Abstract
Background: The chemical instability of antiangiogenic fumagillin, combined with its poor retention during intravascular transit, requires an innovative solution for clinical translation. We hypothesized that an Sn-2 lipase-labile fumagillin prodrug, in combination with a contact-facilitated drug delivery mechanism, could be used to address these problems. Methods: αvβ3-targeted and nontargeted nanoparticles with and without fumagillin in the prodrug or native forms were evaluated in vitro and in vivo in the Matrigel™ (BD Biosciences, CA, USA) plug model of angiogenesis in mice. Results: In vitro experiments demonstrated that the new fumagillin prodrug decreased viability at least as efficacious as the parent compound, on an equimolar basis. In the Matrigel mouse angiogenesis model, αvβ3-fumagillin prodrug decreased angiogenesis as measured by MRI (3T), while the neovasculature was unaffected with the control nanoparticles. Conclusion: The present approach resolved the previously intractable problems of drug instability and premature release in transit to target sites.
Original language | English |
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Pages (from-to) | 1507-1519 |
Number of pages | 13 |
Journal | Nanomedicine |
Volume | 7 |
Issue number | 10 |
DOIs | |
State | Published - Oct 2012 |
Keywords
- angiogenesis
- fumagillin
- nanomedicine
- nanoparticle
- prodrug
- therapy