title: Construction and evaluation of pH-sensitive immunoliposomes for enhanced delivery of anticancer drug to ErbB2 over-expressing breast cancer cells.
abstract: 1,5-Dihexadecyl N,N-diglutamyl-lysyl-L-glutamate (GGLG) liposomes were previously developed to enhance drug delivery efficiency in tumor cells owing to its pH-responsive properties. Herein, we report the modification of GGLG liposomes by conjugating a Fab' fragment of an ErbB2 antibody to the terminus of PEG (polyethylene glycol)-lipid (Fab'-GGLG liposomes). The conjugation of Fab' fragments did not affect the antibody activity, drug (doxorubicin, DOX) encapsulation efficiency, stability during storage or pH-sensitivity. However, the binding affinity of Fab'-GGLG liposomes was enhanced to ErbB2-overexpressing HCC1954 cells specifically, and the cell association increased 10-fold in comparison to GGLG liposomes. Consequently, intracellular DOX delivery was enhanced, with an increased cytotoxicity in HCC1954 cells (i.e., IC50of 1.17 and 3.08 μg/mL for Fab'-GGLG-DOX and GGLG-DOX liposomes, respectively). Further, a significantly enhanced tumor growth inhibition was obtained in an ErbB2-overexpressing breast cancer-bearing mouse model. Therefore, a potent anticancer drug delivery system was constructed by the immunological modification of pH-sensitive liposomes.
authors.affiliation: Research Organization for Nano & Life Innovation, Waseda University (TWIns), Tokyo, Japan.
authors.forename: Tianshu
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University (TWIns), Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Amari
authors.affiliation: Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University (TWIns), Tokyo, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Semba
authors.affiliation: Okinawa Institute of Science and Technology Graduate University, Okinawa, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: Research Organization for Nano & Life Innovation, Waseda University (TWIns), Tokyo, Japan; Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University (TWIns), Tokyo, Japan. Electronic address: takeoka@waseda.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeoka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D003692:Delayed-Action Preparations / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D018698:Glutamic Acid / Q000031:analogs & derivatives / Q000276:immunology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D018796:Immunoconjugates / Q000737:chemistry / Q000276:immunology*; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry / Q000276:immunology; D008081:Liposomes / Q000737:chemistry / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D003692:Delayed-Action Preparations; D004317:Doxorubicin; D018698:Glutamic Acid; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D008081:Liposomes; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: Anticancer; Drug delivery system; ErbB2-antibody; Immunoliposomes; pH-sensitive