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Colorectal cancer (CRC) is one of the main causes of cancer-related morbidity and mortality across the globe. Although serum biomarkers such as carcinoembryonic antigen (CEA) and carbohydrate antigen 19–9 (CA-199) have been prevalently used as biomarkers in various cancers, they are neither very sensitive nor highly specific. Repeated tissue biopsies at different times of the disease can be uncomfortable for cancer patients. Additionally, the existence of tumor heterogeneity and the results of local biopsy provide limited information about the overall tumor biology. Against this backdrop, it is necessary to look for reliable and noninvasive biomarkers of CRC. Circulating tumor cells (CTCs), which depart from a primary tumor, enter the bloodstream, and imitate metastasis, have a great potential for precision medicine in patients with CRC. Various efficient CTC isolation platforms have been developed to capture and identify CTCs. The count of CTCs, as well as their biological characteristics and genomic heterogeneity, can be used for the early diagnosis, prognosis, and prediction of treatment response in CRC. This study reviewed the existing CTC isolation techniques and their applications in the clinical diagnosis and treatment of CRC. The study also presented their limitations and provided future research directions.

The isolation of specific and sensitive circulating tumor cells (CTCs) is significant for applying them in cancer diagnosis and monitoring. In this work, dual aptamer-modified poly(lactic-co-glycolic acid) (PLGA) nanofiber-based microfluidic devices were fabricated to achieve the highly efficient capture and specific release of epithelial and mesenchymal CTCs of ovarian cancer. Dual aptamer targeting epithelial cell adhesion molecules (EpCAM) and N-cadherin proteins to improve the capture sensitivity, bovine serum albumin (BSA) to guarantee the capture purity and the nanofibers to increase the capture efficiency via synchronously and effectively capturing the epithelial and mesenchymal CTCs with good capture specificity and sensitivity from blood samples were used. We used the target cells including the ovarian cancer A2780 cells (N-cadherin-high, EpCAM-low) and OVCAR-3 cells (EpCAM-high, N-cadherin-low) to test the devices, which exhibited good capture efficiency (91% for A2780 cells, 89% for OVCAR-3 cells), release efficiency (95% for A2780 cells, 88% for OVCAR-3 cells), and sensitivity for rare cells (92% for A2780 cells, 88% for OVCAR-3 cells). Finally, the clinical blood samples of ovarian cancer patients were detected by the PLGA nanofiber-based microfluidic device, and 1 to 13 CTCs were successfully confirmed to be captured with the help of immunofluorescence staining identification. The results exhibited that the dual aptamer-modified PLGA nanofiber-based microfluidic device used as a tool for CTC capture has the potential for clinical application to guide the diagnosis, treatment, and prognosis of ovarian cancer patients.

Circulating tumor cells (CTCs) are an important part of liquid biopsy as they represent a potentially rich source of information for cancer diagnosis, monitoring, prognosis, and treatment guidance. It has been proved that the nanotopography interaction between cells and the surface of CTC detection platforms can significantly improve the capture efficiency of CTCs, whereas many mature nanostructure substrates have been developed based on chemistry materials. In this work, a natural biointerface with unique biological properties is fabricated for efficient isolation and nondestructive release of CTCs from blood samples using the cancer cell membranes. The cell membrane interfaces are proved to have a good antiadhesion property for nonspecific cells because of their own electronegativity. A natural surface nanostructure is provided by the cancer cell membrane to nicely match with the surface nanotopography of CTCs. Bovine serum albumin (BSA) as a linker and DNA aptamer against the epithelial cell adhesion molecule (EpCAM) as a specific affinity molecule are then introduced onto the cell membrane interfaces to achieve the highly efficient and specific capture of CTCs. Finally, the captured target cells can be intactly released from the substrate using the complementary DNA sequence with controlling the incubation time. This study provides a smart strategy in the development of a natural biological interface for the isolation and release of CTCs with high purity.

Analysis of circulating tumor cells (CTCs) can provide significant clinical information for tumors, which has proven to be helpful for cancer diagnosis, prognosis monitoring, treatment efficacy, and personalized therapy. However, CTCs are an extremely rare cell population, which challenges the isolation of CTCs from patient blood. Over the last few decades, many strategies for CTC detection have been developed based on the physical and biological properties of CTCs. Among them, nanostructured interfaces have been widely applied as CTC detection platforms to overcome the current limitations associated with CTC capture. Furthermore, aptamers have attracted significant attention in the detection of CTCs due to their advantages, including good affinity, low cost, easy modification, excellent stability, and low immunogenicity. In addition, effective and nondestructive release of CTCs can be achieved by aptamer-mediated methods that are used under mild conditions. Herein, we review some progress in the detection and release of CTCs through aptamer-functionalized nanostructured interfaces.

The success of complex tissue and internal organ reconstruction relies principally on the fabrication of a 3D vascular network, which guarantees the delivery of oxygen and nutrients in addition to the disposal of waste. In this study, a rapidly forming cell-encapsulated double network (DN) hydrogel is constructed by an ultrasonically activated silk fibroin network and bioorthogonal-mediated polyethylene glycol network. This DN hydrogel can be solidified within 10 s, and its mechanical property gradually increases to ∼20 kPa after 30 min. This work also demonstrates that coencapsulation of human umbilical vein endothelial cells (HUVECs) and umbilical cord-derived mesenchymal stem cells (UCMSCs) into the DN hydrogel can facilitate the formation of more mature vessels and complete the capillary network in comparison with the hydrogels encapsulated with a single cell type both

The majority of current methods of isolating circulating tumor cells (CTCs) rely on a biomarker. However, the isolation efficiency may be compromised due to the heterogeneity of CTCs. In this work, a simple and broad-spectrum method is established to efficiently isolate the heterogeneous CTCs from patient blood samples using tannic acid (TA)-functionalized magnetic nanoparticles (MNPs). The TA-functionalized MNPs (MNPs-TA) inhibit the nonspecific adhesion of peripheral blood mononuclear cell (PBMC) and enhance cancer cell capture, resulting from the unique interaction between TA and glycocalyx on cancer cells. The MNPs-TA was demonstrated to effectively capture seven kinds of cancer cells (HeLa, PC-3, T24, MAD-MB-231, MCF-7, HT1080, A549) from artificial samples (62.3-93.7%). Moreover, this epithelial cell adhesion molecule (EpCAM)-independent CTC isolation method was also tested using clinical blood samples from patients with different cancers (21 patients), which may provide a universal tool to detect CTCs in the clinic.

Circulating tumor cells (CTCs) acquire mesenchymal markers (e.g., N-cadherin) and lose epithelial markers (e.g., epithelial cell adhesion molecule, EpCAM) during the epithelial-mesenchymal transition (EMT) and are therefore ideal biomarkers of tumor metastasis. However, it is still a challenge to efficiently capture and detect circulating tumor cells with different phenotypes simultaneously. In this work, to obtain aptamers targeting N-cadherin in the native conformation on live cells, we established stable N-cadherin overexpressing cells (N-cadherin cells) and used these cells to identify a panel of N-cadherin-specific aptamers through the cell-SELEX approach. Two aptamer candidates obtained after 12 rounds of selection showed a low equilibrium dissociation constant in the nanomolar range, indicating high binding affinity. The truncated aptamer candidate NC3S showed the highest binding affinity to N-cadherin cells with a low Kd value of 20.08 nM. The SYL3C aptamer was reported to target cancer cell surface biomarker EpCAM. Then, we synthesized two kinds of aptamer-modified magnetic nanoparticles (SYL3C-MNPs and NC3S-MNPs). Both SYL3C and NC3S aptamers possess excellent capture specificity and efficiency for the target cells. The aptamer-MNP cocktail exhibits a considerable capture efficiency and sensitivity for rare cancer cells of epithelial and mesenchymal phenotypes. Furthermore, no CTCs were found in blood samples from healthy donors, while CTCs were successfully isolated by using the aptamer-MNP cocktail for 15 out of 16 samples collected from patients. In summary, the two kinds of aptamer-modified MNPs could be utilized as a promising tool for capturing CTCs from clinical samples.

