Polymers in Small-Interfering RNA Delivery

Abstract

This review will cover the current strategies that are being adopted to efficiently deliver small interfering RNA using nonviral vectors, including the use of polymers such as polyethylenimine, poly(lactic-co-glycolic acid), polypeptides, chitosan, cyclodextrin, dendrimers, and polymers-containing different nanoparticles. The article will provide a brief and concise account of underlying principle of these polymeric vectors and their structural and functional modifications which were intended to serve different purposes to affect efficient therapeutic outcome of small-interfering RNA delivery. The modifications of these polymeric vectors will be discussed with reference to stimuli-responsiveness, target specific delivery, and incorporation of nanoconstructs such as carbon nanotubes, gold nanoparticles, and silica nanoparticles. The emergence of small-interfering RNA as the potential therapeutic agent and its mode of action will also be mentioned in a nutshell.

RNAi Therapeutic Potentials and Prospects in CNS Disease

“…There are many approaches that are being developed to achieve the efficient delivery of siRNA. In that, non-viral vectors have advantages of reproducibility, low immunogenicity, and relatively low production cost [14]; therefore, non-viral vectors made siRNA to be a potential therapeutic and nucleic acid-based drugs, such as plasmid DNAs or antisense oligonucleotides (ASOs) [15].…”

Vehicles for Small Interfering RNA transfection: Exosomes versus Synthetic Nanocarriers

“…The major classes of synthetic carriers are shown in Table 1, together with the most pronounced advantages and drawbacks in their usage for siRNA transfection [21]. The number of synthetic molecules for nucleic acid transfection is large and continuously increasing as their performance is enhanced by chemical modifications.…”

“…Therefore, exosomes reflect the physiological status of the cells they originate from and can potentially serve as predictive biomarkers in the diagnosis of malignancies and other diseases [15][16][17]. [21]. Furthermore, examples for modifications are given which were introduced to improve transfection parameters.…”

“…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 …”

“…Although siRNAs show reduced strength of that interaction due to their short length, adaptations of the composition of transfection mixtures overcome that problem [21].…”