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- Title
Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470.
- Authors
Satchi-Fainaro, Ronit; Puder, Mark; Davies, John W.; Tran, Hai T.; Sampson, David A.; Greene, Arin K.; Corfas, Gabriel; Folkman, Judah
- 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.
- Subjects
NEOVASCULARIZATION; BLOOD-vessel development; ANTINEOPLASTIC agents; CANCER treatment; COPOLYMERS; TUMOR growth
- Publication
Nature Medicine, 2004, Vol 10, Issue 3, p255
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm1002