title: Nanoparticle-mediated targeting of phosphatidylinositol-3-kinase  signaling inhibits angiogenesis.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  Our study, for the first time, shows that targeting of the PI3K pathway using nanoparticles can offer an attractive strategy for inhibiting tumor angiogenesis.
authors.affiliation: Harvard-MIT Division of Health Sciences and Technology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rania
authors.initials: R
authors.lastname: Harfouche
authors.forename: Sudipta
authors.initials: S
authors.lastname: Basu
authors.forename: Shivani
authors.initials: S
authors.lastname: Soni
authors.forename: Dirk M
authors.initials: DM
authors.lastname: Hentschel
authors.forename: Raghunath A
authors.initials: RA
authors.lastname: Mashelkar
authors.forename: Shiladitya
authors.initials: S
authors.lastname: Sengupta
mesh_terms: D000230:Adenocarcinoma / Q000098:blood supply*; D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply*; D018827:Carcinoma, Lewis Lung / Q000098:blood supply*; D045744:Cell Line, Tumor / Q000637:transplantation; D002478:Cells, Cultured / Q000187:drug effects; D002867:Chromones / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers / Q000008:administration & dosage*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D008546:Melanoma, Experimental / Q000098:blood supply*; D051379:Mice; D009025:Morpholines / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D053769:Nanocapsules / Q000008:administration & dosage* / Q000648:ultrastructure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D014471:Umbilical Veins; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
chemical_list: D002867:Chromones; D004337:Drug Carriers; D009025:Morpholines; D053769:Nanocapsules; D009363:Neoplasm Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494918:AKT1 protein, human; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt