Background: Liquid biopsies have long promised to enable earlier cancer diagnosis and tailored therapy. However, circulating tumor cells (CTCs) are extremely rare (1-10 cells per mL blood), limiting their clinical utility. There are too few CTCs in a standard 5-10 mL blood sample for culture and drug susceptibility testing, or for comprehensively profiling a molecularly heterogeneous cancer and its metastases for drug resistance mutations. To achieve large-scale CTC enrichment, new strategies are needed that can rapidly and effectively interrogate large blood volumes.
Aim: To design a flexible magnetic wire capable of high-throughput intravascular enrichment and retrieval of rare biomarkers, including CTCs, from the entire circulating blood volume to attain a much higher biomarker yield for earlier cancer detection and personalized treatment.
Methods: We present a promising platform for in vivo enrichment of rare biomarkers, the Magnetic Wire for Intravascular Retrieval and Enrichment (MagWIRE): a flexible, self-contained magnetic wire consisting of a string of small magnets with alternating polarities, achieving high local field gradients along its entire length to capture magnetically labeled targets from a large surrounding volume. The platform is proposed to work as follows: Blood biomarkers are immunomagnetically labeled by injecting a patient with antibody-coated magnetic particles (MPs), similar to FDA-approved Feraheme®. The MagWIRE is then inserted through a standard IV catheter into a superficial vein in the arm or through an existing chemotherapy port to magnetically capture passing MP-bound biomarkers. Within an hour, ~5 liters has circulated through a 2-3-mm-diameter human vein, allowing most of the patient’s blood volume to be sampled. The magnets can then be displaced from the MagWIRE sheath to elute the bound targets into buffer for downstream analysis. We performed proof-of-concept demonstrations in: 1) a closed-loop blood circulation system consisting of a pump, tubing, and a blood reservoir, and 2) in vivo within a porcine ear vein model. To model CTC capture, we targeted H1650 lung cancer cells with 1-μm superparamagnetic iron oxide particles coated with antibodies against epithelial cell adhesion molecule (EpCAM), a commonly used CTC marker. We couple the MagWIRE with a unique approach for rapid (<10 seconds) magnetic labeling of CTCs in flow for immediate downstream capture by the wire on a single pass.
Results: Considerable gains are achievable by sampling from large volumes, even at relatively low capture efficiencies. In our closed-loop setup, the MagWIRE demonstrated capture efficiencies in whole blood of 56.14+/-15.80% for pre-labeled cells and 10.17+/-5.41% for cells labeled in flow. In a porcine ear model, we captured cells with efficiencies up to 8%, corresponding to 80-fold enrichment when integrated over a 5-liter blood volume compared with a 5 mL blood draw.
Citation Format: Ophir Vermesh, Amin Aalipour, Tianjia J. Ge, Yamil Saenz, Yue Guo, Seung-min Park, Yoshiaki Mitsutake, Michael Bachmann, Chin Chun Ooi, Kerstin Mueller, Hamed Arami, Alfredo Green, Shan X. Wang, Sanjiv S. Gambhir. An intravascular magnetic wire for high-throughput in vivo enrichment of rare circulating cancer biomarkers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3796. doi:10.1158/1538-7445.AM2017-3796