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![Physicochemical characterization of CLCNs and CLCNs/siRNA complexes. (A) Transmission electron microscope images of CLCN1 and CLCN1 after conjugation with siRNA. (B) Transmission electron microscope images of CLCN2 and CLCN2 after conjugation with siRNA. (C) Physicochemical characterization (size of CLCNs and CLCNs/siRNA, zeta potential of CLCNs and CLCNs/siRNA complex and polydispersity index [PDI] by dynamic light scattering. Amount of siRNA conjugated by fluorescence analysis (%). Size: (**) p value 0.0063; zeta potential: (**) p value 0.0022 and (**) p value 0.0016 (unpaired two-tailed Student t test). (D) Gel retardation assay to evaluate the nanoparticle retardation inside the gel and the siRNA condensation inside the CLCNs and relative density of the bands (fold change value). (E) CLCN1 and CLCN1-siRNA complex size distribution per milliliters of solution using a NanoSight instrument for NTA (Table 1). (F) CLCN2 and CLCN2-siRNA complex size distribution per milliliters of solution using a NanoSight instrument for NTA (Table 1).](publication/317488598/figure/fig2/AS:569713387814912@1512841664138/Physicochemical-characterization-of-CLCNs-and-CLCNs-siRNA-complexes-A-Transmission.png)
Physicochemical characterization of CLCNs and CLCNs/siRNA complexes. (A) Transmission electron microscope images of CLCN1 and CLCN1 after conjugation with siRNA. (B) Transmission electron microscope images of CLCN2 and CLCN2 after conjugation with siRNA. (C) Physicochemical characterization (size of CLCNs and CLCNs/siRNA, zeta potential of CLCNs and CLCNs/siRNA complex and polydispersity index [PDI] by dynamic light scattering. Amount of siRNA conjugated by fluorescence analysis (%). Size: (**) p value 0.0063; zeta potential: (**) p value 0.0022 and (**) p value 0.0016 (unpaired two-tailed Student t test). (D) Gel retardation assay to evaluate the nanoparticle retardation inside the gel and the siRNA condensation inside the CLCNs and relative density of the bands (fold change value). (E) CLCN1 and CLCN1-siRNA complex size distribution per milliliters of solution using a NanoSight instrument for NTA (Table 1). (F) CLCN2 and CLCN2-siRNA complex size distribution per milliliters of solution using a NanoSight instrument for NTA (Table 1).
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RNA interference (RNAi)-based therapeutics have been used to silence the expression of targeted pathological genes. Small interfering RNA (siRNAs) and microRNA (miRNAs) inhibitor have performed this function. However, short half-life, poor cellular uptake, and nonspecific distribution of small RNAs call for the development of novel delivery systems...
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... investigation was performed with a Transmission Electron Microscopy (TEM) operating at 80 kV (Figure 2A, 2B). TEM is a vital characterization tool for directly imaging nanomaterials to obtain quantitative measures of particle and/or grain size, size distribution, and morphology. ...
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... few microliters of the CLCN formulations were scanned using magnifications of 200000x and resolution of 100 nm and the images were recorded. The Figure 2A shows the formulation CLCN1 alone and conjugated with the siRNA. The Figure 2B shows the formulation CLCN2 alone and conjugated with the siRNA. ...
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... Figure 2A shows the formulation CLCN1 alone and conjugated with the siRNA. The Figure 2B shows the formulation CLCN2 alone and conjugated with the siRNA. CLCN1 and CLCN2 alone and conjugated with siRNA appear monodisperse systems with no sign of agglomeration but in both CLCNs conjugated with the siRNA homogenous and round spheres and core- shell structures are distinguishable. ...
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... quantitative physicochemical characterization of CLCNs was conducted with use of dynamic light scattering (DLS) to determine the size and homogeneity of the CLCNs ( Figure 2C), and a Zetasizer Nano Z to measure the zeta potential (Charge) of the nanoparticles surface ( Figure 2C). The physicochemical analysis revealed that CLCNs alone have a diameter ranging from 60 to 100 nm, with CLCN1's at about 70 nm and CLCN2's at about 90 nm. ...
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... quantitative physicochemical characterization of CLCNs was conducted with use of dynamic light scattering (DLS) to determine the size and homogeneity of the CLCNs ( Figure 2C), and a Zetasizer Nano Z to measure the zeta potential (Charge) of the nanoparticles surface ( Figure 2C). The physicochemical analysis revealed that CLCNs alone have a diameter ranging from 60 to 100 nm, with CLCN1's at about 70 nm and CLCN2's at about 90 nm. ...
