title: An orally delivered small-molecule formulation with antiangiogenic and anticancer activity.
abstract: Targeting angiogenesis, the formation of blood vessels, is an important modality for cancer therapy. TNP-470, a fumagillin analog, is among the most potent and broad-spectrum angiogenesis inhibitors. However, a major clinical limitation is its poor oral availability and short half-life, necessitating frequent, continuous parenteral administration. We have addressed these issues and report an oral formulation of TNP-470, named Lodamin. TNP-470 was conjugated to monomethoxy-polyethylene glycol-polylactic acid to form nanopolymeric micelles. This conjugate can be absorbed by the intestine and selectively accumulates in tumors. Lodamin significantly inhibits tumor growth, without causing neurological impairment in tumor-bearing mice. Using the oral route of administration, it first reaches the liver, making it especially efficient in preventing the development of liver metastasis in mice. We show that Lodamin is an oral nontoxic antiangiogenic drug that can be chronically administered for cancer therapy or metastasis prevention.
authors.affiliation: Vascular Biology Program and Department of Surgery, Children's Hospital Boston, Harvard Medical School, 1 Blackfan Circle, St. Karp Research Building, Boston, Massachusetts 02215, USA. ofra.bennyratsaby@childrens.harvard.edu
authors.forename: Ofra
authors.initials: O
authors.lastname: Benny
authors.forename: Ofer
authors.initials: O
authors.lastname: Fainaru
authors.forename: Avner
authors.initials: A
authors.lastname: Adini
authors.forename: Flavia
authors.initials: F
authors.lastname: Cassiola
authors.forename: Lauren
authors.initials: L
authors.lastname: Bazinet
authors.forename: Irit
authors.initials: I
authors.lastname: Adini
authors.forename: Elke
authors.initials: E
authors.lastname: Pravda
authors.forename: Yaakov
authors.initials: Y
authors.lastname: Nahmias
authors.forename: Samir
authors.initials: S
authors.lastname: Koirala
authors.forename: Gabriel
authors.initials: G
authors.lastname: Corfas
authors.forename: Robert J
authors.initials: RJ
authors.lastname: D'Amato
authors.forename: Judah
authors.initials: J
authors.lastname: Folkman
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D003510:Cyclohexanes / Q000008:administration & dosage*; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011091:Polyesters / Q000008:administration & dosage*; D012717:Sesquiterpenes / Q000008:administration & dosage*; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D003510:Cyclohexanes; D011091:Polyesters; D012717:Sesquiterpenes; C585731:lodamin; D000077609:O-(Chloroacetylcarbamoyl)fumagillol