title: P-selectin is a nanotherapeutic delivery target in the tumor microenvironment.
abstract: Disseminated tumors are poorly accessible to nanoscale drug delivery systems because of the vascular barrier, which attenuates extravasation at the tumor site. We investigated P-selectin, a molecule expressed on activated vasculature that facilitates metastasis by arresting tumor cells at the endothelium, for its potential to target metastases by arresting nanomedicines at the tumor endothelium. We found that P-selectin is expressed on cancer cells in many human tumors. To develop a targeted drug delivery platform, we used a fucosylated polysaccharide with nanomolar affinity to P-selectin. The nanoparticles targeted the tumor microenvironment to localize chemotherapeutics and a targeted MEK (mitogen-activated protein kinase kinase) inhibitor at tumor sites in both primary and metastatic models, resulting in superior antitumor efficacy. In tumors devoid of P-selectin, we found that ionizing radiation guided the nanoparticles to the disease site by inducing P-selectin expression. Radiation concomitantly produced an abscopal-like phenomenon wherein P-selectin appeared in unirradiated tumor vasculature, suggesting a potential strategy to target disparate drug classes to almost any tumor.
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Yosi
authors.initials: Y
authors.lastname: Shamay
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. The Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel.
authors.forename: Moshe
authors.initials: M
authors.lastname: Elkabets
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Li
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Janki
authors.initials: J
authors.lastname: Shah
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Brook
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Oncology, Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Brandeis University, Waltham, MA 02453, USA.
authors.forename: Keren
authors.initials: K
authors.lastname: Adler
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Baut
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Scaltriti
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Prakrit V
authors.initials: PV
authors.lastname: Jena
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Pharmacology Graduate Training Program, Johns Hopkins University, Baltimore, MD 21287, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Gardner
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Poirier
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Adriana
authors.initials: A
authors.lastname: Haimovitz-Friedman
authors.affiliation: Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. hellerd@mskcc.org.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Heller
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy / Q000556:secondary; D008545:Melanoma / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000532:radiotherapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry*; D019007:P-Selectin / Q000378:metabolism*; D011134:Polysaccharides / Q000737:chemistry / Q000627:therapeutic use; D011839:Radiation, Ionizing; D018874:Spheroids, Cellular / Q000187:drug effects / Q000528:radiation effects; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019007:P-Selectin; D011134:Polysaccharides; C007789:fucoidan