Synergistic inhibition of migration and invasion of breast cancer cells by dual docetaxel/quercetin-loaded nanoparticles via Akt/MMP-9 pathway.
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.
School of Pharmacy, Shanghai Jiao Tong University,Dongchuan Road 800, Shanghai 200240, China.
Jing
J
Li
School of Pharmacy, Shanghai Jiao Tong University,Dongchuan Road 800, Shanghai 200240, China.
Jun
J
Zhang
School of Pharmacy, Shanghai Jiao Tong University,Dongchuan Road 800, Shanghai 200240, China.
Yiyue
Y
Wang
School of Pharmacy, Shanghai Jiao Tong University,Dongchuan Road 800, Shanghai 200240, China.
Xiao
X
Liang
School of Pharmacy, Shanghai Jiao Tong University,Dongchuan Road 800, Shanghai 200240, China.
Zaitongguli
Z
Wusiman
School of Pharmacy, Shanghai Jiao Tong University,Dongchuan Road 800, Shanghai 200240, China.
Yunzhi
Y
Yin
School of Pharmacy, Shanghai Jiao Tong University,Dongchuan Road 800, Shanghai 200240, China. Electronic address: qshen@sjtu.edu.cn.
Qi
Q
Shen
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000975:Antioxidants / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000077143:Docetaxel; D005260:Female; D006820:Hyaluronic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D007097:Imines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D019344:Lactic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D011095:Polyethylenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D011100:Polyglycolic Acid / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011794:Quercetin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D014945:Wound Healing / Q000187:drug effects
D000970:Antineoplastic Agents; D000975:Antioxidants; D007097:Imines; D061965:Matrix Metalloproteinase Inhibitors; D011095:Polyethylenes; D043823:Taxoids; C505405:poly(ethylene imine); D000077143:Docetaxel; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D006820:Hyaluronic Acid; D011794:Quercetin; D051057:Proto-Oncogene Proteins c-akt; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
Akt/MMP-9 pathway; Breast cancer; Hyaluronic acid; Metastasis docetaxel; Quercetin