Nanoparticle-mediated targeting of phosphatidylinositol-3-kinase  signaling inhibits angiogenesis.
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.
Harfouche
Rania
R
Harvard-MIT Division of Health Sciences and Technology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Basu
Sudipta
S
Soni
Shivani
S
Hentschel
Dirk M
DM
Mashelkar
Raghunath A
RA
Sengupta
Shiladitya
S
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
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