Ovarian cancer (OC) is a lethal disease occurring in women worldwide. Due to the lack of obvious clinical symptoms and sensitivity biomarkers, OC patients are often diagnosed in advanced stages and suffer a poor prognosis. Circulating tumor cells (CTCs), released from tumor sites into the peripheral blood, have been recognized as promising biomarkers in cancer prognosis, treatment monitoring, and metastasis diagnosis. However, the number of CTCs in peripheral blood is low, and it is a technical challenge to isolate, enrich, and identify CTCs from the blood samples of patients. This work develops a simple, effective, and inexpensive strategy to capture and identify CTCs from OC blood samples using the folic acid (FA) and antifouling-hydrogel-modified fluorescent-magnetic nanoparticles. The hydrogel showed a good antifouling property against peripheral blood mononuclear cells (PBMCs). The FA was coupled to the hydrogel surface as the targeting molecule for the CTC isolation, held a good capture efficiency for SK-OV-3 cells (95.58%), and successfully isolated 2–12 CTCs from 10 OC patients’ blood samples. The FA-modified fluorescent-magnetic nanoparticles were successfully used for the capture and direct identification of CTCs from the blood samples of OC patients.

Herein, we developed an inexpensive titanium dioxide (TiO

Extreme rarity and inherent heterogeneity of circulating tumor cells (CTCs) result in a tremendous challenge for the CTC isolation from patient blood samples with high efficiency and purity. Current CTC isolation approaches mainly rely on the epithelial cell adhesion molecule (EpCAM), which may significantly reduce the ability to capture CTCs when the expression of EpCAM is lost or down-regulated in epithelial-mesenchymal transition. Here, a rapid and highly efficient method is developed to isolate and identify heterogeneous CTCs with high efficiency from patient blood samples using the fluorescent-magnetic nanoparticles (F-MNPs). A dual-antibody interface targeting EpCAM and N-cadherin is fabricated onto the F-MNPs to capture epithelial CTCs as well as mesenchymal CTCs from whole blood samples. The poly(carboxybetaine methacrylate) brushes of excellent antifouling properties are employed to decrease nonspecific cell adhesion. Moreover, the F-MNPs provide a prompt identification strategy for heterogeneous CTCs (F-MNPs+, Hoechst 33342+, and CD45-) that can directly identify CTCs in a gentle one-step processing within 1 h after isolation from patient blood samples. This has been demonstrated through artificial samples as well as patient samples in details.

A novel bispecific α-Gal liposome was constructed by self-assembling AS1411 aptamers into the α-Gal containing liposomes. The α-Gal liposomes were prepared using cell membranes of red blood cells from rabbit, which are composed of cholesterol, phospholipids, and α-Gal glycolipids. AS1411 is a DNA aptamer with high specificity and affinity for nucleolin and could integrate into liposomes by the modification of cholesterol. The bispecific α-Gal liposomes surface-functionalized by α-Gal and AS1411 aptamer could recognize anti-Gal antibodies and nucleolin overexpressed by tumor cells simultaneously, followed by activating the immune system to attack the tumor cells, resulting in the lysis of the tumor cells by antibody dependent cell-mediated cytotoxicity. Under simulated tumor environment, the lysis rate of MCF-7 cells treated by the AS1411 modified α-Gal liposomes drastically increased compared to the liposomes without AS1411 aptamer. This study suggests that the AS1411 modified α-Gal liposomes can recognize nucleolin-overexpressing tumor cells selectively, subsequently improve the effect of the immunotherapy with high specificity. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 1176-1183, 2019.