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Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470.
- Source :
- Nature Medicine; Mar2004, Vol. 10 Issue 3, p255-261, 7p
- Publication Year :
- 2004
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 10788956
- Volume :
- 10
- Issue :
- 3
- Database :
- Complementary Index
- Journal :
- Nature Medicine
- Publication Type :
- Academic Journal
- Accession number :
- 12394003
- Full Text :
- https://doi.org/10.1038/nm1002