Is small smarter? Nanomaterial-based detection and elimination of circulating tumor cells: current knowledge and perspectives

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.

Keywords: cancer biomarker; liquid biopsy; metastasis; nanomedicine; nanotherapy; therapy resistance.

Figure 1

Timeline of PubMed entries. Notes: Search criteria included “nanotechnology” AND “CTCs”, “nano” AND “CTCs”, and “nano” AND “circulating tumor cells” to determine number of publications (columns). Timeline of World Health Organization International Clinical Trials Registry Platform entries to display the number of registered clinical trials using search criteria “circulating tumor cells” AND “nano”.

Figure 2

Workflow of patient-derived CTCs for CTC analysis, drug-resistance detection, and personalized drug-delivery systems. Notes: Patients’ blood samples are screened and potential CTCs captured and isolated. Potential CTCs can be enumerated, determined, and stained or cultivated for further analysis. CTC culture can be used for drug-resistance detection and personalized drug development, thereby increasing patient-survival rates. Abbreviation: CTCs, circulating tumor cells.

Figure 3

Characteristic stages of tumor-cell dissemination during metastasis. Notes: Cells from primary tumors undergo epithelial–mesenchymal transition (EMT), leading to the loss of cell–cell adhesion and promoting local invasion into the blood vessels (intravasation). The CTCs produced are able to escape from blood vessels into distant organs of future metastasis (extravasation) after the reverse process (MET), induced by interaction with the local microenvironment. Abbreviations: CTCs, circulating tumor cells; MET, mesenchymal-to-epithelial transition.

Figure 4

Illustration of methods for CTC isolation by magnetic separation using magnetic nanoparticles (NPs). Notes: (A) The CellSearch system enriches CTCs using iron NPs linked with anti-EpCAM antibodies (Abs). Labeled cells are magnetically separated, and can be evaluated by immunofluorescence staining. (B) AdnaTest allows the immunomagnetic enrichment of CTCs via epithelial and tumor-specific antigens. After separation of potential CTCs from PBMCs, labeled cells are lysed, in order to analyze CTC gene expression via multiplex PCR. (C) Process of MACS using superparamagnetic Fe NPs within a magnetized steel-wool column. Abbreviations: CTCs, circulating tumor cells; PBMCs, peripheral blood mononuclear cells; MACS, magnetically activated cell sorting; RT, real time.

Figure 5

Microfluidic chip design of CTC chip (A) and herringbone chip (B). Notes: Whole-blood sample is pushed through the surface of the chip, which is coated with a CTC-specific antibody, such as EpCAM. Chips differ in their architecture, containing either Ab-coated microposts (A) or herringbone-etched microchannels (B). Captured cells are stained for CK, CD45, and DAPI. Identified CTCs can be enumerated. Abbreviations: CTC, circulating tumor cell; Ab, antibody; MNPs, magnetic nanoparticles.

Figure 6

Synergetic detection and destruction of CTCs by a “sense-and-treat” DNA nanosystem. Notes: Reproduced with permission from Chen N, Qin S, Yang X, Wang Q, Huang J, Wang K. “Sense-and-treat” DNA nanodevice for synergetic destruction of circulating tumor cells. ACS Appl Mater Interfaces. 2016;8(40):26552–26558. Copyright © 2016 American Chemical Society. Abbreviations: CTCs, circulating tumor cells; Dox, doxorubicin.