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Designer tetrahedral DNA framework-based microfluidic technology for multivalent capture and release of circulating tumor cells

ABSTRACT: Circulating tumor cells (CTCs) have been recognized as a general biomarker for the early detection, diagnosis and therapy monitoring of cancer. Due to their extreme rarity in peripheral blood, the isolation and analysis of CTCs with high efficiency, high purity and high viability remains a tremendous technological challenge. Herein, we combined tetrahedral DNA framework (TDFs), herringbone channel (HB) chip, together with aptamer-triggered hybridization chain reaction (apt-HCR) to develop an efficient microfluidic system (T-μFS) for capture and release of simulated CTCs. The capture efficiency of MCF-7 cells was from 83.3% to 94.2% when the cell numbers ranged from 10 to 103 using our T-μFS in the whole blood. The release efficiency of the MCF-7 cells was 96.2% and the MCF-7 cell viability after release was 94.6% using our T-μFS in PBS buffer. Reculture and RT-qPCR studies showed that there was almost no damage by the capture and release treatment for the MCF-7 cells viability. These results revealed that our T-μFS could be developed as an integrated and automatic technical platform with great performance for multivalent capture and release of CTCs and have a wide application prospect for tumor liquid biopsy. Graphical abstract Image 1 Highlights • Three-dimensional amine modified tetrahedral DNA frameworks (TDFs) as rigid scaffolds were anchored on the aldehyde modified substrate of HB-chip, which provided the better spatial orientation compared with single-stranded DNA.• Aptamer partially hybridized to an initiator was employed to trigger HCR reaction, and HCR produced modified long products with multi-branched arms for multivalent binding on TDFs to improve the capture efficiency of CTCs.• This is the first time that only employed DNA nanostructures in a microfluidic device system to capture CTCs, and all DNA nanostructures could be efficiently removed by enzymes without harming cells.

SUBMITTER: Wang C

PROVIDER: S-EPMC9272028 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cancer cells metastasize through the bloodstream either as single migratory circulating tumor cells (CTCs) or as multicellular groupings (CTC-clusters). Existing technologies for CTC enrichment are designed primarily to isolate single CTCs, and while CTC-clusters are detectable in some cases, their true prevalence and significance remain to be determined. Here, we developed a microchip technology (Cluster-Chip) specifically designed to capture CTC-clusters independent of tumor-specific markers from unprocessed blood. CTC-clusters are isolated through specialized bifurcating traps under low shear-stress conditions that preserve their integrity and even two-cell clusters are captured efficiently. Highly parallel architecture of the chip allows deterministic screening of clinically relevant volumes of blood samples at slow, and hence, non-damaging flow rates. Using the Cluster-Chip, we identify CTC-clusters in 30-40% of patients with metastatic cancers of the breast, prostate and melanoma. RNA sequencing of CTC-clusters confirms their tumor origin and identifies leukocytes within the clusters as being tissue-derived macrophages. Together, the development of a device for efficient capture of CTC-clusters will enable detailed characterization of their biological properties and role in cancer metastasis. We used the Cluster-Chip to capture CTC-clusters from the blood of a breast cancer patient with high CTC counts, released CTC-clusters in solution, stained them with TexasRed-conjugated antibodies against the leukocyte cell surface markers CD45, CD14 and CD16, and then isolated intact CTC-clusters individually using a micromanipulator. From a single time point, we retrieved 15 CTC-clusters, and each of those clusters was individually subjected to RNA-sequencing analysis using a next generation platform (SOLiD 5500). In addition, two leukocytes were isolated from the blood of a healthy donor were individually subjected to RNA-sequencing analysis using the same platform.

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Designer tetrahedral DNA framework-based microfluidic technology for multivalent capture and release of circulating tumor cells

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