title: Targeted delivery of CCR2 antagonist to activated pulmonary endothelium prevents metastasis.
abstract: Enhanced levels of the inflammatory chemokine CCL2 are known to correlate with increased tumorigenesis and metastases, and thereby poor prognosis for cancer patients. The CCL2-CCR2 chemokine axis was shown to facilitate the metastatic initiation through the recruitment of inflammatory monocytes and the activation of endothelial cells at metastatic sites. Both steps are required for efficient cancer cell trans-endothelial migration and seeding in the targeted tissue. The translation of preclinical evidence proved to be challenging due to systemic effects of chemokine inhibition and limited target specificity. Here we tested an approach of a targeted delivery of the CCR2 antagonist Teijin Compound 1 to metastatic sites. VCAM-1 binding peptide tagged liposomes carrying the CCR2 antagonist enabled a specific delivery to cancer cell-activated endothelium. The subsequent binding of target-sensitive liposomes triggered the release of the Teijin Compound 1 and thereby local inhibition of CCR2 in the lungs. Blocking of CCR2 resulted in reduced induction of the lungs vascular permeability, and thereby reduced tumor cell extravasation. However, the recruitment of inflammatory monocytes to the pre-metastatic lungs remained unaltered. Endothelial VCAM-1 targeted delivery of the CCR2 antagonist resulted in inhibition of pulmonary metastases both in a murine (MC-38GFP cells) and a human xenograft (patient-derived cells) model. Thus, timely- and spatially-defined inhibition of CCR2 signaling represents a potential therapeutic approach for treatment of metastasis without affecting homeostatic functions.
authors.affiliation: Institute of Physiology, University of Zürich and Zürich Center for Integrative Human Physiology, CH-8057 Zurich, Switzerland.
authors.forename: Marko
authors.initials: M
authors.lastname: Roblek
authors.affiliation: Institute of Cellular Biology and Pathology "N. Simionescu" of the Romanian Academy, Bucharest, Romania.
authors.forename: Manuela
authors.initials: M
authors.lastname: Calin
authors.affiliation: Department of Pharmacy, Rheinische Friedrich-Wilhelms-University Bonn, 53121 Bonn, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schlesinger
authors.affiliation: Institute of Cellular Biology and Pathology "N. Simionescu" of the Romanian Academy, Bucharest, Romania.
authors.forename: Daniela
authors.initials: D
authors.lastname: Stan
authors.affiliation: Experimental Pharmacology & Oncology Berlin Buch GmbH, 13125 Berlin, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Zeisig
authors.affiliation: Institute of Cellular Biology and Pathology "N. Simionescu" of the Romanian Academy, Bucharest, Romania.
authors.forename: Maya
authors.initials: M
authors.lastname: Simionescu
authors.affiliation: Department of Pharmacy, Rheinische Friedrich-Wilhelms-University Bonn, 53121 Bonn, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Bendas
authors.affiliation: Institute of Physiology, University of Zürich and Zürich Center for Integrative Human Physiology, CH-8057 Zurich, Switzerland. Electronic address: lborsig@access.uzh.ch.
authors.forename: Lubor
authors.initials: L
authors.lastname: Borsig
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D001549:Benzamides / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D018920:Coculture Techniques; D004339:Drug Compounding; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D008081:Liposomes; D008175:Lung Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary*; D051379:Mice; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D054390:Receptors, CCR2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects; D020298:U937 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C515335:Ccr2 protein, mouse; D008081:Liposomes; C541285:N-(carbamoylmethyl)-3-trifluoromethyl benzamido-4-chlorobenzyl 3-aminopyrrolidine; D010455:Peptides; D011759:Pyrrolidines; D054390:Receptors, CCR2; D019010:Vascular Cell Adhesion Molecule-1
keywords: Chemokine; Endothelium; Liposomes; Metastasis; Targeting; VCAM-1