An orally delivered small-molecule formulation with antiangiogenic and anticancer activity

• Published in: Nature biotechnology 2008-07, Vol.26 (7), p.799-807
• Main Authors: Adini, Avner, Nahmias, Yaakov, Koirala, Samir, Benny, Ofra, Pravda, Elke, Cassiola, Flavia, Corfas, Gabriel, Fainaru, Ofer, Bazinet, Lauren, Adini, Irit, Folkman, Judah, D'Amato, Robert J
• Format: Article
• Language: English
• Subjects: Administration, Oral; Agriculture; Angiogenesis inhibitors; Angiogenesis Inhibitors - administration & dosage; Animals; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Cell Line, Tumor; Chemotherapy; Complications and side effects; Cyclohexanes - administration & dosage; Dosage and administration; Drug dosages; Drug therapy; Health aspects; Humans; Inhibitor drugs; Life Sciences; Liver; Lung Neoplasms - blood supply; Lung Neoplasms - drug therapy; Medical sciences; Metastasis; Mice; Molecular biology; Neovascularization; Neovascularization, Pathologic - drug therapy; Neurological complications; O-(Chloroacetylcarbamoyl)fumagillol; Oncology; Pharmacology. Drug treatments; Polyesters - administration & dosage; Polylactic acid; Prevention; Sesquiterpenes - administration & dosage; Treatment Outcome; Tumors
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt1415

Widespread use of antiangiogenic drugs for cancer therapy is limited in part by the requirement for intravenous injection. Benny et al . describe an oral formulation of an antiangiogenic small molecule that inhibits tumor growth and prevents liver metastases in mice. 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.