A single-monomer derived linear-like PEI-co-PEG for siRNA delivery and silencing

Tsai, Lin-Ren; Chen, Minhua; Chien, Chih-Te; Chen, Meng-Kai; Lin, Fong-Sian; Lin, Keh Ming; Hwu, Y.; Yang, Chung‐Shi; Lin, Shu‐Yi

doi:10.1016/j.biomaterials.2011.01.059

Cited by 30 publications

(11 citation statements)

References 39 publications

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“…29 Most cationic systems used to deliver nucleic acids to cells present a protection pattern to siRNA that is consistent with the amount of the cationic moiety employed to formulate the complexes, increasing from the lowest to the highest charge ratios. 30,31 However, the thermoresponsive copolymers studied herein did not present such behavior. Apparently, the polymer/ siRNA charge ratio did not affect the release of the siRNAs or showed an opposite effect to that described for nonthermoresponsive systems (Figure 4).…”

Section: Molecular Pharmaceuticsmentioning

confidence: 67%

Application of Thermoresponsive PNIPAAM-b-PAMPTMA Diblock Copolymers in siRNA Delivery

et al. 2014

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Gene knockdown has emerged as an important tool for cancer gene therapy as well as for viral infections and dominantly inherited genetic disorders. The generation of suitable siRNA delivery systems poses some challenges, namely, to avoid nuclease degradation, to surpass the cytoplasmic membrane, and to release the nucleic acids into the cytosol. Aiming at evaluating the ability of thermoresponsive block copolymers formed by units of N-isopropylacrylamide and of (3-acrylamidopropyl)trimethylammonium chloride to efficiently deliver siRNAs, an extensive study was performed with four different copolymers using a human fibrosarcoma cell line as cell model. The silencing ability and cytotoxicity of the generated copolymer-based siRNA delivery systems were found to be dependent on the cloud point of the polymer, which corresponds to the transition temperature at which the aggregation or precipitation of the polymer molecules becomes thermodynamically more favorable than their solubilization. In the present study, a system capable of delivering siRNAs efficiently, specifically and without presenting relevant cytotoxicity, even in the presence of serum, was developed. Confocal fluorescence experiments showed that the ability of the generated systems to silence the target gene is related to some extent to nucleic acid internalization, being also dependent on polymer/siRNA dissociation at 37 °C. Thus, a delicate balance between nucleic acid internalization and intracellular release must be met in order to reach an ideal knockdown efficiency. The special features and potential for manipulation of the N-isopropylacrylamide-based copolymers make them suitable materials for the design and synthesis of new and promising siRNA delivery systems.

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Section: Molecular Pharmaceuticsmentioning

confidence: 67%

Application of Thermoresponsive PNIPAAM-b-PAMPTMA Diblock Copolymers in siRNA Delivery

et al. 2014

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“…Liposomes versatile and flexible system protection of the siRNA targeting possible membrane fusion and triggered drug release form aggregates with serum proteins immunogenic limited delivery efficiency in vivo [63] PEGylation decreased blood clearence [64] incorporation of fusogenic lipids enhanced bioavailability of siRNA [65] apolipoprotein A 95% knockdown without immunotoxicity targeted to the liver [66] pH-sensitive histidinelysine peptide inhibition of tumor growth in a pancreatic cancer model [67] peptide from Rabies Virus glycoprotein brain targeting [68] SNALPs -Stabilized Nucleic Acid Lipid Particles PEG-derivatized cationic lipid with stabilized lipid bilayer fusogenic prolonged blood circulation 80-90% efficiency after siRNA transfection into liver [34] SPANosomes sorbitan monooleate high siRNA incorporation efficiency efficient endosomal escape and cytosolic delivery 60-80% gene knockdown [69,70] Polyethylenimine -PEI toxicity of high molecular weight PEI proton sponge effect for efficient release from endosomes [21] hydrophobic lipid anchor improved cellular uptake [71] folate folate receptor mediated uptake [42] galactose and pullulan liver targeted [43,72] PEI-PEG-copolymer efficient siRNA release 75%gene knockdown efficiency suppression of tumor growth [73] bioreducible poly(amido ethylenimine) (SS-PAEI) complete release of siRNA in a reductive environment [62] Poly(dl-lactide-co-glycolide) -PLGA degraded under physiological conditions degradation rate can be controlled by composition of the polymer nucleic acid encapsulation no endosomal escape mechanism [74] cationic segments (polyamines) good binding and protections of siRNA disruption of endosomal membranes [75] poly(ethylene glycol)-poly (d,l-lactide) cationic lipic suppressed tumor growth in a breast cancer murine xenograft model [76] Chitosan biodegradable, no/low immunogenicity low siRNA transfection efficiency [77,78] salt complexes excellent cell survival high gene silencing [79] α-tocopherol succinate enhanced cellular uptake [47] thiamine pyrophosphate >70% gene silencing [80] RGD peptide targeting to cancer cells [44] guanidinylation decreased cytotoxicity and enhanced cellular internalization of siRNA enhanced gene-silencing efficiency …”

