title: Nanoparticle-mediated drug delivery to tumor vasculature suppresses metastasis.
abstract: Integrin alphanubeta3 is found on a subset of tumor blood vessels where it is associated with angiogenesis and malignant tumor growth. We designed an alphanubeta3-targeted nanoparticle (NP) encapsulating the cytotoxic drug doxorubicin (Dox) for targeted drug delivery to the alphanubeta3-expressing tumor vasculature. We observed real-time targeting of this NP to tumor vessels and noted selective apoptosis in regions of the alphanubeta3-expressing tumor vasculature. In clinically relevant pancreatic and renal cell orthotopic models of spontaneous metastasis, targeted delivery of Dox produced an antimetastatic effect. In fact, alphanubeta3-mediated delivery of this drug to the tumor vasculature resulted in a 15-fold increase in antimetastatic activity without producing drug-associated weight loss as observed with systemic administration of the free drug. These findings reveal that NP-based delivery of cytotoxic drugs to the alphanubeta3-positive tumor vasculature represents an approach for treating metastatic disease.
authors.affiliation: Department of Pathology, Moores Cancer Center, University of California at San Diego, 3855 Health Sciences Drive, La Jolla, CA 92093, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Murphy
authors.forename: Bharat K
authors.initials: BK
authors.lastname: Majeti
authors.forename: Leo A
authors.initials: LA
authors.lastname: Barnes
authors.forename: Milan
authors.initials: M
authors.lastname: Makale
authors.forename: Sara M
authors.initials: SM
authors.lastname: Weis
authors.forename: Kimberly
authors.initials: K
authors.lastname: Lutu-Fuga
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wrasidlo
authors.forename: David A
authors.initials: DA
authors.lastname: Cheresh
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D002292:Carcinoma, Renal Cell / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use*; D016503:Drug Delivery Systems; D004727:Endothelium / Q000187:drug effects / Q000473:pathology; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D007680:Kidney Neoplasms / Q000473:pathology; D051379:Mice; D053758:Nanoparticles; D009362:Neoplasm Metastasis / Q000188:drug therapy*; D009369:Neoplasms / Q000098:blood supply* / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; D004317:Doxorubicin