A flexible magnetic wire inserted in a blood vessel improves the capture of magnetically labelled circulating tumour cells.
The presence of tumour cells in blood can be an early hallmark of a tumour’s invasive character and of the possibility of tumour metastases1. Also, such circulating tumour cells (CTCs) can serve as a source of cancer biomarkers (including DNA mutations, and cancer-relevant RNA, protein and epigenetic markers) for biologically and clinically important information that can help improve the understanding of cancer2. Unfortunately, capturing and characterizing CTCs is challenging because of their very low numbers in circulation (as low as 1 CTC per 106–107 leukocytes in the blood of cancer patients3). Although a number of CTC-capture methods have been tested in animals and in pilot studies in humans, only the CellSearch system (sold by Veridex), has been approved for clinical use4. The system takes advantage of magnetic cell targeting: magnetic particles functionalized with a CTC-binding antibody are incubated with a blood sample, and then the magnetically labelled CTCs are collected via a magnet5. Although CellSearch can capture as low as 1 CTC from about 7.5 ml of blood, methods with significantly higher CTC-capturing efficiency could enable a more accurate molecular-level characterization of the CTCs and the detection of CTCs at earlier cancer stages6. Reporting in Nature Biomedical Engineering, Sanjiv Gambhir and colleagues now show, in pigs, that a flexible magnetic wire inserted into a blood vessel through a standard catheter can process and capture CTCs bound to antibody-functionalized magnetic microbeads from the entire circulating blood in the body (Fig. 1), thereby providing enhanced CTC-capture efficiency7. The iron-oxide-based magnetic microbeads, which are commercially available, were functionalized with an antibody that binds the epithelial cell adhesion molecule (EpCAM), a glycoprotein commonly expressed on the surface of CTCs.
For capturing magnetic targets in the fast-circulating bloodstream, the presence of a sufficiently strong magnetic force is needed. Considering that magnetic force is proportional to the magnetic moment of the magnetic microparticles and to the magnetic-field gradient8, the magnetic force can be adjusted by altering either parameter, or both. Gambhir and co-authors engineered the magnetic wire (which they named MagWIRE) to generate a large magnetic-field gradient by alternating the wire’s magnetic polarity (Fig. 1a)9. The MagWIRE generates a magnetic flux density that is more than an order-of-magnitude higher than that of a typical magnetic wire with constant magnetic polarity. Also, the MagWIRE can attract magnetically labelled targets over a longer distance. In fact, the MagWIRE showed a larger capture efficiency for CTCs than immunocapture-based techniques.
The idea of attracting or capturing cells via an implantable magnetic device is not new; for example, implanted magnetic cardiac stents can attract magnetically labelled stem cells, for therapeutic purposes10. Gambhir and colleagues’ work is distinct in that the MagWIRE does not require the pre-labelling of CTCs with magnetic particles. Owing to the fast binding kinetics between antibody-functionalized magnetic microparticles and CTCs, the magnetic labelling of cells can be achieved in situ by infusing antibody-functionalized magnetic particles at about 10–20 cm upstream from the implanted MagWIRE (Fig. 1b,c). When passing through the infusion zone, where the magnetic particle concentration is high, CTCs have a higher chance of colliding with the magnetic particles and of forming a CTC–magnetic particle complex that can then be captured by the MagWIRE (Fig. 1c). By allowing CTCs to pass through the infusion and MagWIRE sites for several cycles, the capture efficiency can be significantly increased.
Following collection and enrichment, CTCs can be retrieved intact from the MagWIRE, for further characterization. For CTCs collected by conventional immunocapture-based methods, the retrieval process is conducted by typical cell-biology and molecular-biology techniques, such as cell detachment via the reduction of adhesive forces in cells, via flowing fluid (through shear forces), or via enzyme digestion by trypsinization2. However, such processes often result in undesired damage to the CTCs, which may hinder downstream analyses. The MagWIRE helps avoid such difficulties owing to its magnetic core and detachable polymer cover (Fig. 1d). Because the polymer cover has no magnetic-field gradient, the captured CTCs on the MagWIRE can be easily and safely retrieved. In fact, the retrieved CTCs showed no statistically meaningful transcriptomic alterations, compared with unlabelled control CTCs.
Albeit promising for diagnostic applications, the MagWIRE would need to be adapted and thoroughly tested before it can be used in clinical practice. Although a preliminary in vivo safety study in pigs showed no evidence of toxicity, despite the slow clearance of the magnetic microbeads accumulated in the liver and spleen, long-term toxicology and pharmacokinetics studies will be necessary. Also, because a number of formulations of nanoscale iron oxides are approved by the United States Food and Drug administration11, further research on developing smaller and stronger magnetic nanomaterials on the basis of chemical strategies such as transition metal doping8 and structural tuning9 could not only lead to improved capture efficiencies but also provide a better chance for clinical translation. Moreover, the capture method could be adapted for the capture of other blood-circulating cancer biomarkers such as tumour deoxyribonucleic acid and tumour exosomes.
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Shin, TH., Cheon, J. An intravenous wire captures rare tumour cells. Nat Biomed Eng 2, 635–636 (2018). https://doi.org/10.1038/s41551-018-0294-y