Covalent chemistry on nanostructured substrates enables noninvasive quantification of gene rearrangements in circulating tumor cells

Dong, Jiantong; Jan, Yu Jen; Cheng, Ju; Zhang, Ryan Y.; Meng, Meng; Smalley, Matthew; Chen, Pin‐Jung; Tang, Xiao; Tseng, Patrick; Bao, Lirong; Huang, Tzu‐Yang; Zhou, Dongjing; Yp, Liu; Chai, Xiangping; Zhang, Haibo; Zhou, Anqi; Agopian, Vatche G.; Posadas, Edwin M.; Shyue, Jing‐Jong; Jonas, Steven J.; Weiss, Paul S.; Li, Mengyuan; Zheng, Guangjuan; Yu, Hsiao‐hua; Zhao, Meiping; Tseng, Hsian-Rong; Zhu, Yazhen

doi:10.1126/sciadv.aav9186

Cited by 36 publications

(30 citation statements)

References 40 publications

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“…The fabrication of Tz-grafted SiNWS began with introducing 10-15 µm densely packed Si nanowires (diameter = 100-200 nm) onto SiNWS, offering~30 times more surface area (in contrast to a flat substrate) for facilitating click chemistry-mediated HCC EV capture. The incorporation of disulfide bonds and terminal Tz motifs onto SiNWS was carried out via a 3-step procedure 40 ( Supplementary Fig. 2).…”

Section: Resultsmentioning

confidence: 99%

“…2). To confirm successful preparation of Tz-grafted SiNWS, X-ray photoelectron spectroscopy (XPS) was employed to monitor functional group transformation at each step 9,40 . The passive mixing behavior of the flow-through EVs in EV Click Chips was simulated ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…An EV Click Chip (Fig. 1 ) is composed of two functional components: (i) Tz-grafted SiNWS: a patterned SiNWS 32 covalently functionalized with disulfide bonds that link to terminal Tz motifs 40 , and (ii) an overlaid PDMS chaotic mixer 41 (Supplementary Fig. 1 ), housed in a custom-designed microfluidic chip holder.…”

Section: Resultsmentioning

confidence: 99%

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Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring

et al. 2020

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We report a covalent chemistry-based hepatocellular carcinoma (HCC)-specific extracellular vesicle (EV) purification system for early detection of HCC by performing digital scoring on the purified EVs. Earlier detection of HCC creates more opportunities for curative therapeutic interventions. EVs are present in circulation at relatively early stages of disease, providing potential opportunities for HCC early detection. We develop an HCC EV purification system (i.e., EV Click Chips) by synergistically integrating covalent chemistry-mediated EV capture/release, multimarker antibody cocktails, nanostructured substrates, and microfluidic chaotic mixers. We then explore the translational potential of EV Click Chips using 158 plasma samples of HCC patients and control cohorts. The purified HCC EVs are subjected to reverse-transcription droplet digital PCR for quantification of 10 HCC-specific mRNA markers and computation of digital scoring. The HCC EV-derived molecular signatures exhibit great potential for noninvasive early detection of HCC from at-risk cirrhotic patients with an area under receiver operator characteristic curve of 0.93 (95% CI, 0.86 to 1.00; sensitivity = 94.4%, specificity = 88.5%).

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring

et al. 2020

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“…However, the incubation time of 40–60 min for GSH treatment is relatively long. Dong et al created “Click Chips” [225] that leverage bioorthogonal ligation-mediated CTC capture and disulfide cleavage-driven CTC release in an SiNW-embedded microfluidic system (Figure 11e). CTCs were captured by inverse-electron-demand Diels-Alder reactions between trans -cyclooctene (TCO) and tetrazine (Tz) with enhanced capture efficiency (94% with TCO-anti-EpCAM as low as 0.1 ng) and specificity (≈2000 WBCs).…”

Section: Strategies For Rare-cell Retrieval From Nanostructured Substmentioning

confidence: 99%

Nanostructured Substrates for Detection and Characterization of Circulating Rare Cells: From Materials Research to Clinical Applications

et al. 2019

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Circulating rare cells in the blood are of great significance for both materials research and clinical applications. For example, circulating tumor cells (CTCs) have been demonstrated as useful biomarkers for “liquid biopsy” of the tumor. Circulating fetal nucleated cells (CFNCs) have shown potential in noninvasive prenatal diagnostics. However, it is technically challenging to detect and isolate circulating rare cells due to their extremely low abundance compared to hematologic cells. Nanostructured substrates offer a unique solution to address these challenges by providing local topographic interactions to strengthen cell adhesion and large surface areas for grafting capture agents, resulting in improved cell capture efficiency, purity, sensitivity, and reproducibility. In addition, rare-cell retrieval strategies, including stimulus-responsiveness and additive reagent-triggered release on different nanostructured substrates, allow for on-demand retrieval of the captured CTCs/CFNCs with high cell viability and molecular integrity. Several nanostructured substrate-enabled CTC/CFNC assays are observed maturing from enumeration and subclassification to molecular analyses. These can one day become powerful tools in disease diagnosis, prognostic prediction, and dynamic monitoring of therapeutic response—paving the way for personalized medical care.

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“…The CTC detection system demonstrated the merits of high throughput and high sensitivity. On the basis of previous experience using the “NanoVelcro” substrate, Dong et al designed a covalent chemistry-based SiNW substrate (“Click Chip”) to address the unmet clinical need of quantifying gene rearrangements in CTCs [ 79 ].…”

Section: Nanotechnology-assisted Circulating Tumor Cell (Ctc) Isolmentioning

confidence: 99%

Nanotechnology-Assisted Isolation and Analysis of Circulating Tumor Cells on Microfluidic Devices

et al. 2020

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Circulating tumor cells (CTCs), a type of cancer cell that spreads from primary tumors into human peripheral blood and are considered as a new biomarker of cancer liquid biopsy. It provides the direction for understanding the biology of cancer metastasis and progression. Isolation and analysis of CTCs offer the possibility for early cancer detection and dynamic prognosis monitoring. The extremely low quantity and high heterogeneity of CTCs are the major challenges for the application of CTCs in liquid biopsy. There have been significant research endeavors to develop efficient and reliable approaches to CTC isolation and analysis in the past few decades. With the advancement of microfabrication and nanomaterials, a variety of approaches have now emerged for CTC isolation and analysis on microfluidic platforms combined with nanotechnology. These new approaches show advantages in terms of cell capture efficiency, purity, detection sensitivity and specificity. This review focuses on recent progress in the field of nanotechnology-assisted microfluidics for CTC isolation and detection. Firstly, CTC isolation approaches using nanomaterial-based microfluidic devices are summarized and discussed. The different strategies for CTC release from the devices are specifically outlined. In addition, existing nanotechnology-assisted methods for CTC downstream analysis are summarized. Some perspectives are discussed on the challenges of current methods for CTC studies and promising research directions.

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Covalent chemistry on nanostructured substrates enables noninvasive quantification of gene rearrangements in circulating tumor cells

Cited by 36 publications

References 40 publications

Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring

Purification of HCC-specific extracellular vesicles on nanosubstrates for early HCC detection by digital scoring

Nanostructured Substrates for Detection and Characterization of Circulating Rare Cells: From Materials Research to Clinical Applications

Nanotechnology-Assisted Isolation and Analysis of Circulating Tumor Cells on Microfluidic Devices

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