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Enhanced siRNA Delivery and Selective Apoptosis Induction in H1299 Cancer Cells by Layer-by-Layer-Assembled Se Nanocomplexes: Toward More Efficient Cancer Therapy.

ABSTRACT: Nanotechnology has made an important contribution to oncology in recent years, especially for drug delivery. While many different nano-delivery systems have been suggested for cancer therapy, selenium nanoparticles (SeNPs) are particularly promising anticancer drug carriers as their core material offers interesting synergistic effects to cancer cells. Se compounds can exert cytotoxic effects by acting as pro-oxidants that alter cellular redox homeostasis, eventually leading to apoptosis induction in many kinds of cancer cells. Herein, we report on the design and synthesis of novel layer-by-layer Se-based nanocomplexes (LBL-Se-NCs) as carriers of small interfering RNA (siRNA) for combined gene silencing and apoptosis induction in cancer cells. The LBL-Se-NCs were prepared using a straightforward electrostatic assembly of siRNA and chitosan (CS) on the solid core of the SeNP. In this study, we started by investigating the colloidal stability and protection of the complexed siRNA. The results show that CS not only functioned as an anchoring layer for siRNA, but also provided colloidal stability for at least 20 days in different media when CS was applied as a third layer. The release study revealed that siRNA remained better associated with LBL-Se-NCs, with only a release of 35% after 7 days, as compared to CS-NCs with a siRNA release of 100% after 48 h, making the LBL nanocarrier an excellent candidate as an off-the-shelf formulation. When applied to H1299 cells, it was found that they can selectively induce around 32% apoptosis, while significantly less apoptosis (5.6%) was induced in NIH/3T3 normal cells. At the same time, they were capable of efficiently inducing siRNA downregulation (35%) without loss of activity 7 days post-synthesis. We conclude that LBL-Se-NCs are promising siRNA carriers with enhanced stability and with a dual mode of action against cancer cells.

SUBMITTER: Sharifiaghdam M

PROVIDER: S-EPMC8093573 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Nanoparticulate systems have shown great promise in overcoming the considerable trafficking barriers associated with systemic nucleic acid delivery, which must be addressed to unlock the full potential of technologies such as RNAi and gene editing in vivo. In addition to mediating the cytoplasmic delivery of nucleic cargo and shielding it from nuclease degradation and immunostimulation, nucleic-acid-containing nanomaterials delivered intravenously must also be stable in the bloodstream after administration to avoid toxicity and off-target delivery. To this end, the hydrophilic molecule polyethylene glycol (PEG) has been deployed in many different nanoparticle systems to prevent aggregation and recognition by the reticuloendothelial system. However, the optimal strategy for incorporating PEG into self-assembled nucleic acid delivery systems to obtain nanoparticle stability while retaining important functions such as receptor targeting and cargo activity remains unclear. In this work, we develop substantially improved formulations of tumor-penetrating nanocomplexes (TPNs), targeted self-assembled nanoparticles formulated with peptide carriers and siRNA that have been shown to mitigate tumor burden in an orthotopic model of ovarian cancer. We specifically sought to tailor TPNs for intravenous delivery by systematically comparing formulations with three different classes of modular PEG incorporation (namely PEG graft polymers, PEG lipids, and PEGylated peptide), each synthesized using straightforward bioconjugation techniques. We found that the addition of PEG lipids or PEGylated peptide carriers led to the formation of small and stable nanoparticles, but only nanoparticles formulated with PEGylated peptide carriers retained substantial activity in a gene silencing assay. In vivo, this formulation significantly decreased accumulation in off-target organs and improved initial availability in circulation compared to results from the original non-PEGylated particles. Thus, from among a set of candidate strategies, we identified TPNs with admixed PEGylated peptide carriers as the optimal formulation for systemic administration of siRNA on the basis of their performance in a battery of physicochemical and biological assays. Moreover, this optimized formulation confers pharmacologic advantages that may enable further translational development of tumor-penetrating nanocomplexes, highlighting the preclinical value of comparing formulation strategies and the relevance of this systematic approach for the development of other self-assembled nanomaterials.

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Enhanced siRNA Delivery and Selective Apoptosis Induction in H1299 Cancer Cells by Layer-by-Layer-Assembled Se Nanocomplexes: Toward More Efficient Cancer Therapy.

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