A naturally occurring multivalent binding effect is manipulated by engineering cell capture surfaces using dendrimers. The enhanced binding through the multivalent effect significantly improves detection of tumor cells. This improvement can be potentially translated into clinically significant detection of circulating tumor cells from the blood of cancer patients.

Ein natürlicher Multivalenzeffekt wurde bei der Modifizierung einer Zellen einfangenden Oberfläche mit Dendrimeren genutzt. Die verstärkte Bindung aufgrund dieses Multivalenzeffekts verbessert den Nachweis von Tumorzellen deutlich, was für klinische Tests auf zirkulierende Tumorzellen im Blut von Krebspatienten interessant sein könnte.

Multivalent interactions, simultaneous binding of multiple ligands toward their multiple receptors, commonly occur in physiological and pathological events, which have been utilized to enhance targeting efficacy. The multivalent binding can be leveraged to develop an extremely sensitive device for detection of rare cells such as circulating tumor cell (CTC). Accurate enumeration of CTCs is of clinical importance in diagnosis and prognosis of cancer metastasis; however the rareness of CTCs, comprising as few as one tumor cell in the background of one million-one billion of normal blood cells, has made the effective detection of the cells extremely difficult. Here we report a novel surface chemistry that utilizes the multivalent effect for a highly stable cancer cell capture. Poly(amidoamine) (PAMAM) dendrimers have been reported as an excellent multivalent binding mediator due to their deformability and multiple functional groups. PAMAM dendrimers were conjugated with anti-epithelial cell adhesion molecules (aEpCAM), a commonly used antibody for CTC detection. A direct, quantitative analysis using surface plasmon resonance (SPR) revealed that the aEpCAM-dendrimer conjugates exhibited a dramatically enhanced binding avidity by a million-fold, compared to free aEpCAM. Dendrimers and aEpCAM were successfully immobilized on the surfaces, as confirmed by x-ray photoelectron spectroscopy and fluorescence microscopy. The surfaces were tested using in vitro cell lines (MDA-MB-361, MCF-7, and MDA-MB-231 cells as a CTC model). Surface immobilization of the dendrimer-aEpCAM conjugates resulted in a significantly enhanced tumor cell detection than the surfaces with the linear PEG-aEpCAM conjugates by ∼1.9 fold with higher binding stability over agitation (up to 69.1-fold). The enhancement through dendrimer-mediated multivalent binding effect was further increased up to 7-fold with addition of E-selectin that recruits the cancer cells onto the surface and induces their rolling under flow. This study demonstrates a novel surface engineering approach to exploiting the strong multivalent binding for sensitive detection of tumor cells, which has great potential for clinically significant detection of CTCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2388. doi:1538-7445.AM2012-2388

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