Dual gene targeted multimeric siRNA for combinatorial gene silencing

Lee, Soo Hyun; Mok, Hyejung; Jo, Sungduk; Hong, Cheol Am; Park, Tae Gwan

doi:10.1016/j.biomaterials.2010.11.062

Cited by 33 publications

(22 citation statements)

References 62 publications

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Section: Tumor‐targeting Multifunctional Nanoparticlesmentioning

confidence: 99%

“…siRNAs against survivin and Bcl‐2 were selected because upregulated Blc‐2 and survivin genes in cancer cells block the apoptotic pathways. Dual gene‐targeted multimeric siRNA systems led to more HeLa cell death compared with single gene‐targeted multimeric siRNA against survivin or Blc‐2 each, or their mixture . Co‐delivery of Mcl‐1 and Ribosomal protein S6 kinase (RPS6KA5) siRNA significantly inhibited tumor growth in both drug‐sensitive and ‐resistant breast cancer model …”

Section: Tumor‐targeting Multifunctional Nanoparticlesmentioning

confidence: 99%

See 1 more Smart Citation

Tumor‐Targeting Multifunctional Nanoparticles for siRNA Delivery: Recent Advances in Cancer Therapy

Kim

Choi

et al. 2014

Adv Healthcare Materials

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RNA interference (RNAi) is a naturally occurring regulatory process that controls posttranscriptional gene expression. Small interfering RNA (siRNA), a common form of RNAi-based therapeutics, offers new opportunities for cancer therapy via silencing specific genes, which are associated to cancer progress. However, clinical applications of RNAi-based therapy are still limited due to the easy degradation of siRNA during body circulation and the difficulty in the delivery of siRNA to desired tissues and cells. Thus, there have been many efforts to develop efficient siRNA delivery systems, which protect siRNA from serum nucleases and deliver siRNA to the intracellular region of target cells. Here, the recent advances in siRNA nanocarriers, which possess tumor-targeting ability are reviewed; various nanoparticle systems and their antitumor effects are summarized. The development of multifunctional nanocarriers for theranostics or combinatorial therapy is also discussed.

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Section: Tumor‐targeting Multifunctional Nanoparticlesmentioning

confidence: 99%

Section: Tumor‐targeting Multifunctional Nanoparticlesmentioning

confidence: 99%

Tumor‐Targeting Multifunctional Nanoparticles for siRNA Delivery: Recent Advances in Cancer Therapy

Kim

Choi

et al. 2014

Adv Healthcare Materials

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“…14 Larger assemblies can be achieved by other approaches such as noncovalent polymerization of siRNA via sticky ends 15 or employing disulfide chemistry. 16,17 The number of siRNA units in such multimeric assemblies is largely not well defined. A strategy commonly pursued is the formation of larger defined structures containing multiple siRNA units.…”

Section: Introductionmentioning

confidence: 99%

DNA as Tunable Adaptor for siRNA Polyplex Stabilization and Functionalization

Heissig

Klein

Hadwiger³

et al. 2016

Molecular Therapy - Nucleic Acids

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siRNA and microRNA are promising therapeutic agents, which are engaged in a natural mechanism called RNA interference that modulates gene expression posttranscriptionally. For intracellular delivery of such nucleic acid triggers, we use sequence-defined cationic polymers manufactured through solid phase chemistry. They consist of an oligoethanamino amide core for siRNA complexation and optional domains for nanoparticle shielding and cell targeting. Due to the small size of siRNA, electrostatic complexes with polycations are less stable, and consequently intracellular delivery is less efficient. Here we use DNA oligomers as adaptors to increase size and charge of cargo siRNA, resulting in increased polyplex stability, which in turn boosts transfection efficiency. Extending a single siRNA with a 181-nucleotide DNA adaptor is sufficient to provide maximum gene silencing aided by cationic polymers. Interestingly, this simple strategy was far more effective than merging defined numbers (4–10) of siRNA units into one DNA scaffolded construct. For DNA attachment, the 3′ end of the siRNA passenger strand was beneficial over the 5′ end. The impact of the attachment site however was resolved by introducing bioreducible disulfides at the connection point. We also show that DNA adaptors provide the opportunity to readily link additional functional domains to siRNA. Exemplified by the covalent conjugation of the endosomolytic influenza peptide INF-7 to siRNA via a DNA backbone strand and complexing this construct with a targeting polymer, we could form a highly functional polyethylene glycol–shielded polyplex to downregulate a luciferase gene in folate receptor–positive cells.

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“…Hyeung et al demonstrated that multimeric siRNA can be synthesized by dimerizing self-crosslinked single-stranded sense and antisense strands using a GSH-cleavable maleimide containing linker and then creating nanosize particles using a cationic polymer, such as linear PEI [108,109]. This multimerized siRNA provided a unique opportunity to target multigenes and demonstrated effective gene release in a reductive environment.…”

Section: Triggers For Gene Release In Cancer Cells Using Gene Tranmentioning

confidence: 99%

Trigger-Responsive Gene Transporters for Anticancer Therapy

et al. 2017

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In the current era of gene delivery, trigger-responsive nanoparticles for the delivery of exogenous nucleic acids, such as plasmid DNA (pDNA), mRNA, siRNAs, and miRNAs, to cancer cells have attracted considerable interest. The cationic gene transporters commonly used are typically in the form of polyplexes, lipoplexes or mixtures of both, and their gene transfer efficiency in cancer cells depends on several factors, such as cell binding, intracellular trafficking, buffering capacity for endosomal escape, DNA unpacking, nuclear transportation, cell viability, and DNA protection against nucleases. Some of these factors influence other factors adversely, and therefore, it is of critical importance that these factors are balanced. Recently, with the advancements in contemporary tools and techniques, trigger-responsive nanoparticles with the potential to overcome their intrinsic drawbacks have been developed. This review summarizes the mechanisms and limitations of cationic gene transporters. In addition, it covers various triggers, such as light, enzymes, magnetic fields, and ultrasound (US), used to enhance the gene transfer efficiency of trigger-responsive gene transporters in cancer cells. Furthermore, the challenges associated with and future directions in developing trigger-responsive gene transporters for anticancer therapy are discussed briefly.

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Dual gene targeted multimeric siRNA for combinatorial gene silencing

Cited by 33 publications

References 62 publications

Tumor‐Targeting Multifunctional Nanoparticles for siRNA Delivery: Recent Advances in Cancer Therapy

Tumor‐Targeting Multifunctional Nanoparticles for siRNA Delivery: Recent Advances in Cancer Therapy

DNA as Tunable Adaptor for siRNA Polyplex Stabilization and Functionalization

Trigger-Responsive Gene Transporters for Anticancer Therapy

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