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... physicochemical analysis revealed that CLCNs alone have a diameter ranging from 60 to 100 nm, with CLCN1's at about 70 nm and CLCN2's at about 90 nm. CLCNs conjugation with siRNA did not affect overall particle size, but CLCN2 conjugated with siRNA showed larger size (at about 100 nm) than CLCN1 conjugated with same siRNA (at about 90 nm) ( Figure 2C size). CLCNs were homogeneous and stable nanoparticles, as demonstrated by a very low polydispersity index (PDI) ranging from 0.10 to 0.20 (Figure 2C PDI). ...
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... were homogeneous and stable nanoparticles, as demonstrated by a very low polydispersity index (PDI) ranging from 0.10 to 0.20 (Figure 2C PDI). In particular, both formulations displayed a lower PDI when conjugated with siRNA, confirming homogenous and monodisperse shape and structure shown in the TEM analysis ( Figure 2A, 2B). The positive charge on the CLCN surface was between +25 and +35 mV. ...
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... positive charge on the CLCN surface was between +25 and +35 mV. For CLCN1 and CLCN2 alone, the surface charges were, respectively, ~+35 and ~+30 mV ( Figure 2C zeta potential). When CLCN1 and CLCN2 were conjugated with siRNA, the surface charges were, respectively, ~+30 and ~+45 mV ( Figure 2C zeta potential). ...
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... CLCN1 and CLCN2 alone, the surface charges were, respectively, ~+35 and ~+30 mV ( Figure 2C zeta potential). When CLCN1 and CLCN2 were conjugated with siRNA, the surface charges were, respectively, ~+30 and ~+45 mV ( Figure 2C zeta potential). If all of the particles in suspension have a large positive zeta potential, they will not tend to aggregate or to flocculate. ...
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... with zeta potentials that are more positive than +30 mV are normally considered stable. The surface charge did not change from positive to negative after siRNA conjugation, suggesting complete internalization of the RNAi within the hydrophilic core and a stable nanoparticle suspension ( Figure 2C zeta potential). The amount of RNAi conjugated to the CLCNs was measured using a red fluorescent siRNA (Cy5). ...
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... results was around 80% for both formulations. (Figure 2C amount siRNA Cy5 conjugated (%)). ...
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... retardation assays were performed to evaluate the nanoparticle retardation inside the gel and the siRNA condensation inside the CLCNs ( Figure 2D). Electrophoresis in 1% Agarose gels were carried out at 100 V for 20 minutes. ...
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... the percentage of the Area for each peaks resulted from the Agarose gel analysis was calculated and the Percent value for each sample (CLCN1 and CLCN2; CLCN1-siRNA and CLCN2-siRNA) was divided by the Percent value for the standard (free siRNA) to obtain the relative band density (fold change value). The condensation of siRNA inside the CLCNs was around 80% for both formulations indicating that the binding between the carrier and the siRNA was strong enough to withstand dissociation during electrophoresis, whereas the siRNA not complexed into CLCNs was free to run on the bottom of the agarose gel ( Figure 2D). ...
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... visualize, measure, and count the nanoparticles a Nanoparticle tracking analysis (NTA) was performed ( Figure 2E, 2F) ( Table 1). In this analysis, each nanoparticle in solution is individually but simultaneously analyzed by direct observation and measurement of diffusion events, producing high- resolution results for particle size distribution and www.impactjournals.com/oncotarget ...
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... showed a higher particle concentration when CLCNs were alone. Specifically, CLCN1's concentration was ~7.23e+008 particles/ml, and CLCN2's was ~5.05e+008 particles/ml ( Figure 2E, 2F) (Table 1); however, CLCNs complexed with siRNA displayed a lower concentration: CLCN1-siRNA's was 3.82e + 008 particles/ml, and CLCN2-siRNA was 1.69e+008 particles/ml ( Figure 2E, 2F) ( Table 1). ...
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... showed a higher particle concentration when CLCNs were alone. Specifically, CLCN1's concentration was ~7.23e+008 particles/ml, and CLCN2's was ~5.05e+008 particles/ml ( Figure 2E, 2F) (Table 1); however, CLCNs complexed with siRNA displayed a lower concentration: CLCN1-siRNA's was 3.82e + 008 particles/ml, and CLCN2-siRNA was 1.69e+008 particles/ml ( Figure 2E, 2F) ( Table 1). ...
