title: Redox-active polymer microcapsules for the delivery of a survivin-specific siRNA in prostate cancer cells.
abstract: In this report, we describe the delivery of small interfering RNA (siRNA) using LbL-assembled microcapsules. The microcapsules are based on negatively charged poly(methacrylic acid) nanometer thin films containing cross-linking disulfide bonds. One system is polycation-free and another contains polylysine for siRNA complexation in the microcapsule void. When microcapsules containing a siRNA targeting survivin were delivered to PC-3 prostate cancer cells, a significant inhibition of the expression of the antiapoptotic protein was observed. However, down-regulation of survivin was also observed in PC-3 cells exposed to microcapsules embedded with a scrambled siRNA as well as in cells treated with empty microcapsules. These findings indicate a capsule-dependent off-target effect, which is supported by a reduction in the expression of other survivin-unrelated proteins. The microcapsules and their polymeric constituents do not affect cell proliferation, as determined by a metabolic assay, even after 4 days of exposure. In addition, in PC-3 cells exposed to microcapsules, we observed a marked accumulation of LC3b, a marker related to autophagy (i.e., self-digestion), a degradation pathway involved in the maintenance of cell homeostasis in response to different stresses. This evidence suggests that empty microcapsules can induce a perturbation of the intracellular environment, which causes the activation of a cell safeguard mechanism that may limit the therapeutic effect of the microcapsules in tumor cells.
authors.affiliation: Department of Chemical and Biomolecular Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Alisa L
authors.initials: AL
authors.lastname: Becker
authors.forename: Nicola Ivan
authors.initials: NI
authors.lastname: Orlotti
authors.forename: Marco
authors.initials: M
authors.lastname: Folini
authors.forename: Francesca
authors.initials: F
authors.lastname: Cavalieri
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Zelikin
authors.forename: Angus P R
authors.initials: AP
authors.lastname: Johnston
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.forename: Frank
authors.initials: F
authors.lastname: Caruso
mesh_terms: D017209:Apoptosis; D002214:Capsules; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D051034:Inhibitor of Apoptosis Proteins / Q000172:deficiency* / Q000235:genetics*; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D055616:Microtechnology / Q000379:methods*; D008958:Models, Molecular; D009691:Nucleic Acid Denaturation; D010084:Oxidation-Reduction; D010316:Particle Size; D011108:Polymers / Q000737:chemistry*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D012822:Silicon Dioxide / Q000737:chemistry; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; D002214:Capsules; D004337:Drug Carriers; D051034:Inhibitor of Apoptosis Proteins; D011108:Polymers; D034741:RNA, Small Interfering; D000077022:Survivin; D012822:Silicon Dioxide