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

Speaker：鄭至暐                                                                          Time：2004/4/14

Commentator：周楠華 老師                                                         Place：Room 601

Abstract：   

Angiogenesis, the growth of new capillary blood vessels from preexisting vasculature, is important in tumor progression and metastasis. Because endothelial cells in tumors are genetically stable, drug resistance may be less likely to develop with antiangiogenesis agents. Thus, antiangiogenesis may be an attractive anticancer strategy. Fumagillin, a nature product isolated fromAspergillus fumigatus, has been shown to strongly inhibit endothelial cell proliferation. However, the clinical utility of fumagillin is limited by severe weight loss and neurotoxicity. TNP-470, a derivative of fumagillin, exhibits 50-fold more potent antiangiogenesis activity and lower toxicity compared with fumagillin, but the dose-limiting toxicity of TNP-470 remains the major obstacle to its use as an anticancer agent. Here, the authors proposed the use of water-soluble synthetic polymers, HPMA copolymers, as specific carriers of angiogenesis inhibitor. HPMA copolymers are biocompatible, nonimmunogenic and nontoxic, and their body distribution is well characterized. The HPMA copolymer-TNP-470 accumulated selectively in the tumor site because of the enhanced permeability and retention (PER) effect, which is due to the abnormal vasculature with an increased vessel permeability and the poor lymphatic drainage of tumors. Polymer-angiogenesis inhibitor conjugates can take advantage of PER effect and have better anticancer efficiency. TNP-470, when conjugated with HPMA copolymers, also decreased its penetration through the BBB, increased its circulation time and solubility, and decreased overall toxicity. This study represents an example of how an effective angiogenesis inhibitor can be substantially improved and its toxicity decreased by conjugating it to a polymer.

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3.     Satchi-Fainaro, R. et al. Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470. Nature Medicine 10, 255-261, 2004