title: The architecture and biological function of dual antibody-coated dendrimers: enhanced control of circulating tumor cells and their hetero-adhesion to endothelial cells for metastasis prevention.
abstract: Dissemination of circulating tumor cells (CTCs) in blood and their hetero-adhesion to vascular endothelial bed of distant metastatic secondary organs are the critical steps to initiate cancer metastasis. The rarity of CTCs made their in vivo capture technically challenging. Current techniques by virtue of nanostructured scaffolds monovalently conjugated with a single antibody and/or drug seem less efficient and specific in capturing CTCs. Here, we report a novel platform developed to re-engineer nanoscale dendrimers for capturing CTCs in blood and interfering their adhesion to vascular endothelial bed to form micrometastatic foci. The nanoscale dendrimers were spatiotemporally accommodated with dual antibodies to target two surface biomarkers of colorectal CTCs. Physiochemical characterization, including spectra, fluorescence, electron microscope, dynamic light scattering, electrophoresis, and chromatography analyses, was conducted to demonstrate the successful conjugation of dual antibodies to dendrimer surface. The dual antibody conjugates were able to specifically recognize and bind CTCs, moderately down-regulate the activity of the captured CTCs by arresting them in S phase. The related adhesion assay displayed that the dual antibody conjugates interfered the hetero-adhesion of CTCs to fibronectin (Fn)-coated substrates and human umbilical vein endothelial cells (HUVECs). The dual antibody conjugates also showed the enhanced specificity and efficiency in vitro and in vivo in restraining CTCs in comparison with their single antibody counterparts. The present study showed a novel means to effectively prevent cancer metastatic initiation by binding, restraining CTCs and inhibiting their hetero-adhesion to blood vessels, not by traditional cytotoxic-killing of cancer cells.
authors.affiliation: 1. Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Xie
authors.affiliation: 1. Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Rongli
authors.initials: R
authors.lastname: Zhao
authors.affiliation: 1. Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Songen
authors.initials: S
authors.lastname: Gu
authors.affiliation: 1. Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Dong
authors.affiliation: 1. Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Jichuang
authors.initials: J
authors.lastname: Wang
authors.affiliation: 1. Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Yusheng
authors.initials: Y
authors.lastname: Lu
authors.affiliation: 2. Rutgers, The State University of New Jersey, 160 Frelinghuysen Road, Piscataway, NJ, 08854, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Sinko
authors.affiliation: 1. Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Yu
authors.affiliation: 3. Department of Medicine Oncology, East Hospital of Xiamen University, Fuzhou 350004, China.
authors.forename: Fangwei
authors.initials: F
authors.lastname: Xie
authors.affiliation: 3. Department of Medicine Oncology, East Hospital of Xiamen University, Fuzhou 350004, China.
authors.forename: Lie
authors.initials: L
authors.lastname: Wang
authors.affiliation: 1. Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China. ; 4. Biopharmaceutical photocatalysis, State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou 350002, China.
authors.forename: Jingwei
authors.initials: J
authors.lastname: Shao
authors.affiliation: 1. Cancer Metastasis Alert and Prevention Center, College of Chemistry, Fuzhou University, Fuzhou 350002, China. ; 4. Biopharmaceutical photocatalysis, State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou 350002, China.
authors.forename: Lee
authors.initials: L
authors.lastname: Jia
mesh_terms: D000818:Animals; D000906:Antibodies / Q000737:chemistry*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D050091:Dendrimers / Q000737:chemistry*; D061307:Human Umbilical Vein Endothelial Cells / Q000473:pathology*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009360:Neoplastic Cells, Circulating / Q000737:chemistry*
chemical_list: D000906:Antibodies; D050091:Dendrimers
keywords: Cancer metastasis; Cell adhesion.; Cell binding and regulation; Circulating tumor cells; Dual antibody conjugation; PAMAM dendrimers