Drug delivery of siRNA therapeutics: potentials and limits of nanosystems

Reischl, Daniela; Zimmer, Andreas

doi:10.1016/j.nano.2008.06.001

Cited by 216 publications

(166 citation statements)

References 112 publications

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“…3 However, progress of siRNA cancer therapy relies on the development of safe and effective delivery systems. The usage of novel nanocarriers offers substantial advantages including the prevention of degradation, possibility of delivering high concentrations of siRNA into tumor tissues, specific targeting, and controlled release.…”

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confidence: 99%

Poly-l-lysine Functionalized Large Pore Cubic Mesostructured Silica Nanoparticles as Biocompatible Carriers for Gene Delivery

et al. 2012

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Large pore mesoporous silica nanoparticles (LP-MSNs) functionalized with poly-l-lysine (PLL) were designed as a new carrier material for gene delivery applications. The synthesized LP-MSNs are 100–200 nm in diameter and are composed of cage-like pores organized in a cubic mesostructure. The size of the cavities is about 28 nm with an entrance size of 13.4 nm. Successful grafting of PLL onto the silica surface through covalent immobilization was confirmed by X-ray photoelectron spectroscopy, solid-state 13C magic-angle spinning nuclear magnetic resonance, Fourier transformed infrared, and thermogravimetric analysis. As a result of the particle modification with PLL, a significant increase of the nanoparticle binding capacity for oligo-DNAs was observed compared to the native unmodified silica particles. Consequently, PLL-functionalized nanoparticles exhibited a strong ability to deliver oligo DNA-Cy3 (a model for siRNA) to Hela cells. Furthermore, PLL-functionalized nanoparticles were proven to be superior as gene carriers compared to amino-functionalized nanoparticles and the native nanoparticles. The system was tested to deliver functional siRNA against minibrain-related kinase and polo-like kinase 1 in osteosarcoma cancer cells. Here, the functionalized particles demonstrated great potential for efficient gene transfer into cancer cells as a decrease of the cellular viability of the osteosarcoma cancer cells was induced. Moreover, the PLL-modified silica nanoparticles also exhibit a high biocompatibility, with low cytotoxicity observed up to 100 μg/mL.

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Poly-l-lysine Functionalized Large Pore Cubic Mesostructured Silica Nanoparticles as Biocompatible Carriers for Gene Delivery

et al. 2012

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“…To address these problems, two strategies have been pursued: development of noncharged and nonbiodegradable siRNA surrogates (10) and, more directly, development of delivery vehicles and strategies that would enable or enhance the entry of siRNA itself. Several siRNA delivery technologies have been reported thus far, including direct covalent conjugation of siRNA to lipids, peptides, or to aptamers; and noncovalent complexation of siRNA with polymers, biopolymers, nanotubes, lipid-based vehicles (e.g., lipopolyplexes, stable nucleic acid lipid nanoparticles), cyclodextrin polymer-based nanoparticles, fusion proteins, membrane translocation-modified magnetic nanoparticles, and antibodyprotamine conjugates (4,6,(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22).In 2000, we reported an extensive reverse engineering effort directed at the highly cationic HIV-Tat 9-mer peptide (RKKRRQRRR), showing that its ability to enter cells is related to its arginine content and, more specifically, to the number and array of its guanidinium groups (23). This finding led to the design of oligoarginine and guanidinium-rich peptoid cell penetrating agents and, subsequently, a wide range of designed nonpeptidic agents, more generally and accurately dubbed molecular transporters, differing in backbone structure but uniformly incorporating the key guanidinium head groups (24).…”

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confidence: 99%

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.

109

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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“…Thus, the major limitation for the use of siRNA in vivo is the inability of naked siRNA to passively diffuse through cellular membranes; i.e., there is a strong anionic charge of the phosphate backbone and consequent electrostatic repulsion from the anionic cell membrane surface. 4 The other obstacles to the delivery of siRNAs in vivo, such as degradation by nuclease(s) in blood and interaction with blood components, indeed exist. 5 To overcome these obstacles, many delivery systems, such as hydrodynamic approaches 6 and bioconjugating approaches including cationic liposomes, 7 cationic polymers, 8 and cell penetrating peptides, 9 have been developed.…”

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confidence: 99%

Systemic delivery of siRNA specific to tumor mediated by atelocollagen: Combined therapy using siRNA targeting Bcl‐xL and cisplatin against prostate cancer

Nagahara

Makita

et al. 2009

Intl Journal of Cancer

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The largest obstacle to the effective use of short interfering RNA (siRNA) in an animal body is the ability to deliver it to the target tissue. Here we showed a systemic delivery method of siRNA specific to pregrown solid tumors via atelocollagen. Atelocollagen facilitated the selective uptake of siRNA into the tumors when an siRNA/atelocollagen complex was administered intravenously to mice. We chose a Bcl‐xL protein as a model target to prove the therapeutic efficacy of the atelocollagen‐mediated method. Bcl‐xL acts as an anti‐apoptotic factor, which is overexpressed in many cancers, including prostate cancer. One of the four designed siRNAs to human Bcl‐xL potently inhibited the expression of Bcl‐xL by the PC‐3 human prostate cancer cell line in vitro, leading to cell apoptosis. Intravenous injections for3 consecutive days (siRNA, 100 μg/injection per day as a complex with atelocollagen) effectively downregulated Bcl‐xL expression in the PC‐3 xenograft. We administered four series of 3 consecutive days of intravenous injections each, for a total of 12 injections, which significantly inhibited tumor growth when the treatment was combined with cisplatin (2 mg/kg). Local injection of Bcl‐xL siRNA also potently inhibited tumor growth. All of the tumors treated with Bcl‐xL siRNA/atelocollagen complex via both intravenous and intratumoral injection showed terminal deoxynucleotidyl transferase‐mediated dUTP nick‐end labeling‐positive apoptosis. There were no severe side effects such as interferon‐α induction and liver or renal damage in mice. Our results indicate that systemic delivery of siRNA via atelocollagen, which specifically targets tumors, is safe and feasible for cancer therapy. © 2009 UICC

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Drug delivery of siRNA therapeutics: potentials and limits of nanosystems

Cited by 216 publications

References 112 publications

Poly-l-lysine Functionalized Large Pore Cubic Mesostructured Silica Nanoparticles as Biocompatible Carriers for Gene Delivery

Poly-l-lysine Functionalized Large Pore Cubic Mesostructured Silica Nanoparticles as Biocompatible Carriers for Gene Delivery

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

Systemic delivery of siRNA specific to tumor mediated by atelocollagen: Combined therapy using siRNA targeting Bcl‐xL and cisplatin against prostate cancer

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