Reformulated Oral Angiogenesis Inhibitor is Effective and Nontoxic

Cancer researchers have modified a powerful angiogenesis-inhibiting drug to be nontoxic and suitable for oral administration.

The original drug, the fumagillin analog TNP-470, was discovered nearly 20 years ago. It is among the most potent and broad-spectrum angiogenesis inhibitors available to clinical researchers. However, a major clinical limitation is its poor oral availability and short half-life, necessitating frequent, continuous parenteral administration.

Several years ago TNP-470 was reformulated by attaching a large polymer to prevent it from crossing the blood-brain barrier. In this formulation, Caplostatin has no neurotoxicity and is in development for clinical trials. However, it too must be given intravenously.

The current article in the June 29, 2008, online edition of the journal Nature Biotechnology describes a new version of TNP-470 that has been modified by being conjugated to monomethoxy-polyethylene glycol–polylactic acid to form nanopolymeric micelles. This conjugate, called Lodamin (based on the Hebrew word meaning "no blood”), can be absorbed by the intestine and selectively accumulates in tumors. Lodamin significantly inhibits tumor growth, without causing neurologic 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.

"This was one of the most surprising things I saw,” said first author Dr. Ofra Benny, a researcher at Children's Hospital (Boston, MA, USA). "When I looked at the livers of the mice, the treated group was almost clean. In the control group, you could not recognize the livers--they were a mass of tumors. I had never expected such a strong effect on these aggressive tumor models.”


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