Antiangiogenic nanotherapy with lipase-labile Sn-2 fumagillin prodrug.
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.


CONCLUSIONS
The present approach resolved the previously intractable problems of drug instability and premature release in transit to target sites.
Division of Cardiology, Washington University School of Medicine, 4320 Forest Park Avenue, Saint Louis, MO 63108, USA. dipanjan@wustl.edu
Dipanjan
D
Pan
Nibedita
N
Sanyal
Anne H
AH
Schmieder
Angana
A
Senpan
Benjamin
B
Kim
Xiaoxia
X
Yang
Grace
G
Hu
John S
JS
Allen
Richard W
RW
Gross
Samuel A
SA
Wickline
Gregory M
GM
Lanza
D000818:Animals; D001682:Biological Availability; D002478:Cells, Cultured; D003510:Cyclohexanes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D005231:Fatty Acids, Unsaturated / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008049:Lipase / Q000627:therapeutic use*; D051379:Mice; D050997:Nanomedicine; D009389:Neovascularization, Pathologic / Q000628:therapy*; D011355:Prodrugs / Q000627:therapeutic use*; D051381:Rats; D012717:Sesquiterpenes / Q000493:pharmacokinetics / Q000627:therapeutic use
D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D011355:Prodrugs; D012717:Sesquiterpenes; C026211:fumagillin; D008049:Lipase