Research abstract
Article abstract
Nature Biotechnology 26, 799 - 807 (2008)
Published online: 29 June 2008 | doi:10.1038/nbt1415
An orally delivered small-molecule formulation with antiangiogenic and anticancer activity
Ofra Benny1, Ofer Fainaru1, Avner Adini1, Flavia Cassiola1, Lauren Bazinet1, Irit Adini1, Elke Pravda1, Yaakov Nahmias2, Samir Koirala3, Gabriel Corfas3, Robert J D'Amato1,4 & Judah Folkman1
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.
- 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.
- Center for Engineering in Medicine, Massachusetts General Hospital, Harvard Medical School, 114 16th Street, Charlestown, Massachusetts 02129, USA.
- Department of Neurology, F.M. Kirby Neurobiology Center, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.
- Department of Ophthalmology, Harvard Medical School, Children's Hospital Boston, 1 Blackfan Circle, St. Karp Research Building, Boston, Massachusetts 02215, USA.
Correspondence to: Ofra Benny1 e-mail: ofra.bennyratsaby@childrens.harvard.edu
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