Abstract
Metastasis impedes the successful chemotherapy for breast cancer. In this study, an Akt inhibitor (quercetin, Qu) was co-delivered with a chemotherapeutic agent (docetaxel, DTX) by using hyaluronic acid (HA)-modified nanoparticles (NPs) as vectors to block metastasis. Dual DTX/Qu-loaded HA/polylactic-co-glycolic acid-polyethyleneimine NPs (PP-HA/NPs) were prepared through a modified emulsion solvent evaporation technique. The particle size of PP-HA/NPs with narrow polydispersity was 209.8±10.8nm. Wound healing assay revealed that Qu co-delivery and HA modification elicited synergistic inhibitory effects on cell motility. The downregulation of p-Akt and matrix metalloproteinase-9 (MMP-9) expression contributed to the significant inhibition of cell migration and invasion with inhibition rates of 95.6% and 99.3%, respectively. Further studies indicated that PP-HA/NPs could be efficiently uptaken by 4T1 breast cancer cells and could further induce cytotoxicity, decrease colony formation and promote cell apoptosis. Biodistribution assay demonstrated PP-HA/NPs also enhanced drug accumulation in the tumor and lungs and predicted that PP-HA/NPs could be employed as an effective therapy for primary tumor and pulmonary metastasis. Therefore, PP-HA/NPs could be a promising delivery system to treat metastatic breast cancer effectively.
Keywords:
Akt/MMP-9 pathway; Breast cancer; Hyaluronic acid; Metastasis docetaxel; Quercetin.
Copyright © 2017 Elsevier B.V. All rights reserved.
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacokinetics
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Antioxidants / administration & dosage*
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Antioxidants / chemistry
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Antioxidants / pharmacokinetics
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Apoptosis / drug effects
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Breast Neoplasms
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Survival / drug effects
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Docetaxel
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Female
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Hyaluronic Acid / administration & dosage
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Hyaluronic Acid / chemistry
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Hyaluronic Acid / pharmacokinetics
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Imines / administration & dosage
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Imines / chemistry
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Imines / pharmacokinetics
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Lactic Acid / administration & dosage
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Lactic Acid / chemistry
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Lactic Acid / pharmacokinetics
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Matrix Metalloproteinase 9 / metabolism
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Matrix Metalloproteinase Inhibitors / administration & dosage*
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Matrix Metalloproteinase Inhibitors / chemistry
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Matrix Metalloproteinase Inhibitors / pharmacokinetics
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Mice, Inbred BALB C
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Nanoparticles / administration & dosage*
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Nanoparticles / chemistry
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Polyethylenes / administration & dosage
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Polyethylenes / chemistry
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Polyethylenes / pharmacokinetics
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Polyglycolic Acid / administration & dosage
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Polyglycolic Acid / chemistry
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Polyglycolic Acid / pharmacokinetics
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Polylactic Acid-Polyglycolic Acid Copolymer
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Quercetin / administration & dosage*
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Quercetin / chemistry
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Quercetin / pharmacokinetics
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Taxoids / administration & dosage*
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Taxoids / chemistry
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Taxoids / pharmacokinetics
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Wound Healing / drug effects
Substances
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Antineoplastic Agents
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Antioxidants
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Imines
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Matrix Metalloproteinase Inhibitors
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Polyethylenes
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Taxoids
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poly(ethylene imine)
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Docetaxel
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Polylactic Acid-Polyglycolic Acid Copolymer
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Polyglycolic Acid
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Lactic Acid
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Hyaluronic Acid
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Quercetin
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Proto-Oncogene Proteins c-akt
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Matrix Metalloproteinase 9
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Mmp9 protein, mouse