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

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...

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Veröffentlicht in:Nature medicine 2004-03, Vol.10 (3), p.255-261
Hauptverfasser: Folkman, Judah, Satchi-Fainaro, Ronit, Puder, Mark, Davies, John W, Tran, Hai T, Sampson, David A, Greene, Arin K, Corfas, Gabriel
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Sprache:eng
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Zusammenfassung: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.
ISSN:1078-8956
1546-170X
DOI:10.1038/nm1002