Targeted nanomedicine for detection and treatment of circulating tumor cells
2011; Future Medicine; Volume: 6; Issue: 4 Linguagem: Inglês
10.2217/nnm.11.17
ISSN1748-6963
AutoresMadaswamy S. Muthu, Si‐Shen Feng,
Tópico(s)Microfluidic and Bio-sensing Technologies
ResumoNanomedicineVol. 6, No. 4 EditorialFree AccessTargeted nanomedicine for detection and treatment of circulating tumor cellsMadaswamy S Muthu & Si-Shen FengMadaswamy S Muthu† Author for correspondenceDepartment of Chemical & Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576, Singapore and Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221005, India. & Si-Shen FengDepartment of Chemical & Biomolecular Engineering, National University of Singapore, 4 Engineering Drive 4, Singapore 117576, Singapore and Division of Bioengineering, National University of Singapore, 7 Engineering Drive 1, Singapore 117576, Singapore and Nanoscience & Nanotechnology Initiative, National University of Singapore, 2 Engineering Drive 3, Singapore 117587, SingaporePublished Online:30 Jun 2011https://doi.org/10.2217/nnm.11.17AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInRedditEmail Keywords: active targetingcancercirculating tumor cellin vivo diagnosismetastasistheranosticCancer is the second leading cause of death worldwide, and is projected to become the leading cause in many countries. Many decades of research have led to innovative improvements in cancer research, especially in the area of diagnosis, enabling earlier cancer chemotherapy to start reducing cancer deaths [1–5]. Metastasis is the spread of cancer cells between organs, and plays a major role in cancer deaths. Circulating tumor cells (CTCs) are a common marker for the development of metastasis [6]. The first report of CTCs shed by a solid tumor was provided in 1869 by an Australian physician named Thomas Ashworth. He used a microscope to examine blood from a patient who had died of metastatic cancer, in which he noted cells that looked identical to those in the patient's tumors. It was the first instance showing a mode of origin for multiple tumors (metastasis) in cancer patients. Detection at different stages determines the prognosis. Early-stage detection usually results in cure, even for fatal diseases such as cancer. Therefore, novel diagnostic strategies are in progress to detect extremely low concentrations of CTCs before they form metastases [6–8].Generally, in vitro flow cytometry is used as an efficient tool for the detection of individual cells at the subcellular and molecular levels. However, this technique is unable to detect rare cells (<1 cell/ml), such as CTCs, in blood circulations because of low sensitivity and limited sample volume (5–20 ml). To overcome these limitations, in vivo flow cytometry is introduced to detect the CTCs directly in the bloodstream. This in vivo approach can identify the rare CTCs in much larger volumes compared with a method using a low sample volume. Fluorescent labeling of cells is the most commonly used technique in the in vivo flow cytometry for the detection of CTCs, although it has some drawbacks (e.g., potential toxicity). Alternatively, various research groups have developed in vivo blood and lymph flow cytometry with photothermal (PT), photoacoustic (PA), Raman and scattering detection techniques. It allows fluorescent label-free detection of cells with appropriate intrinsic properties (e.g., strong pigmentation) [6,9,10].The fluorescent label-free detection of CTCs using targeted systems (low toxicity contrast nanoparticles attached to a targeting ligand) made cancer cell diagnosis more sensitive and specific than those techniques based on the in vivo flow cytometry technique. It makes concentrated CTCs from a large volume of blood in the vessels, and showed the potential of the early detection of CTCs to prevent metastasis [11]. Similarly, detection of tumor-initiating cancer stem cells (stem CTCs) by flow cytometry is another emerging field in cancer research, as it could be responsible for the growth and regrowth of primary and metastatic tumors [11].The first US FDA-approved CTC detector, CellSearch®, can detect cancers that arise in the epithelial tissue lining organs, such as the breast and colon. The device traps CTCs using magnetic beads coated with an antibody that sticks to a protein, called an epithelial cell-adhesion molecule (EpCAM), found on tumor cells but not on blood cells [7]. However, researchers are still searching for a better method of detection and treatment of the rare and important CTCs shed by primary tumors that circulate in the blood of cancer patients.Current state-of-the-art in the nanoplatforms of CTC detection & cancer therapyRecently, nanocarriers have been designed and evaluated for PA detection and PT treatment of CTCs. For example, Galanzha and colleagues have developed a multicolor PA and PT flow cytometry nanoplatform (i.e., golden carbon nanotubes [GNTs]) [11]. It is reported that folic acid receptors are highly expressed (70–90%) in breast bulk CTCs, while CD44 expression occurs preferentially in stem CTCs within some breast cancer cells. Therefore, GNTs were attached to targeting ligands, such as folic acid