title: Development of TMTP-1 targeted designer biopolymers for gene delivery to prostate cancer.
abstract: Designer biopolymers (DBPs) represent state of the art genetically engineered biomacromolecules designed to condense plasmid DNA, and overcome intra- and extra- cellular barriers to gene delivery. Three DBPs were synthesized, each with the tumor molecular targeting peptide-1 (TMTP-1) motif to specifically target metastases. Each DBP was complexed with a pEGFP-N1 reporter plasmid to permit physiochemical and biological assay analysis. Results indicated that two of the biopolymers (RMHT and RM3GT) effectively condensed pEGFP-N1 into cationic nanoparticles <100 nm and were capable of transfecting PC-3 metastatic prostate cancer cells. Conversely the anionic RMGT DBP nanoparticles could not transfect PC-3 cells. RMHT and RM3GT nanoparticles were stable in the presence of serum and protected the cargo from degradation. Additionally it was concluded that cell viability could recover post-transfection with these DBPs, which were less toxic than the commercially available transfection reagent Lipofectamine(®) 2000. With both DBPs, a higher transfection efficacy was observed in PC-3 cells than in the moderately metastatic, DU145, and normal, PNT2-C2, cell lines. Blocking of the TMTP-1 receptors inhibited gene transfer indicating internalization via this receptor. In conclusion RMHT and RM3GT are fully functional DBPs that address major obstacles to gene delivery and target metastatic cells expressing the TMTP-1 receptor.
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK.
authors.forename: John W
authors.initials: JW
authors.lastname: McBride
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK.
authors.forename: Ashley S
authors.initials: AS
authors.lastname: Massey
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK.
authors.forename: J
authors.initials: J
authors.lastname: McCaffrey
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK.
authors.forename: Cian M
authors.initials: CM
authors.lastname: McCrudden
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Coulter
authors.affiliation: School of Mechanical and Aerospace Engineering, Queen's University Belfast, Stranmillis Road, Belfast BT9 5AH, UK.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Dunne
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK.
authors.forename: Tracy
authors.initials: T
authors.lastname: Robson
authors.affiliation: School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK. Electronic address: h.mccarthy@qub.ac.uk.
authors.forename: Helen O
authors.initials: HO
authors.lastname: McCarthy
mesh_terms: D001704:Biopolymers / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000008:administration & dosage* / Q000737:chemistry; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D008297:Male; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009842:Oligopeptides / Q000378:metabolism*; D010957:Plasmids; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism
chemical_list: D001704:Biopolymers; D009842:Oligopeptides; C531959:asparagyl-valyl-valyl-arginyl-glutamine; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D004247:DNA
keywords: Biopolymer; Delivery system; Gene Therapy; Nanoparticles; TMTP-1