| | - Kevin A Tam
- Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL, USA
| | - Sin-jung Park
- Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL, USA
| | - Ashley Cha
- Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL, USA
| | - Seungpyo Hong
- Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL, USA.,Integrated Science and Engineering Division, Underwood International College, Yonsei University, Incheon, South Korea
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41
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Czarnecka AM, Kornakiewicz A, Kukwa W, Szczylik C. Frontiers in clinical and molecular diagnostics and staging of metastatic clear cell renal cell carcinoma. Future Oncol 2015; 10:1095-111. [PMID: 24941992 DOI: 10.2217/fon.13.258] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
The last few years have brought advances in the understanding of the molecular biology of metastatic clear cell renal cell carcinoma (RCC). Both preclinical research and clinical trials brought together results from the latest advancements in RCC diagnostic and staging. Understanding of the complex molecular alterations involved in the development and progression of RCC enables development of immunohistochemical and genetic diagnostic tools and is also opening the doors for experimental targeted therapies. At the same time, improvements of medical and molecular imaging improves the sensitivity and specificity of metastatic disease diagnosis. Moreover, independent validation of molecular profiles across high-throughput platforms, methods, laboratories and cancer populations has recently been successfully performed in RCC. Generation of informative, clinical diagnostic tools is likely to contribute to development of novel personalized diagnostic and treatment protocols and ensure prolonged survival of RCC patient in the near future.
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Affiliation(s)
- Anna M Czarnecka
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141 Warsaw, Poland
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42
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Guo M, Li X, Zhang S, Song H, Zhang W, Shang X, Zheng Y, Jiang H, Lv Q, Jiang Y, Hao H. Real-time quantitative RT-PCR detection of circulating tumor cells from breast cancer patients. Int J Oncol 2014; 46:281-9. [PMID: 25353649 DOI: 10.3892/ijo.2014.2732] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 09/22/2014] [Indexed: 11/06/2022] Open
Abstract
Circulating tumor cells (CTCs) were recognized as novel tumor biomarker for prognostic and predictive purposes in various cancers. Various detection technologies and devices have been developed to enumerate and characterize CTCs. Most of those approaches are based on the positive enrichment strategy and immunocytological techniques. However, the sensitivity of these approaches proved to be limited in metastatic tumors and the detection of early tumor cell dissemination was problematic. In the present study, we developed a novel CTC detection method by real-time RT-PCR technique in combination of negative enrichment strategy. The developed enrichment approach could recover more than 75% of spiked breast cancer cells from peripheral blood. The detection limit of duplex real-time RT-PCR assay using KRT19 and ERBB2 as targeted genes was consistently one breast tumor cell. Moreover, CTC detection by duplex real-time RT-PCR assay had higher detection sensitivity than that by immunostaining, especially in early breast cancer. In summary, the results of the present study indicated the potential clinical utilities of CTCs identification on breast cancer by duplex real-time RT-PCR in combination with negative enrichment.
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Affiliation(s)
- Maowen Guo
- School of Pharmacy, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Xiaotian Li
- School of Pharmacy, Zhengzhou University, Zhengzhou, Henan 450001, P.R. China
| | - Shaohua Zhang
- Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Hua Song
- Affiliated Hospital of Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Wenhui Zhang
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Xueyi Shang
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Yuling Zheng
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Hua Jiang
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Qingyu Lv
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Yongqiang Jiang
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, P.R. China
| | - Huaijie Hao
- State Key Laboratory of Pathogen and Biosecurity, Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing 100071, P.R. China
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Toy R, Bauer L, Hoimes C, Ghaghada KB, Karathanasis E. Targeted nanotechnology for cancer imaging. Adv Drug Deliv Rev 2014; 76:79-97. [PMID: 25116445 PMCID: PMC4169743 DOI: 10.1016/j.addr.2014.08.002] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 07/26/2014] [Accepted: 08/04/2014] [Indexed: 02/02/2023]
Abstract
Targeted nanoparticle imaging agents provide many benefits and new opportunities to facilitate accurate diagnosis of cancer and significantly impact patient outcome. Due to the highly engineerable nature of nanotechnology, targeted nanoparticles exhibit significant advantages including increased contrast sensitivity, binding avidity and targeting specificity. Considering the various nanoparticle designs and their adjustable ability to target a specific site and generate detectable signals, nanoparticles can be optimally designed in terms of biophysical interactions (i.e., intravascular and interstitial transport) and biochemical interactions (i.e., targeting avidity towards cancer-related biomarkers) for site-specific detection of very distinct microenvironments. This review seeks to illustrate that the design of a nanoparticle dictates its in vivo journey and targeting of hard-to-reach cancer sites, facilitating early and accurate diagnosis and interrogation of the most aggressive forms of cancer. We will report various targeted nanoparticles for cancer imaging using X-ray computed tomography, ultrasound, magnetic resonance imaging, nuclear imaging and optical imaging. Finally, to realize the full potential of targeted nanotechnology for cancer imaging, we will describe the challenges and opportunities for the clinical translation and widespread adaptation of targeted nanoparticles imaging agents.