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Citations
... In this system, a photo-responsive liposome decorated with VEGFR2 monoclonal antibodies (mAb) is used to encapsulate DNA. The light sensitivity allows for degradation of the liposomal carrier upon Cationic DOTAP Pancreatic siRNA [40] Skin siRNA [ 15,28,29,41,42] Breast siRNA [43] Ovarian siRNA [44] Leukemia Plasmid DNA [45] Lung miRNA [ 46,47] siRNA [47] Plasmid DNA [48] Liver miRNA [49] siRNA [ 14,25,50] Colorectal miRNA [ 51,52] Brain miRNA [53] DOTMA Lung siRNA [ 54,55] Liver siRNA [56] miRNA [56] Colon siRNA [57] Neuroblastoma siRNA [58] DMAPAP Skin siRNA [21][22][23] Staramine Lung siRNA [31] Stearylamine Breast miRNA [59] Colorectal miRNA [52] Anionic DOPG Breast siRNA [ 60,61] Neuroblastoma siRNA [35] DSPE Liver miRNA [62] CHEMS Lung siRNA [63] Liver siRNA [36] Neutral DOPC Ovarian siRNA [64][65][66] DPPE Ovarian siRNA [37] illumination. The presence of VEGFR2 monoclonal antibodies allows for specific VEGFR2 receptor targeting. ...
... In this system, a photo-responsive liposome decorated with VEGFR2 monoclonal antibodies (mAb) is used to encapsulate DNA. The light sensitivity allows for degradation of the liposomal carrier upon Cationic DOTAP Pancreatic siRNA [40] Skin siRNA [ 15,28,29,41,42] Breast siRNA [43] Ovarian siRNA [44] Leukemia Plasmid DNA [45] Lung miRNA [ 46,47] siRNA [47] Plasmid DNA [48] Liver miRNA [49] siRNA [ 14,25,50] Colorectal miRNA [ 51,52] Brain miRNA [53] DOTMA Lung siRNA [ 54,55] Liver siRNA [56] miRNA [56] Colon siRNA [57] Neuroblastoma siRNA [58] DMAPAP Skin siRNA [21][22][23] Staramine Lung siRNA [31] Stearylamine Breast miRNA [59] Colorectal miRNA [52] Anionic DOPG Breast siRNA [ 60,61] Neuroblastoma siRNA [35] DSPE Liver miRNA [62] CHEMS Lung siRNA [63] Liver siRNA [36] Neutral DOPC Ovarian siRNA [64][65][66] DPPE Ovarian siRNA [37] illumination. The presence of VEGFR2 monoclonal antibodies allows for specific VEGFR2 receptor targeting. ...
Gene regulation using RNA interference (RNAi) therapy has been developed as one of the frontiers in cancer treatment. The ability to tailor the expression of genes by delivering synthetic oligonucleotides to tumor cells has transformed the way scientists think about treating cancer. However, its clinical application has been limited due to the need to deliver synthetic RNAi oligonucleotides efficiently and effectively to target cells. Advances in nanotechnology and biomaterials have begun to address the limitations to RNAi therapeutic delivery, increasing the likelihood of RNAi therapeutics for cancer treatment in clinical settings. Herein, innovations in the design of nanocarriers for the delivery of oligonucleotides for successful RNAi therapy are discussed.
... electrostatic force (Reinhard and Wagner, 2017), vibration and PH, lipophilisation or liposome are needed. This RNAi therapeutic has been performed by small interfering RNA (siRNAs) and microRNA (miRNAs) inhibitors (Gentile et al., 2017). Abnormal methylation of DNA in cancer and neurological disorders wa s noted (Mutalib et al., 2017;De Carvalho et al., 2012). ...
... Small to long non-coding RNAs (lncRNAs), have emerged as key regulators of gene expression, genome stability and defence against foreign genetic elements could be seen in Table 1. RNA-mediated epigenetic regulation of gene expression (Holoch and Moazed, 2015) Ten years after the discovery of dsRNA gene silencing by Fire and Melo's Nobel Prize, notable progress was made in RNAi (Almeida et al., 2017). Changes in the chemical structure of synthetic oligonucleotides (Li et al., 2011) make it more stable and specific, and these approaches have developed potential in the RNAi pharmaceutical industry market, particularly in researching new drug targets. ...
