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Nanoparticle-mediated targeting of phosphatidylinositol-3-kinase signaling inhibits angiogenesis Harfouche R; Basu S; Soni S; Hentschel DM; Mashelkar RA; Sengupta SAngiogenesis 2009[]; 12 (4): 325-38OBJECTIVE: 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.|*Phosphoinositide-3 Kinase Inhibitors[MESH]|Adenocarcinoma/*blood supply[MESH]|Animals[MESH]|Breast Neoplasms/*blood supply[MESH]|Carcinoma, Lewis Lung/*blood supply[MESH]|Cell Line, Tumor/transplantation[MESH]|Cells, Cultured/drug effects[MESH]|Chromones/*administration & dosage/pharmacology/therapeutic use[MESH]|Drug Carriers/*administration & dosage[MESH]|Endothelial Cells/cytology/*drug effects[MESH]|Humans[MESH]|Melanoma, Experimental/*blood supply[MESH]|Mice[MESH]|Morpholines/*administration & dosage/pharmacology/therapeutic use[MESH]|Nanocapsules/*administration & dosage/ultrastructure[MESH]|Neoplasm Proteins/*antagonists & inhibitors[MESH]|Neovascularization, Pathologic/*drug therapy[MESH]|Neovascularization, Physiologic/*drug effects[MESH]|Phosphorylation/drug effects[MESH]|Protein Processing, Post-Translational/*drug effects[MESH]|Proto-Oncogene Proteins c-akt/*antagonists & inhibitors[MESH]|Umbilical Veins[MESH]|Xenograft Model Antitumor Assays[MESH]|Zebrafish[MESH] |