Section: Sirna Delivery System Examples For Modifications Characterismentioning

confidence: 99%

Vehicles for Small Interfering RNA transfection: Exosomes versus Synthetic Nanocarriers

Duechler¹

2013

DNA and RNA Nanotechnology

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Therapies based on RNA interference (RNAi) hold a great potential for targeted interference of the expression of specific genes. Small-interfering RNAs (siRNA) and micro-RNAs interrupt protein synthesis by inducing the degradation of messenger RNAs or by blocking their translation. RNAibased therapies can modulate the expression of otherwise undruggable target proteins. Full exploitation of RNAi for medical purposes depends on efficient and safe methods for delivery of small RNAs to the target cells. Tremendous effort has gone into the development of synthetic carriers to meet all requirements for efficient delivery of nucleic acids into particular tissues. Recently, exosomes unveiled their function as a natural communication system which can be utilized for the transport of small RNAs into target cells. In this review, the capabilities of exosomes as delivery vehicles for small RNAs are compared to synthetic carrier systems. The step by step requirements for efficient transfection are considered: production of the vehicle, RNA loading, protection against degradation, lack of immunogenicity, targeting possibilities, cellular uptake, cytotoxicity, RNA release into the cytoplasm and gene silencing efficiency. An exosomebased siRNA delivery system shows many advantages over conventional transfection agents, however, some crucial issues need further optimization before broad clinical application can be realized.

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“…As also discussed in the literature, polyethylenimines have been the most widely used vectors for such purposes in vitro and in vivo. 12–17 Branched polyethylenimine (bPEI, 25 kDa), which consists of 1°, 2°, and 3° amines in the ratio of 1:2:1, displays high transfection efficiency but exhibits high toxicity due to high charge density. On the contrary, linear polyethylenimine (lPEI, 25 kDa) is a nontoxic polymer but exhibits poor transfection activity due to inefficient binding of nucleic acids.…”

Section: Introductionmentioning

confidence: 99%

Engineered polymeric amphiphiles self-assembling into nanostructures and acting as efficient gene and drug carriers

Bansal

Kumar

2017

J Biomater Appl

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Nonviral gene delivery systems are finding widespread use due to their safety, rapid and economical production, and ease of modification. In this work, series of N-alkyl-substituted linear polyethylenimine (CP) polymers have been synthesized, characterized, and investigated about how degree of substitution (hydrophobic-hydrophilic balance) (i.e. N-alkylation) influenced the transfection efficiency. Mobility shift assay demonstrated efficient binding of plasmid DNA (pDNA). Transfection efficiency and cytotoxicity of CP polymers were assessed in vitro, which revealed that all the formulations exhibited higher transfection activity than linear polyethylenimine (lPEI) and commercial transfection reagents, Lipofectamine and Superfect, with negligible toxicity (MTT assay). In the projected series, one of the formulations, CP-3-pDNA complex, displayed the highest transfection efficiency (∼1.6-12 folds vs. lPEI and commercial transfection reagents) and effectively carried GFP-specific siRNA inside the cells as monitored by measuring the suppression in the gene expression of the target gene. Further, flow cytometry experiments confirmed that CP-3-pDNA complex transfected the highest number of cells. Besides, CP-3 was also evaluated in terms of its capability to entrap hydrophobic drug molecules. The results showed that it efficiently encapsulated an anti-cancer drug, etoposide, and released it in a controlled fashion over a period of time. Altogether, the data support that CP-3 is a promising vector for nucleic acid as well as hydrophobic drug delivery.

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A single-monomer derived linear-like PEI-co-PEG for siRNA delivery and silencing

Cited by 30 publications

References 39 publications

Application of Thermoresponsive PNIPAAM-b-PAMPTMA Diblock Copolymers in siRNA Delivery

Application of Thermoresponsive PNIPAAM-b-PAMPTMA Diblock Copolymers in siRNA Delivery

Vehicles for Small Interfering RNA transfection: Exosomes versus Synthetic Nanocarriers

Engineered polymeric amphiphiles self-assembling into nanostructures and acting as efficient gene and drug carriers

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