Delivery strategies and potential targets for siRNA in major cancer types

Lee, So Jin; Kim, Min Ju; Kwon, Ick Chan; Roberts, Thomas M.

doi:10.1016/j.addr.2016.05.010

Cited by 119 publications

(79 citation statements)

References 218 publications

(150 reference statements)

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“…Small interfering RNA (siRNA) with 21–23 base pairs has been proven to be more efficient in gene silencing than other RNAi molecules and opens wide perspectives in therapeutics for the treatment of many diseases linked to elevated expression of identified genes, including cancer and infectious, inflammatory, and neurodegenerative diseases 3, 4. As a result, several clinical trials using siRNA approaches have being conducted in patients with liver cancers and metastatic melanoma 2, 5, 6.…”

Section: Introductionmentioning

confidence: 99%

Dual Tumor-Targeting Nanocarrier System for siRNA Delivery Based on pRNA and Modified Chitosan

Hu²,

Zhang

et al. 2017

Molecular Therapy - Nucleic Acids

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Highly specific and efficient delivery of siRNA is still unsatisfactory. Herein, a dual tumor-targeting siRNA delivery system combining pRNA dimers with chitosan nanoparticles (CNPPs) was designed to improve the specificity and efficiency of siRNA delivery. In this dual delivery system, folate-conjugated and PEGylated chitosan nanoparticles encapsulating pRNA dimers were used as the first class of delivery system and would selectively deliver intact pRNA dimers near or into target cells. pRNA dimers simultaneously carrying siRNA and targeting aptamer, the second class of delivery system, would specifically deliver siRNA into the target cells via aptamer-mediated endocytosis or proper particle size. To certify the delivering efficiency of this dual system, CNPPs, pRNA dimers alone, chitosan nanoparticles containing siRNA with folate conjugation and PEGylation (CNPS), and chitosan nanoparticles containing pRNA dimers alone (CN) were first prepared. Then, we observed that treatment with CNPPs resulted in increased cellular uptake, higher cell apoptosis, stronger cell cytotoxicity, and more efficacious gene silencing compared to the other three formulations. Higher accumulation of siRNA in the tumor site, stronger tumor inhibition, and longer circulating time were also observed with CNPPs compared to other formulations. In conclusion, this dual nanocarrier system showed high targeting and favorable therapeutic efficacy both in vitro and in vivo. Thereby, a new approach is provided in this study for specific and efficient delivery of siRNA, which lays a foundation for the development of pRNA hexamers, which can simultaneously carry six different substances.

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Section: Introductionmentioning

confidence: 99%

Dual Tumor-Targeting Nanocarrier System for siRNA Delivery Based on pRNA and Modified Chitosan

Hu²,

Zhang

et al. 2017

Molecular Therapy - Nucleic Acids

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“…Since the discovery of RNAi it has been signaled as one of the best therapeutic interventions for the treatment of any type of disease including cancer by means of knocking down the genetic expression of the disease causing genes via RNAi inducers [6,79,80,103]. However, the delivery of RNAi inducers including siRNAs is compromised due to their degradation by nucleases, high anionic charge, immunogenicity, and off target effects.…”

Section: Summary and Perspectivementioning

confidence: 99%

“…Active cell targeting is a promising approach that has the potential for precluding the unwanted entry of delivery systems to cells other than the target cells. Conjugation of a particular cell receptor or biomarker specific ligand to the surface of NVCVs would enable cell specific delivery of siRNAs [79,103]. Herein, we are discussing a few examples of NVCVs that when coupled with targeting ligands showed selective siRNA delivery to cancer cells (See Table 2).…”

Section: Incorporation Of Targeting Ligandsmentioning

confidence: 99%

“…The essentials of a successful siRNA delivery system include (i) protection of siRNAs from nuclease mediated degradation during systemic circulation; (ii) promotion of enhanced cellular uptake; (iii) endosomal escape; (iv) target site accumulation while evading nonspecific uptake in normal and non-target tissue; and (v) empowering release of siRNAs in the cytosol [6,15,79,80]. Conventional NVCVs, following complexation with the siRNAs, provide protection against nucleases and also aid in delivering siRNAs across the cell membranes; however, these NVCVs/siRNA complexes failed to produce remarkable gene silencing.…”

