Immobilized surfactant-nanotube complexes support selectin-mediated capture of viable circulating tumor cells in the absence of capture antibodies

Abstract

The metastatic spread of tumor cells from the primary site to anatomically distant organs leads to a poor patient prognosis. Increasing evidence has linked adhesive interactions between circulating tumor cells (CTCs) and endothelial cells to metastatic dissemination. Microscale biomimetic flow devices hold promise as a diagnostic tool to isolate CTCs and develop metastatic therapies, utilizing E-selectin (ES) to trigger the initial rolling adhesion of tumor cells under flow. To trigger firm adhesion and capture under flow, such devices also typically require antibodies against biomarkers thought to be expressed on CTCs. This approach is challenged by the fact that CTCs are now known to exhibit heterogeneous expression of conventional biomarkers. Here, we describe surfactant-nanotube complexes to enhance ES-mediated capture and isolation of tumor cells without the use of capture antibodies. While the majority of tumor cells exhibited weaker rolling adhesion on halloysite nanotubes (HNT) coated with ES, HNT functionalization with the sodium dodecanoate (NaL) surfactant induced a switch to firm cellular adhesion under flow. Conversely, surfactant-nanotube complexes significantly reduced the number of primary human leukocytes captured via ES-mediated adhesion under flow. The switch in tumor cell adhesion was exploited to capture and isolate tumor cells in the absence of EpCAM antibodies, commonly utilized as the gold standard for CTC isolation. Additionally, HNT-NaL complexes were shown to capture tumor cells with low to negligible EpCAM expression, that are not efficiently captured using conventional approaches.

Circulating Tumor Cells: When a Solid Tumor Meets a Fluid Microenvironment

“…Various receptor-ligand bond formations (via a family of selectin adhesion molecules) and hydrodynamic interactions have previously been modeled for leukocytes-endothelium adhesion [26,65,19,23]. Recent experiments in microfluidic devices have also reported either selectin-mediated [40] or platelet-enhanced [37] adhesive capture of tumor cells. Moreover, cell rolling along the endothelium that was observed in in vitro experiments and modeled in silico in the case of leukocytes [3,19,25,38] has also been postulated to work in the case of circulating tumor cells [37,67].…”

Polymeric mechanical amplifiers of immune cytokine-mediated apoptosis

“…Biodegradable particles such as PLGA are particularly advantageous for in vivo administration, where the material can degrade in a safe manner3839. PLGA particles functionalized with an epithelial cell adhesion molecule (EpCAM)-targeting antibody, which binds to EpCAM expressed on tumour cells of epithelial origin40, were bound to the tumour cell surface with minimal effects on cell viability under shear and static conditions (Supplementary Fig. 10a).…”

Materials and microfluidics: enabling the efficient isolation and analysis of circulating tumour cells

“…3B) is a microfluidic technology that uses magnetic affinity-based CTC isolation. 82,155 Blood is first incubated in a static, diffusion-limited environment with Ab-coated magnetic microbeads. The, the iChip uses several concepts to isolate CTCs: 107 (i) the blood is “debulked” by deterministic lateral displacement, 109 a hydrodynamic technique that depletes cells smaller than 8 μm (monocytes, lymphocytes, RBCs, and platelets) and cells larger than 30 μm; 50,107 (ii) the remaining cells are aligned into a single line by inertial focusing; 107,110 and (iii) a magnetic field is applied to separate labelled cells from non-labelled cells.…”

“…Electrostatic or hydrophobic interactions selectively bind cancer cells versus neutrophils and were suggested to be associated with an extracellular matrix specific to cancer cells. 155 In another example, the halloysite nanotubes were coated with liposomes containing doxorubicin, which were functionalized with E-selectin to cause liposomal-CTC binding and selective chemotherapy delivery to the CTCs. 156 …”