Nature Medicine10, 255 - 261 (2004)
Published online: 22 February 2004; | doi:10.1038/nm1002
Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470
Ronit Satchi-Fainaro1, Mark Puder1, John W Davies2, Hai T Tran3, David A Sampson1, Arin K Greene1, Gabriel Corfas4
& Judah Folkman1
1
Vascular Biology Program and Department of Surgery, Boston Children's Hospital and Harvard Medical School, 1 Blackfan Circle, New Research Building, Boston, Massachusetts 02115, USA.
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.
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