Section: Functionalization Of Nvcvs For Sirna Deliverymentioning

confidence: 99%

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Functionalized non-viral cationic vectors for effective siRNA induced cancer therapy

Gupta

Puri

Shapiro

2017

DNA and RNA Nanotechnology

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RNA interference (RNAi) has been regarded as a vital asset in the field of therapeutics as it has the capability to silence various disease causing genes including those that cause cancer. Small non-coding RNA molecules such as short interfering RNAs (siRNAs) are one of the extensively studied RNAi inducers for gene modulations. However, the delivery of RNAi inducers including siRNAs is compromised due to the barriers imposed by the biological system such as degradation by nucleases, rapid clearance, high anionic charge, immunogenicity and off-target effects. Viral vectors, in general exhibit high transfection efficiencies but are expensive and likely to confer immunological and safety issues. Therefore, non-viral cationic vectors (NVCVs) have received considerable attention to not only address these issues but also for developing efficacious siRNA delivery vectors. In this review, we will first discuss the historical development of various NVCVs and then will discuss functionalized NVCVs with linkers that provide stability, as well as respond to the cancer cell environment and with cancer cell receptor specific ligands to explicitly target them for improved siRNA efficacy. Multifunctional NVCVs (MNVCVs) that employ multiple synergistically working components to aid siRNA delivery efficacy are also discussed.

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“…8,9 However, in order to siRNA be applied in the clinical setting, various challenges including physiological barriers such as serum ribonucleases degradation, renal clearance, low cellular uptake efficiency, and poor endosomal escape after endocytosis have to be overcome. [10][11][12][13][14][15] Development of a suitable carrier that effectively delivers siRNA to tumor cells is crucial to enhance its therapeutic efficiency.…”

mentioning

confidence: 99%

siRNA-loaded poly(histidine-arginine)<sub>6</sub>-modified chitosan nanoparticle with enhanced cell-penetrating and endosomal escape capacities for suppressing breast tumor metastasis

Park¹,

Huang²,

Kang³

et al. 2017

IJN

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An ideal carrier that delivers small interfering RNA (siRNA) should be designed based on two criteria: cellular-mediated internalization and endosomal escape. Poly(histidine-arginine) 6 (H6R6) peptide was introduced into chitosan (CS) to create a new CS derivative for siRNA delivery, 6-polyarginine (R6) as cell-penetrating peptides facilitated nanoparticle cellular internalization has been proved in our previous research, and 6-polyhistidine (H6) mediated the nanoparticle endosome escape resulted in the siRNA rapid releasing into tumor cytoplasm. H6R6-modified CS nanoparticles showed higher transfection efficiency and better endosomal escape capacity compared to ungroomed CS nanoparticle in vitro. Noticeably, H6R6-modified CS nanoparticles effectively inhibited tumor cell growth and metastases in vivo and significantly improved survival ratio. Therefore, we concluded that H6R6-modified CS copolymer can act as an ideal carrier for siRNA delivery and as a promising candidate in breast cancer therapy.

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Delivery strategies and potential targets for siRNA in major cancer types

Cited by 119 publications

References 218 publications

Dual Tumor-Targeting Nanocarrier System for siRNA Delivery Based on pRNA and Modified Chitosan

Dual Tumor-Targeting Nanocarrier System for siRNA Delivery Based on pRNA and Modified Chitosan

Functionalized non-viral cationic vectors for effective siRNA induced cancer therapy

siRNA-loaded poly(histidine-arginine)<sub>6</sub>-modified chitosan nanoparticle with enhanced cell-penetrating and endosomal escape capacities for suppressing breast tumor metastasis

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