An insight into the gene delivery mechanism of the arginine peptide system: Role of the peptide/DNA complex size

Choi, Hong Seok; Kim, Hyun Hee; Yang, Jai Myung; Shin, Sungho

doi:10.1016/j.bbagen.2006.09.011

Cited by 39 publications

(38 citation statements)

References 41 publications

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“…These are average sizes and by filtration one can obtain smaller (<200 nm) or larger particle sizes. Over the course of the hour measurement period, some of the co-oligomer complexes increased in size, a phenomenon that has been observed previously in the complexation of polynucleotides with oligoguanidiniums (31). Solutions of only the co-oligomer without siRNA did not form measurable particles at the concentrations used for siRNA∶co-oligomer complex formation.…”

Section: Resultsmentioning

confidence: 61%

Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells

Geihe

Cooley

Simon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

108

145

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The polyanionic nature of oligonucleotides and their enzymatic degradation present challenges for the use of siRNA in research and therapy; among the most notable of these is clinically relevant delivery into cells. To address this problem, we designed and synthesized the first members of a new class of guanidinium-rich amphipathic oligocarbonates that noncovalently complex, deliver, and release siRNA in cells, resulting in robust knockdown of target protein synthesis in vitro as determined using a dual-reporter system. The organocatalytic oligomerization used to synthesize these co-oligomers is step-economical and broadly tunable, affording an exceptionally quick strategy to explore chemical space for optimal siRNA delivery in varied applications. The speed and versatility of this approach and the biodegradability of the designed agents make this an attractive strategy for biological tool development, imaging, diagnostics, and therapeutic applications.amphipathic co-oligomers | nanoparticles | oligonucleotide delivery | biodegradable oligomers | organocatalysis R NA interference (RNAi) is an emerging technology that is revolutionizing many strategic approaches to biochemical pathway analysis, drug discovery, and therapy (1-6). As part of the RNAi pathway, small interfering RNAs (siRNAs) induce post-transcriptional, sequence-specific gene silencing utilizing endogenous intracellular machinery to selectively suppress gene expression and, thereby, reduce target protein synthesis (7). The net effect is equivalent to protein inhibition without the use of small molecule inhibitors. The specificity of RNAi also allows one to make inhibitors against previously undruggable targets. Both the ubiquity of the RNAi pathway within the body and the ease with which siRNA can be used to suppress a specific target of interest have made siRNAs a promising class of molecules for the treatment of cancer, viral infections, ocular disorders, and genetic diseases (5). In 2004, the first siRNA-based therapy entered Phase 1 clinical trials (4). Since then, several other RNAi-based therapies have reached clinical evaluation for a number of indications including cancer, viral infections, and genetic skin disorders (5,8,9). Notwithstanding this progress, formidable challenges remain for the application of RNAi technology in basic research and therapy, the most fundamental of which is delivery of siRNA across biological barriers.The siRNAs are double-stranded RNA molecules typically consisting of a 19-23 base-paired region with two 3′ overhanging nucleotides. It is polyanionic, polar, and large (ca. 13 kDa), compared to small molecule therapeutics. These physical properties suppress or prevent its unassisted passage through nonpolar membranes and, thus, its access to the intracellular RNA-induced silencing complex (RISC) components required for target protein knockdown (6). This problem is further exacerbated by siRNA's susceptibility to enzymatic degradation (i.e., RNases) (3). To address these problems, two strategies have been pursued: d...

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Section: Resultsmentioning

confidence: 61%

Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells

Geihe

Cooley

Simon

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

108

145

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“…In preparation to transfect plant cells, we have obtained complex particles of size 2.6-6.4 lm with 1-h incubation period of the Tat2-linear DNA complex (13). Choi et al (38) have reported complexes of R15 peptide with plasmid DNA expressing the b-gal gene with an initial size of 0.4 lm that can reach up to 26 lm with increasing time of incubation. Complexes larger than 6 lm resulted in higher b-gal gene expression in 293T cells than complexes of smaller size.…”

Section: Structural-functional Relationship Of Cppsmentioning

confidence: 99%

“…Complex particles of various sizes can be made, and the size of the complex is directly related to the incubation period of the peptide-DNA mixture (38). In preparation to transfect plant cells, we have obtained complex particles of size 2.6-6.4 lm with 1-h incubation period of the Tat2-linear DNA complex (13).…”

Section: Structural-functional Relationship Of Cppsmentioning

confidence: 99%

Cell‐penetrating peptides: Nanocarrier for macromolecule delivery in living cells

2010

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SummaryNovel classes and applications of cell-penetrating peptides (CPPs) are being constantly discovered since they were first identified 2 decades ago. These short cationic peptides (nanomolecules) either by covalent binding or by noncovalent binding can traverse cell membranes and deliver a variety of molecules that are unable to overcome the permeability barrier in their own capacity. The ability of the CPPs to deliver variety of macromolecules, such as oligonucleotides, therapeutic drugs, proteins, and medical imaging agents, by forming nanoparticulate carriers in a range of cells has led them to emerge as a potential tool for both macromolecule delivery application and to gain insight into the fundamentals of mechanism of cellular uptake across the plasma membrane. This review explores the recent advances, challenges, and future prospects in the field of CPP-mediated cargo delivery in mammalian and plant cells. Studies have been conducted into the peptide chemistry and stability of CPP-macromolecular complexes. Most of the CPPs have been shown to be nontoxic and do not interfere with the functionality of the macromolecules delivered across the cell membrane. The mechanism of uptake of CPP-cargo complexes and the uptake of CPPs alone across the plasma membrane remains unresolved. As the world of CPPs is rapidly advancing in both mammalian and plant system, there is a promising future for the various applications of transduction and transfection into intact cells.

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“…Whether vesicles from different origin eventually merge is another unresolved issue. Furthermore, both the size (Choi et al, 2006) and shape (Sharma et al, 2010) can affect the uptake of a particle and its in vivo distribution (Decuzzi et al, 2010). However, these physical parameters of tat or other CPP complexes are seldom reported.…”

Section: Tatmentioning

confidence: 99%

Peptides as Promising Non-Viral Vectors for Gene Therapy

Seow¹,

George²

2011

Non-Viral Gene Therapy

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An insight into the gene delivery mechanism of the arginine peptide system: Role of the peptide/DNA complex size

Cited by 39 publications

References 41 publications

Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells

Designed guanidinium-rich amphipathic oligocarbonate molecular transporters complex, deliver and release siRNA in cells

Cell‐penetrating peptides: Nanocarrier for macromolecule delivery in living cells

Peptides as Promising Non-Viral Vectors for Gene Therapy

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