and CD44 (hualuronic acid receptor) antibodies, for targeting CTCs and stem CTCs, respectively. Furthermore, folic acid or CD44 antibody-attached GNTs (nanoplatforms) were studied using in vivo cytometry. The variation in PA signal amplitude was analyzed for the detection of CTCs and stem CTCs. It was demonstrated that diagnosis can be integrated with targeted therapy of cancer as a multifunctional nanoplatform [11]. Furthermore, authors have demonstrated the threshold sensitivity of these carriers of approximately 1 CTC/ml in vivo.In another study, Galanzha and colleagues evaluated a combination of targeted magnetic nanoparticles and targeted GNTs for detecting CTCs [12]. The magnetic nanoparticles were used to trap CTCs in the bloodstream of mice under magnetization, followed by the rapid detection using PA techniques and GNTs. Magnetic nanoparticles were targeted to the urokinase plasminogen-activated receptors, which are highly expressed in CTCs, whereas the GNTs were targeted to folate receptors expressed in CTCs, but absent in normal cells. These nanocarriers respond optimally to different wavelengths of light, and a two-wavelength system can uniquely identify CTCs labeled with both nanoparticles. During the in vivo study in mice, a magnet was attached to the mice, and CTCs targeted and captured by the nanoparticles under magnetization were monitored using a sensitive PA detection system. When the tissue surface is illuminated with a nanosecond pulsed laser light, the subsurface light is absorbed by the nanoparticles. The light energy that is converted to heat induces a rapid thermoelastic expansion, resulting in ultrasound waves that are detected by the PA system. Here, they applied multiplex targeting and a multicolor-detection strategy, and increased the specificity of the nanoparticles for better CTC detection. One concern in this study is that macrophages may bind to these particles and become a source of false-positive results [12]. In addition, Zharov and co-workers trapped and detected the CTCs using targeted nanoplatforms without interference from free nanoparticles [13]. Once the magnet was removed, cells previously trapped under the magnet were released, and the PA signals were decreased [13].Future perspective for nanotechnology-based CTC detection & cancer therapyCurrently, PA diagnosis and PT-based cancer therapy demonstrate a potential future scope for human use. In the future, nanotechnology-based CTC detection and cancer therapy will face many challenges, such as surface modification, multireceptor cancer targeting, drug loading for therapy, toxicology and relevant regulations, including stability testing [14–16]. The emerging nanomedicine techniques will be theranostic in nature, with a multifunctional platform capable of simultaneous diagnosis and therapy [15]. The future development may encompass multifunctional properties in nanomedicine developed for CTC detection. A multidisciplinary approach on the development of these nanocarriers will bring valuable products for CTC detection and cancer therapy.ConclusionTheranostic nanomedicine for the detection and treatment of CTCs is another novel product of nanotechnology. Theranostic platforms targeted to CTCs will be successful products for CTC detection and therapy once their quality aspects have been investigated by the relevant regulatory authorities. The recent investigation of magnetic nanoparticles and GNTs has demonstrated their feasibility for detection and treatment of CTCs by in vivo flow cytometry. In comparison to currently available in vivo diagnostic techniques (i.e., MRI, PET or optical assays), PA in vivo flow cytometry, combined with PT techniques, demonstrated better dynamic capability for CTC detection. However, major issues need to be addressed before the benefits can be exploited, including surface modification of these nanocarriers and their sensitivity and selectivity to CTCs in vivo. Furthermore, these targeted nanomedicines for detecting CTCs are mainly dependent on their surface markers. Unfortunately, such surface cell marker proteins may not be expressed in all CTCs, or in some cancer types [7].Financial & competing interests disclosureMS Muthu acknowledges the Department of Science and Technology (DST), New Delhi, India, for the award of BOYSCAST Fellowship (SR/BY/L-41/09) to his post doctoral research in the year of 2009–2010. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Papers of special note have been highlighted as: ▪▪ of considerable interestBibliography1 Feng SS: Nanoparticles of biodegradable polymers for new concepts chemotherapy. Expert Rev. Med. Devices1,115–125 (2004).▪▪ Provides comprehensive discussion of concepts of nanomedicine and cancer chemotherapy.Crossref, Medline, CAS, Google Scholar2 Weissleder R, Pittet MJ: Imaging in the era of molecular oncology. Nature452,580–589 (2008).Crossref, Medline, CAS, Google Scholar3 Muthu MS, Rajesh CV, Mishra A, Singh S: Stimulus responsive targeted nanomicelles for effective cancer therapy. 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The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download
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