Abstract
Redox-active polymers and carriers are oxidizing nanoagents that can potentially trigger intracellular off-target effects. In the present study, we investigated the occurrence of off-target effects in prostate cancer cells following exposure to redox-active polymer and thin multilayer capsules with different chemical properties. We show that, depending on the intracellular antioxidant capacity, thiol-functionalized poly(methacrylic acid), PMA(SH) triggers cell defense responses/perturbations that result in off-target effects (i.e., induction of autophagy and down-regulation of survivin). Importantly, the conversion of the carboxyl groups of PMA(SH) into the neutral amides of poly(hydroxypropylmetacrylamide) (pHPMA(SH)) nullified the off-target effects and cytotoxicity in tested cell lines. This suggests that the simultaneous action of carboxyl and disulfide groups in PMA(SH) polymer or capsules may play a role in mediating the intracellular off-target effects. Our work provides evidence that the rational design of redox-active carriers for therapeutic-related application should be guided by a careful investigation on potential disturbance of the cellular machineries related to the carrier association.
Highlights
The assessment of off-target effects and cell survival mechanisms associated with the therapeutic exploitation of nanomaterials represents an active research area in the field of biomedical nanotechnologies
Our work provides evidence that the rational design of redox-active carriers for therapeutic-related application should be guided by a careful investigation on potential disturbance of the cellular machineries related to the carrier association
To obtain a redox-active neutral polymer, pHPMASH, all carboxyl groups of PMASH were converted to neutral amide groups
Summary
The assessment of off-target effects and cell survival mechanisms associated with the therapeutic exploitation of nanomaterials represents an active research area in the field of biomedical nanotechnologies. Regardless of the release mechanisms, our previous study shows that the siRNA-PLL complexes embedded into the μCs are at least partially released in the cytosol and are able to significantly inhibit survivin gene expression.[2] we observed that the exposure of PCa cells to PMASH μCs resulted in a less pronounced down-regulation of survivin expression levels and induction of autophagy. These effects occurred regardless of the cargo, as both control siRNA-loaded PMASH μCs and empty μCs elicited a response. Our findings indicate that redox-active polymers or μCs can potentially interfere with the intracellular milieu and that understanding this behavior has important implications for biomedical applications of biomaterials
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