title: Brain tumor tandem targeting using a combination of monoclonal antibodies attached to biopoly(beta-L-malic acid).
abstract: Tumor-specific targeting using achievements of nanotechnology is a mainstay of increasing efficacy of anti-tumor drugs. To improve drug targeting we covalently conjugated for the first time two different monoclonal antibodies, an anti-mouse transferrin receptor antibody and a mouse autoimmune anti-nucleosome antibody 2C5, onto the drug delivery nanoplatform, poly(beta-L-malic acid). The active anti-tumor drug components attached to the same carrier molecule were antisense oligonucleotides to vascular protein laminin-8. The resulting drug, a new Polycefin variant, was administered intravenously into glioma-bearing xenogeneic animals. The drug delivery system was targeted across mouse endothelial system by the anti-mouse transferring receptor antibody and to the tumor cell surface by the anti-nucleosome antibody 2C5. The targeting efficacies of the Polycefin variants bearing either two antibodies or each single antibody were compared in vitro and in vivo. ELISA confirmed the co-existence of two antibodies on the same nanoplatform molecule and their functional activities. Fluorescence imaging analysis after 24 h of intravenous injection demonstrated significantly higher tumor accumulation of Polycefin variants with the tandem configuration of antibodies than with single antibodies. The results suggest improved efficacy for tandem configuration of antibodies than for single configurations carried by a drug delivery vehicle.
authors.affiliation: Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujita
authors.forename: Bong-Seop
authors.initials: BS
authors.lastname: Lee
authors.forename: Natalya M
authors.initials: NM
authors.lastname: Khazenzon
authors.forename: Manuel L
authors.initials: ML
authors.lastname: Penichet
authors.forename: Kolja A
authors.initials: KA
authors.lastname: Wawrowsky
authors.forename: Rameshwar
authors.initials: R
authors.lastname: Patil
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.forename: Eggehard
authors.initials: E
authors.lastname: Holler
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.forename: Julia Y
authors.initials: JY
authors.lastname: Ljubimova
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001704:Biopolymers / Q000737:chemistry*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry*; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007797:Laminin / Q000008:administration & dosage / Q000627:therapeutic use; D008293:Malates / Q000737:chemistry*; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles / Q000737:chemistry; D009368:Neoplasm Transplantation; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000627:therapeutic use; D011091:Polyesters / Q000737:chemistry*; D011108:Polymers / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D001704:Biopolymers; D004337:Drug Carriers; D007797:Laminin; D008293:Malates; D016376:Oligonucleotides, Antisense; D011091:Polyesters; D011108:Polymers; C110308:laminin 8; C121060:poly(malic acid); C511560:polycefin