Nanoparticle-mediated targeting of phosphatidylinositol-3-kinase signaling inhibits angiogenesis

Angiogenesis. 2009;12(4):325-38. doi: 10.1007/s10456-009-9154-4.


Objective: Dysregulation of the phosphatidylinositol-3-kinase (PI3K) signaling pathway is a hallmark of human cancer, occurring in a majority of tumors. Activation of this pathway is critical for transformation and also for the angiogenic switch, which is a key step for tumor progression. The objective of this study was to engineer a PI3K inhibitor-loaded biodegradable nanoparticle and to evaluate its efficacy.

Methods and results: Here we report that a nanoparticle-enabled targeting of the PI3K pathway results in inhibition of downstream Akt phosphorylation, leading to inhibition of proliferation and induction of apoptosis of B16/F10 melanoma. It, however, failed to exert a similar activity on MDA-MB-231 breast cancer cells, resulting from reduced internalization and processing of nanoparticles in this cell line. Excitingly, the nanoparticle-enabled targeting of the PI3K pathway resulted in inhibition of endothelial cell proliferation and tubulogenesis, two key steps in tumor angiogenesis. Furthermore, it inhibited both B16/F10- and MDA-MB-231-induced angiogenesis in a zebrafish tumor xenotransplant model.

Conclusion: Our study, for the first time, shows that targeting of the PI3K pathway using nanoparticles can offer an attractive strategy for inhibiting tumor angiogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenocarcinoma / blood supply*
  • Animals
  • Breast Neoplasms / blood supply*
  • Carcinoma, Lewis Lung / blood supply*
  • Cell Line, Tumor / transplantation
  • Cells, Cultured / drug effects
  • Chromones / administration & dosage*
  • Chromones / pharmacology
  • Chromones / therapeutic use
  • Drug Carriers / administration & dosage*
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects*
  • Humans
  • Melanoma, Experimental / blood supply*
  • Mice
  • Morpholines / administration & dosage*
  • Morpholines / pharmacology
  • Morpholines / therapeutic use
  • Nanocapsules / administration & dosage*
  • Nanocapsules / ultrastructure
  • Neoplasm Proteins / antagonists & inhibitors*
  • Neovascularization, Pathologic / drug therapy*
  • Neovascularization, Physiologic / drug effects*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects*
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Umbilical Veins
  • Xenograft Model Antitumor Assays
  • Zebrafish


  • Chromones
  • Drug Carriers
  • Morpholines
  • Nanocapsules
  • Neoplasm Proteins
  • Phosphoinositide-3 Kinase Inhibitors
  • 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
  • AKT1 protein, human
  • Akt1 protein, mouse
  • Proto-Oncogene Proteins c-akt