title: Polyion complex micelle based on albumin-polymer conjugates: multifunctional oligonucleotide transfection vectors for anticancer chemotherapeutics.
abstract: Novel biocompatible polyion complex micelles, containing bovine serum albumin (BSA), polymer, and oligonucleotide, were synthesized as a generation of vectors for the gene transfection. Maleimide-terminated poly((N,N-dimethyl amino) ethyl methacrylate) (PDMAEMA) was prepared via reversible addition-fragmentation chain transfer (RAFT) polymerization and subsequently deprotected. Precise one to one albumin-PDMAEMA bioconjugates have been achieved via 1,4-addition with the free thiol group on Cys34 on the BSA protein. SDS-PAGE and GPC (water) confirmed and quantified the successful conjugation. The conjugation efficiency was found to be independent of the molecular weight of PDMAEMA. After careful pH adjustment, the conjugate could efficiently condense anticancer oligonucleotide, ISIS 5132, which resulted in particles of 15-35 nm with a negative zeta-potential. The size was easily controlled by the polymer chain length. The albumin corona provides complete protection of the cationic polymer and genetic drug, which gave rise to lower potential toxicity from the polymer and higher gene transfection efficiency. Although a control experiment with a traditional PEG-based polyion complex micelle could deliver the drug just as effectively, if not more so, to the ovarian cancer cell line OVCAR-3, this carrier had no selectivity toward cancerous cells and proved just as toxic to HS27 (fibroblast) cell line. In contrast, the albumin-coated particles demonstrated desirable selectivity toward cancerous cells and have been shown to have outstanding performance in the cytotoxicity tests of several carcinoma monolayer cell models. In addition, the complex micelles were able to destroy pancreatic multicellular tumor spheroids, while free ISIS 5132 could not penetrate the spheroid at all. Hence, albumin-coated/oligonucleotide complex micelles are far more promising than the most classical gene delivery vectors.
authors.affiliation: Centre for Advanced Macromolecular Design (CAMD), School of Chemistry, University of New South Wales , Sydney, NSW 2052, Australia.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Hongxu
authors.initials: H
authors.lastname: Lu
authors.forename: Yee Yee
authors.initials: YY
authors.lastname: Khine
authors.forename: Aydan
authors.initials: A
authors.lastname: Dag
authors.forename: Martina H
authors.initials: MH
authors.lastname: Stenzel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D002417:Cattle; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005822:Genetic Vectors / Q000008:administration & dosage / Q000737:chemistry*; D006801:Humans; D008823:Micelles; D009841:Oligonucleotides / Q000008:administration & dosage / Q000737:chemistry*; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry*; D012710:Serum Albumin, Bovine / Q000008:administration & dosage / Q000737:chemistry*; D014162:Transfection / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D009841:Oligonucleotides; D011108:Polymers; D012710:Serum Albumin, Bovine