Pendahuluan: Latar belakang: RNA untai ganda (dsRNA), siRNA, miRNA, RNAi, menginduksi metilasi DNA pada tumbuhan dan dalam sel mamalia, termasuk manusia. Kini RNAi menjadi prinsip dalam pengobatan kanker sekarang dan di masa depan. Masalah: Metilasi pulau CpG dan pengulangan DNA CGG merupakan kasus prevalensi tinggi di hutan hujan tropis, tetapi sampai sekarang terabaikan. Prinsip kehati-hatian dalam efek lingkungan harus diambil oleh para pembuat keputusan dan pemegang kebijakan. Tujuan: Mengetahui efek pembungkaman gen terhadap lingkungan. Hipotesis: RNAi menyebabkan hipermetilasi. Metode: Quasi ‘Systematic Review’ dengan Analisis Bayesian. Hasil: Menggunakan mesin pencari Science Direct, 935 referensi tertangkap ditambah 11 referensi yang sudah direkam dalam pustaka Mendeley, dan setelah menyaring abstrak atau judul, 920 dikeluarkan dengan duplikasi yang tidak relevan baik dianalisis dengan jaringan Bayesian terbaru untuk menjawab hipotesis. Menyaring teks lengkap dari 18, kemudian 16 teks lengkap dipilih. 28 teks lengkap diperiksa dan periksa kembali dengan meta-analisis RNA-metilasi menggunakan Science Direct (12 referensi). Diskusi: Sebuah teknik CpG-siRNA telah mempertahankan hipermetilasi pulau CpG, digunakan secara luas dalam terapi tanaman dan kanker untuk menstabilkan gen yang terbungkam.Kesimpulan: Pengaruh teknik pembungkaman gen terhadap lingkungan harus diketahui secara luas oleh pemegang kebijakan dan pengambil keputusan. Keywords: Hipermetilasi, Pulau CpG, RNAi, Pembungkaman gen, Budidaya ikan
... Most recently, Chen et al. [84] exploited the lipid-based NPs as an ideal transporter not merely to address the chal- lenges of transporting bare miRNA together with its chemically unstable properties, extracellular as well as intracellular barriers and innate immune elicitation, but also toward smart targeted transport for cancer treatment. Likewise, Gentile et al. [85] formed novel cationic liquid crystalline nanoparticles (CLCNs) for competently transport synthetic miRNA in vitro and in vivo. CLCNs were developed through high-speed homogenization and assembled with synthetic miRNA molecules in nuclease-free water to produce CLCN-miRNA complexes of about 100 nm in diam- eter having positively charged surfaces. ...
MicroRNAs (miRNA) are small noncoding oligoribonucleotides having potential of silencing/knocking out target genes by regulating posttranscriptional events of gene expression. Since many miRNAs have exhibited change in profile in disease conditions, researchers are attracted toward their role assignment in disease development and control, if any. With the finding that many miRNAs are associated with disease progression, this species of RNA has become an attractive target for therapy. The reestablishment of downregulated miRNAs or inhibition of overexpressed miRNAs to return in their usual state is the basis of miRNA-guided treatment. This chapter focuses on fundamentals of miRNA-based knocking out of target genes using nanocarriers, as they provide physical and biochemical stability to the unstable miRNAs and enhance their efficiency to perform. It also encompasses the recent tools of nonviral delivery, such as, polymer-, lipid-, metal/metal-oxides, and other nanoparticles for in vitro/in vivo transport of miRNA. The immunological responses, linked with the nanocarriers as well as miRNA, are also discussed along with challenges to efficient delivery and toxicity. The size, shape, charge, and surface properties of nanotransporters have also been illustrated, which need to be modified to ensure efficient as well as safe transport of the miRNAs in medical practice. It is anticipated that by overcoming the transport obstacles and with very good understanding of the effects like duration of gene silencing, miRNAs will effectively contribute in practical therapeutics in the near future.
Keywords:
Gene expression,
Gene therapy,
Knockouts,
miRNA,
Nanomaterials,
Nanoparticles,
Toxicity
... Second, ssPBAEI/DOX nanoparticles possess excellent cell entry ability and can effectively carry DOX into brain tumor cells. According to the previous report [32,33], the nanoparticles with a large amount of positive charges can be efficiently uptaken by cancer cells via electrostatic interaction-mediated cell endocytosis. Thus, we believe it is a main mechanism of cell entry of ssPBAEI/DOX nanoparticles. ...
