Year: 2015
Type: article
Abstract: PURPOSE: Cross-talk and feedback between the RAS/RAF/MEK/ERK and PI3K/AKT/mTOR cell signaling pathways is critical for tumor initiation, maintenance, and adaptive resistance to targeted therapy in a variety of solid tumors. Combined blockade of these pathways-horizontal blockade-is a promising therapeutic strategy; however, compounded dose-limiting toxicity of free small molecule inhibitor combinations is a significant barrier to its clinical application. EXPERIMENTAL DESIGN: AZD6244 (selumetinib), an allosteric inhibitor of Mek1/2, and PX-866, a covalent inhibitor of PI3K, were co-encapsulated in a tumor-targeting nanoscale drug formulation-layer-by-layer (LbL) nanoparticles. Structure, size, and surface charge of the nanoscale formulations were characterized, in addition to in vitro cell entry, synergistic cell killing, and combined signal blockade. In vivo tumor targeting and therapy was investigated in breast tumor xenograft-bearing NCR nude mice by live animal fluorescence/bioluminescence imaging, Western blotting, serum cytokine analysis, and immunohistochemistry. RESULTS: Combined MAPK and PI3K axis blockade from the nanoscale formulations (160 ± 20 nm, -40 ± 1 mV) was synergistically toxic toward triple-negative breast (MDA-MB-231) and RAS-mutant lung tumor cells (KP7B) in vitro, effects that were further enhanced upon encapsulation. In vivo, systemically administered LbL nanoparticles preferentially targeted subcutaneous MDA-MB-231 tumor xenografts, simultaneously blocked tumor-specific phosphorylation of the terminal kinases Erk and Akt, and elicited significant disease stabilization in the absence of dose-limiting hepatotoxic effects observed from the free drug combination. Mice receiving untargeted, but dual drug-loaded nanoparticles exhibited progressive disease. CONCLUSIONS: Tumor-targeting nanoscale drug formulations could provide a more safe and effective means to synergistically block MAPK and PI3K in the clinic.
Source: Clinical Cancer Research
Language: English
Subfield: Biomaterials
Field: Materials Science
Domain: Physical Sciences
Open Access status: green
Funders: National Science Foundation, U.S. Department of Defense, Breast Cancer Alliance, Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Honorable Tina Brozman Foundation, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Institutes of Health, Materials Research Science and Engineering Center, Harvard University, National Cancer Institute, National Institute of Biomedical Imaging and Bioengineering, Division of Materials Research
Awards: G1067586170, G1350115407, G2360436881, G337158924, G3725677605, G4292279595, LbL Nanotechnologies for Synergistic Therapy of Advanced Ovarian Carcinoma, G4774430914, G5108852245, MIT Materials Research Science and Engineering Center (MRSEC), G693302148, G7256699606, G9000017315, G9000254200, Cancer Center Support (Core) Grant, G941982536
OpenAlex ID: W2098799992