title: Redox-Sensitive PEG-Polypeptide Nanoporous Particles for Survivin Silencing in Prostate Cancer Cells.
abstract: We report the engineering of intracellular redox-responsive nanoporous poly(ethylene glycol)-poly(l-lysine) particles (NPEG-PLLs). The obtained particles exhibit no toxicity while maintaining the capability to deliver a small interfering RNA sequence (siRNA) targeting the anti-apoptotic factor, survivin, in prostate cancer cells. The redox-mediated cleavage of the disulfide bonds stabilizing the NPEG-PLL-siRNA complex results in the release of bioactive siRNA into the cytosol of prostate cancer PC-3 cells, which, in turn, leads to the effective silencing (∼59 ± 8%) of the target gene. These findings, obtained under optimal conditions, indicate that NPEG-PLLs may protect the therapeutic nucleic acid in the extracellular and intracellular environments, thus preventing the occurrence of competitive interactions with serum and cytosolic proteins as well as degradation by RNase. The intracellular trafficking and final fate of the NPEG-PLLs were investigated by a combination of deconvolution microscopy, fluorescence lifetime imaging microscopy, and super-resolution structured illumination microscopy. A significant impairment of cell survival was observed in cells concomitantly exposed to paclitaxel and siRNA-loaded NPEG-PLLs. Overall, our findings indicate that NPEG-PLLs represent a highly loaded depot for the delivery of therapeutic nucleic acids to cancer cells.
authors.affiliation: †ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, and the Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.|‡Dipartimento di Scienze e Tecnologie Chimiche, Università di Roma Tor Vergata, Via della ricerca scientifica 1, 00173 Roma, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cavalieri
authors.affiliation: §Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Amadeo, 42-20133 Milano, Italy.
authors.forename: Giovanni L
authors.initials: GL
authors.lastname: Beretta
authors.affiliation: †ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, and the Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Cui
authors.affiliation: †ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, and the Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Julia A
authors.initials: JA
authors.lastname: Braunger
authors.affiliation: †ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, and the Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yan
authors.affiliation: †ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, and the Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Richardson
authors.affiliation: §Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Amadeo, 42-20133 Milano, Italy.
authors.forename: Stella
authors.initials: S
authors.lastname: Tinelli
authors.affiliation: §Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Amadeo, 42-20133 Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Folini
authors.affiliation: §Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Amadeo, 42-20133 Milano, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: †ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, and the Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Caruso
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D053758:Nanoparticles / Q000737:chemistry*; D017239:Paclitaxel / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry; D011107:Polylysine / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000378:metabolism*; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D011107:Polylysine; D011092:Polyethylene Glycols; D017239:Paclitaxel