Redox-Active Polymer Microcapsules for the Delivery of a Survivin-Specific siRNA in Prostate Cancer Cells

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 Lob, a marker related to autophagy (Le., 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.