Abstract
BackgroundCancer metastasis caused by circulating tumor cells (CTCs) accounts for 90% cancer-related death worldwide. Blocking the circulation of CTCs in bloodstream and their hetero-adhesion to vascular endothelia of the distant metastatic organs may prevent cancer metastasis. Nanomaterial-based intervention with adhesion between CTCs and endothelia has not been reported. Driven by the novel idea that multivalent conjugation of EpCAM and Slex antibodies to dendrimer surface may enhance the capacity and specificity of the nanomaterial conjugates for capturing and down-regulating colorectal CTCs, we conjugated the dendrimer nanomaterial with the EpCAM and Slex antibodies, and examined the capacity of the dual antibody-coated nanomaterial for their roles in interrupting CTCs-related cancer metastasis.ResultsThe antibody-coated nanomaterial was synthesized and characterized. The conjugates specifically bound and captured colon cancer cells SW620. The conjugate inhibited the cells’ viability and their adhesion to fibronectin (Fn)-coated substrate or human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. In comparison with SW480 and LoVo cell lines, the activity and adhesion of SW620 to Fn-coated substrate and HUVECs were more specifically inhibited by the dual antibody conjugate because of the higher levels of EpCAM and Slex on SW620 cell surface. The hetero-adhesion between SW620 and Fn-coated substrate, or HUVECs was inhibited by about 60-70%. The dual conjugate showed the inhibition capacity more significant than its corresponding single antibody conjugates.ConclusionsThe present study provides the new evidence that coating nanomaterials with more than one antibody against CTCs may effectively interfere with the interaction between SW620 and HUVECs.Electronic supplementary materialThe online version of this article (doi:10.1186/s12951-015-0072-x) contains supplementary material, which is available to authorized users.
Highlights
Cancer metastasis caused by circulating tumor cells (CTCs) accounts for 90% cancer-related death worldwide
Synthesis and physiochemical characterization of Completely carboxylated G6 PAMAM (G6)-5A-5S and PE-5A-G6-5S-fluorescein isothiocyanate (FITC) conjugates Nanostructured PAMAM dendrimers with the functional group of 256 end amines were chosen as the good scaffolds to assemble dual antibodies, owing to their high payload and multivalent binding effect [20,37]
Fluorescence-labeled dual antibody conjugate was synthesized by using phycoerythrin (PE) linked antiEpCAM and fluorescein isothiocyanate (FITC) linked antiSlex, instead (Figure 1a)
Summary
Cancer metastasis caused by circulating tumor cells (CTCs) accounts for 90% cancer-related death worldwide. The progress of cancer metastasis usually depends on a series of consequential events, including the activation of dormant CTCs, the hetero-adhesion of CTCs to vascular endothelial bed of secondary organs, the continued survival and proliferation of CTCs after extravasation, and the formation of initial micrometastatic foci [10] It seems that the effective prevention of cancer metastasis may be achieved by interrupting the circulation or activation of CTCs in blood and/or inhibiting the adhesion between CTCs and vascular endothelial cells. Some techniques were developed to capture CTCs, such as employing the epithelial cell adhesion molecule (EpCAM) antibody-coated threedimensional nanostructured substrates [18,19], dendrimers [20], graphene oxide nanosheets [21] or immunomagnetic nanospheres [20,22,23] These studies were only confined to functionalize nanomaterials with one targeting antibody against a single CTCs surface biomarker. The unbound CTCs still made it possible to drive cancer metastasis
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