Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470

Ronit Satchi-Fainaro, Mark Puder, John W. Davies, Hai T. Tran, David A. Sampson, Arin K. Greene, Gabriel Corfas, Judah Folkman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Angiogenesis is crucial for tumor growth. Angiogenesis inhibitors, such as O-(chloracetyl-carbamoyl) fumagillol (TNP-470), are thus emerging as a new class of anticancer drugs. In clinical trials, TNP-470 slowed tumor growth in patients with metastatic cancer. However, at higher doses necessary for tumor regression, many patients experienced neurotoxicity. We therefore synthesized and characterized a water-soluble conjugate of N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer, Gly-Phe-Leu-Gly linker and TNP-470. This conjugate accumulated selectively in tumor vessels because of the enhanced permeability and retention (EPR) effect. HPMA copolymer-TNP-470 substantially enhanced and prolonged the activity of TNP-470 in vivo in tumor and hepatectomy models. Polymer conjugation prevented TNP-470 from crossing the blood-brain barrier (BBB) and decreased its accumulation in normal organs, thereby avoiding drug-related toxicities. Treatment with TNP-470 caused weight loss and neurotoxic effects in mice, whereas treatment with the conjugate did not. This new approach for targeting angiogenesis inhibitors specifically to the tumor vasculature may provide a new strategy for the rational design of cancer therapies.

Original languageEnglish
Pages (from-to)255-261
Number of pages7
JournalNature Medicine
Volume10
Issue number3
DOIs
StatePublished - Mar 2004
Externally publishedYes

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