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Affiliation(s)
- Randall Toy
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Lisa Bauer
- Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Physics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Christopher Hoimes
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA; University Hospitals Case Medical Center, Cleveland, OH 44106, USA
| | - Ketan B Ghaghada
- Edward B. Singleton Department of Pediatric Radiology, Texas Children's Hospital, Houston, TX 77030, USA; Department of Radiology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Efstathios Karathanasis
- Department of Biomedical Engineering, Case Western Reserve University, Cleveland, OH 44106, USA; Case Center for Imaging Research, Case Western Reserve University, Cleveland, OH 44106, USA; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Radiology, Case Western Reserve University, Cleveland, OH 44106, USA.
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Yoon HJ, Kozminsky M, Nagrath S. Emerging role of nanomaterials in circulating tumor cell isolation and analysis. ACS NANO 2014; 8:1995-2017. [PMID: 24601556 PMCID: PMC4004319 DOI: 10.1021/nn5004277] [Citation(s) in RCA: 191] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
Circulating tumor cells (CTCs) are low frequency cells found in the bloodstream after having been shed from a primary tumor. These cells are research targets because of the information they may potentially provide about both an individual cancer as well as the mechanisms through which cancer spreads in the process of metastasis. Established technologies exist for CTC isolation, but the recent progress and future of this field lie in nanomaterials. In this review, we provide perspective into historical CTC capture as well as current research being conducted, emphasizing the significance of the materials being used to fabricate these devices. The modern investigation into CTCs initially featured techniques that have since been commercialized. A major innovation in the field was the development of a microfluidic capture device, first fabricated in silicon and followed up with glass and thermopolymer devices. We then specifically highlight the technologies incorporating magnetic nanoparticles, carbon nanotubes, nanowires, nanopillars, nanofibers, and nanoroughened surfaces, graphene oxide and their fabrication methods. The nanoscale provides a new set of tools that has the potential to overcome current limitations associated with CTC capture and analysis. We believe the current trajectory of the field is in the direction of nanomaterials, allowing the improvements necessary to further CTC research.
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Gao Y, Yuan Z. Nanotechnology for the detection and kill of circulating tumor cells. NANOSCALE RESEARCH LETTERS 2014; 9:500. [PMID: 25258614 PMCID: PMC4174536 DOI: 10.1186/1556-276x-9-500] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Accepted: 06/19/2014] [Indexed: 05/11/2023]
Abstract
Circulating tumor cells (CTCs) represent a surrogate biomarker of hematogenous metastases and thus could be considered as a 'liquid biopsy' which reveals metastasis in action. But it is absolutely a challenge to detect CTCs due to their extreme rarity. At present, the most common principle is to take advantage of the epithelial surface markers of CTCs which attach to a specific antibody. Antibody-magnetic nanobeads combine with the epithelial surface markers, and then the compound is processed by washing, separation, and detection. However, a proportion of CTC antigen expressions are down-regulated or lost in the process of epithelial-mesenchymal transition (EMT), and thus, this part of CTCs cannot be detected by classical detection methods such as CellSearch. To resolve this problem, some multiple-marker CTC detections have been developed rapidly. Additionally, nanotechnology is a promising approach to kill CTCs with high efficiency. Implantable nanotubes coated with apoptosis-promoting molecules improve the disease-free survival and overall survival. The review introduces some novel CTC detection techniques and therapeutic methods by virtue of nanotechnology to provide a better knowledge of the progress about CTC study.
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Affiliation(s)
- Yang Gao
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Zhou Yuan
- Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
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