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... Simultaneously, investigation of the combination of nanoparticles and RNAi technology for clinical treatment is being pursued (Acharya et al., 2017;Gentile et al., 2017). Recent research has focused on SCI treatment using nano-controlled release systems as siRNA carriers to achieve regulation of specific genes at the site of SCI ( Protein expression of GAP-43 was markedly decreased in the SCI, PEI-ALG, and PEI-ALG/Ctl-siRNA groups compared with the sham group ( §P < 0.05, § §P < 0.01). ...
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... Apart from chemical modifications, the development of improved delivery systems plays a pivotal role in avoiding rapid degradation, excretion and enhances the biological effect. Thus, these synthetic miRNAs can be delivered into cellular systems using various kinds of nanovehicle such as liposomal-nanoparticles (Chen et al., 2010), cationic liquid crystalline nanoparticles (Gentile et al., 2017), polycationic liposomes hyaluronic acid (CLPH) (Medina et al., 2004), 1,2dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) (Peer, 2012), polyethylenimine (PEI)-based systems (Park et al., 2006), dendrimers (Dutta et al., 2010;Hong et al., 2004), poly (lactide-co-glycolide) (PLGA) particles (Cheng and Saltzman, 2012), protamine (Suh et al., 2013), atelocollagen (Minakuchi et al., 2004), hyaluronic acid (HA)-chitosan (Deng et al., 2014), hyaluronic acid (HA)-decorated polyethyleniminepoly(D,L-lactide-co-glycolide) PEI-PLGA (Wang et al., 2016) as well as inorganic materials such as gold (Ghosh et al., 2013) and silica nanoparticles . These combinations of Nano-vehicle and miR aids in preventing the degradation of a particular miRNA in serum. ...
MicroRNAs (miRNAs) are a class of small, non-coding RNAs that are involved in the regulation of gene expression at the post-transcriptional level. MicroRNAs play an important role in cancer cell proliferation, survival and apoptosis. Epigenetic modifiers regulate the microRNA expression. Among the epigenetic players, histone deacetylases (HDACs) function as the key regulators of microRNA expression. Epigenetic machineries such as DNA and histone modifying enzymes and various microRNAs have been identified as the important contributors in cancer initiation and progression. Recent studies have shown that developing innovative microRNA-targeting therapies might improve the human health, specifically against the disease areas of high unmet medical need. Thus microRNA based therapeutics are gaining importance for anti-cancer therapy. Studies on Triple negative breast cancer (TNBC) have revealed the early relapse and poor overall survival of patients which needs immediate therapeutic attention. In this report, we focus the effect of HDAC inhibitors on TNBC cell proliferation, regulation of microRNA gene expression by a series of HDAC genes, chromatin epigenetics, epigenetic remodelling at miR-200 promoter and its modulation by various HDACs. We also discuss the need for identifying novel HDAC inhibitors for modulation of miR-200 in triple negative breast cancer.
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According to the World Health Organization (WHO), chronic respiratory diseases such as asthma, lung cancer, chronic obstructive pulmonary disease, and cystic fibrosis remained as the leading causes of death throughout the world. This may be attributed to the multiple limitations of current conventional therapies, including lack of site-specific targeting and incidences of adverse reactions. These led to advancements in the field of nanotechnology, which have provided new insights into the design and development of various nanomaterials to be used in drug delivery applications. Throughout these years, many studies have found that drug delivery systems developed using nanomaterials achieved effective and sustained delivery of therapeutics with specificity to diseased cells and tissues, thus enhancing therapeutic outcomes and minimising the risks of adverse effects. Besides that, nanomaterials can also help in both the treatment and diagnostics of diseases as they can simultaneously deliver contrast agents, therapeutic agents, and biomacromolecules to targeted sites. In this chapter, we will be highlighting the properties of several types of advanced nanomaterials which have been widely utilized in modern drug delivery applications. Their advantages and disadvantages will also be discussed in this overview, emphasizing some of the most recent studies conducted using these nanomaterials in chronic respiratory diseases.
siRNA therapeutics allows precise regulation of disease specific gene expression to treat various diseases. Although gene silencing approaches using siRNA therapeutics shows some promising results in the treatment of gene-related diseases, the practical applications has been limited by problems such as inefficient in vivo delivery to target cells and nonspecific immune responses after systemic or local administration. To overcome these issues, various in vivo delivery platforms have been introduced. Here we provide an overview for three different platform technologies for the in vivo delivery of therapeutic siRNAs (siRNA–GalNAc conjugate, SAMiRNA technology, and LNP-based delivery method) and their applications in the treatment of various diseases. In addition, a brief introduction to some rare diseases and mechanisms of siRNA therapeutics-mediated treatment is described.
