Antiangiogenic nanotherapy with lipase-labile Sn-2 fumagillin prodrug

作者：Pan Dipanjan^*; Sanyal Nibedita; Schmieder Anne H; Senpan Angana; Kim Benjamin; Yang Xiaoxia; Hu Grace; Allen John S; Gross Richard W; Wickline Samuel A; Lanza Gregory M

来源：Nanomedicine, 2012, 7(10): 1507-1519.

DOI：10.2217/NNM.12.27

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

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: alpha(v)beta(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 (TM) (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, alpha(v)beta(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. Original submitted 1 September 2011; Revised submitted 30 December 2011; Published online 18 June 2012

• 出版日期2012-10