title: Using doxorubicin and siRNA-loaded heptapeptide-conjugated nanoparticles to enhance chemosensitization in epidermal growth factor receptor high-expressed breast cancer cells.
abstract: The aim of this study was to develop the heptapeptide-conjugated active targeting nanoparticles for delivery of doxorubicin and siRNA to epidermal growth factor receptor (EGFR) high-expressed breast cancer cells. The active targeting nanoparticles were prepared by using a synthesized poly(D,L-lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG) copolymer conjugated with a heptapeptide. The particle size of peptide-conjugated nanoparticles was less than 200 nm with narrow size distribution and the surface charge was negative. The uptake of peptide-conjugated nanoparticles was more efficient in EGFR high-expressed MDA-MB-468 cells than in EGFR low-expressed HepG2 cells by 3.9 folds due to peptide specific binding to EGF receptor followed by EGF receptor-mediated endocytosis. The nanoparticles were used to deliver doxorubicin and siRNA, and their in vitro release was faster in pH 4.0 (500 U lipase) than in pH 7.4. The IC50 of doxorubicin-loaded peptide-conjugated nanoparticles was lower than that of peptide-free nanoparticles by 2.3 folds in MDA-MB-468 cells. Similarly, the cellular growth inhibition of siRNA/DOTAP-loaded peptide-conjugated nanoparticles was 2.1 folds higher than that of peptide-free nanoparticles. In conclusion, the heptapeptide-conjugated PLGA-PEG nanoparticles provided active targeting potential to EGFR high-expressed MDA-MB-468 breast cancer cells, and a synergistic cytotoxicity effect was achieved by co-delivery of doxorubicin and siRNA/DOTAP-loaded peptide-conjugated nanoparticles.
authors.affiliation: Graduate Institute of Pharmaceutical Sciences, National Taiwan University, Taipei, Taiwan.
authors.forename: Chia Wen
authors.initials: CW
authors.lastname: Liu
authors.forename: Wen Jen
authors.initials: WJ
authors.lastname: Lin
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D004705:Endocytosis / Q000502:physiology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry*; D010316:Particle Size; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D011098:Polyglactin 910 / Q000008:administration & dosage / Q000737:chemistry; D034741:RNA, Small Interfering / Q000008:administration & dosage* / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D010455:Peptides; D034741:RNA, Small Interfering; C102418:poly(lactic-glycolic acid)-poly(ethyleneglycol) copolymer; D011098:Polyglactin 910; D011092:Polyethylene Glycols; D004317:Doxorubicin; C512478:EGFR protein, human; D066246:ErbB Receptors