Antiangiogenic nanotherapy with lipase-labile Sn-2 fumagillin prodrug

Dipanjan Pan, Nibedita Sanyal, Anne H. Schmieder, Angana Senpan, Benjamin Kim, Xiaoxia Yang, Grace Hu, John S. Allen, Richard W. Gross, Samuel A. Wickline, Gregory M. Lanza

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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 languageEnglish
Pages (from-to)1507-1519
Number of pages13
JournalNanomedicine
Volume7
Issue number10
DOIs
StatePublished - Oct 2012

Keywords

  • angiogenesis
  • fumagillin
  • nanomedicine
  • nanoparticle
  • prodrug
  • therapy

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