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Published on: February 9, 2019
Antiangiogenic nanotherapy with lipase-labile Sn-2 fumagillin prodrug
Dipanjan Pan1, Nibedita Sanyal, Anne H Schmieder
1Division of Cardiology, Washington University School of Medicine, 4320 Forest Park Avenue, Saint Louis, MO 63108, USA. dipanjan@wustl.edu
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:
α(v)β(3)-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, α(v)β(3)-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.
