Journal
ACS NANO
Volume 5, Issue 2, Pages 1335-1344Publisher
AMER CHEMICAL SOC
DOI: 10.1021/nn103044z
Keywords
autophagy; biocompatibility; layer-by-layer; microcapsules; siRNA; survivin
Categories
Funding
- Australian Research Council
- Associazione Italiana per la Ricerca sul Cancro
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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.
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