title: Polymalic acid-based nanobiopolymer provides efficient systemic breast cancer treatment by inhibiting both HER2/neu receptor synthesis and activity.
abstract: Biodegradable nanopolymers are believed to offer great potential in cancer therapy. Here, we report the characterization of a novel, targeted, nanobiopolymeric conjugate based on biodegradable, nontoxic, and nonimmunogenic PMLA [poly(β-l-malic acid)]. The PMLA nanoplatform was synthesized for repetitive systemic treatments of HER2/neu-positive human breast tumors in a xenogeneic mouse model. Various moieties were covalently attached to PMLA, including a combination of morpholino antisense oligonucleotides (AON) directed against HER2/neu mRNA, to block new HER2/neu receptor synthesis; anti-HER2/neu antibody trastuzumab (Herceptin), to target breast cancer cells and inhibit receptor activity simultaneously; and transferrin receptor antibody, to target the tumor vasculature and mediate delivery of the nanobiopolymer through the host endothelial system. The results of the study showed that the lead drug tested significantly inhibited the growth of HER2/neu-positive breast cancer cells in vitro and in vivo by enhanced apoptosis and inhibition of HER2/neu receptor signaling with suppression of Akt phosphorylation. In vivo imaging analysis and confocal microscopy demonstrated selective accumulation of the nanodrug in tumor cells via an active delivery mechanism. Systemic treatment of human breast tumor-bearing nude mice resulted in more than 90% inhibition of tumor growth and tumor regression, as compared with partial (50%) tumor growth inhibition in mice treated with trastuzumab or AON, either free or attached to PMLA. Our findings offer a preclinical proof of concept for use of the PMLA nanoplatform for combination cancer therapy.
authors.affiliation: Department of Neurosurgery and Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Inoue
authors.forename: Hui
authors.initials: H
authors.lastname: Ding
authors.forename: Jose
authors.initials: J
authors.lastname: Portilla-Arias
authors.forename: Jinwei
authors.initials: J
authors.lastname: Hu
authors.forename: Bindu
authors.initials: B
authors.lastname: Konda
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujita
authors.forename: Andres
authors.initials: A
authors.lastname: Espinoza
authors.forename: Sonal
authors.initials: S
authors.lastname: Suhane
authors.forename: Marisa
authors.initials: M
authors.lastname: Riley
authors.forename: Marcus
authors.initials: M
authors.lastname: Gates
authors.forename: Rameshwar
authors.initials: R
authors.lastname: Patil
authors.forename: Manuel L
authors.initials: ML
authors.lastname: Penichet
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Ljubimov
authors.forename: Keith L
authors.initials: KL
authors.lastname: Black
authors.forename: Eggehard
authors.initials: E
authors.lastname: Holler
authors.forename: Julia Y
authors.initials: JY
authors.lastname: Ljubimova
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D001704:Biopolymers / Q000737:chemistry / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007275:Injections, Intravenous; D008293:Malates / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D053758:Nanoparticles / Q000737:chemistry / Q000627:therapeutic use; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001704:Biopolymers; D008293:Malates; D011108:Polymers; D018719:Erb-b2 Receptor Tyrosine Kinases; C121060:poly(malic acid); C508053:ERBB2 protein, human