Recent progress in copolymer-mediated siRNA delivery

Abstract

RNAi-mediated gene silencing has great potential for treating various diseases, including cancer, by delivering a specific short interfering RNA (siRNA) to knock down pathogenic mRNAs and suppress protein translation. Although many researchers are dedicated to devising polymer-based vehicles for exogenous in vitro siRNA transfection, few synthetic vehicles are feasible in vivo. Recent studies have presented copolymer-based vectors that are minimally immunogenic and facilitate highly efficient internalizing of exogenous siRNA, compared with homopolymer-based vectors. Cationic segments, organelle-escape units, and degradable fragments are essential to a copolymer-based vehicle for siRNA delivery. The majority of these cationic segments are derived from polyamines, including polylysine, polyarginine, chitosan, polyethylenimines and polyamidoamine dendrimers. Not only do these cationic polyamines protect siRNA, they can also promote disruption of endosomal membranes. Degradable fragments of copolymers must be derived from various polyelectrolytes to release the siRNA once the complexes enter the cytoplasm. This review describes recent progress in copolymer-mediated siRNA delivery, including various building blocks for biocompatible copolymers for efficient in vitro siRNA delivery, and a useful basis for addressing the challenges of in vivo siRNA delivery.

Delivery strategies and potential targets for siRNA in major cancer types

“…Synthetic polymers have been extensively investigated in the drug delivery field because of their well-defined chemistries and the high degree of molecular diversity obtainable via chemical modifications [46]. PEI is considered the most potent in its ability to form stable complexes with nucleic acids due to its highly positive charged nature.…”

Recent Developments in Nanoparticle-Based siRNA Delivery for Cancer Therapy

“…In addition, high molecular weight chitosans are cytotoxic, thus limiting their use in clinical trials [50]. They still also lack the buffering capacity needed for endosomolysis, which is essential to siRNA release from the endosome [51]. …”

“…PEI, a commonly used cationic polymeric drug carrier with high transfection efficiency, has been widely investigated for siRNA delivery [8, 12, 51]. PEI forms small and compact structures, spontaneously forming polyplexes, with negatively charged siRNA through a simple and short polycation process [12].…”

Vehicles for Small Interfering RNA transfection: Exosomes versus Synthetic Nanocarriers

“…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 …”