Medicinal Chemistry of siRNA Delivery

Stanton, Matthew; Colletti, Steven L.

doi:10.1021/jm1003914

Cited by 58 publications

(73 citation statements)

References 76 publications

(134 reference statements)

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“…Numerous siRNA delivery systems have been explored, including lipid nanoparticles, cationic polymers, antibody constructs, and RNA aptamers. 5,6 While significant progress in siRNA delivery has been made with these various transfection agents, none are ideal and significant formulation/characterization barriers preclude their immediate clinical application.…”

mentioning

confidence: 99%

Functional Delivery of siRNA by Disulfide-Constrained Cyclic Amphipathic Peptides

Welch

Swanekamp

King

et al. 2016

ACS Med. Chem. Lett.

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The promise of oligonucleotide therapeutic agents to perturb expression of disease-related genes remains unrealized, in part due to challenges with functional cellular delivery of these agents. Herein, we describe disulfide-constrained cyclic amphipathic peptides that complex with short-interfering RNA (siRNA) and affect functional cytosolic delivery and knockdown of target gene products in cell culture and in vivo to mouse lung. Reduction of the constraining disulfide bond and subsequent proteolytic clearance of the peptide are key design features that allow unmasking of the siRNA cargo and presentation to the RNA interference machinery.

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mentioning

confidence: 99%

Functional Delivery of siRNA by Disulfide-Constrained Cyclic Amphipathic Peptides

Welch

Swanekamp

King

et al. 2016

ACS Med. Chem. Lett.

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“…The properties that have been validated in chemotherapeutics are also exploited for siRNA packaging and delivery 41-46. The effort began with stable association of siRNA molecules with the nanoparticles and their retention in circulation.…”

Section: Nanoparticles In Rnai Therapeuticsmentioning

confidence: 99%

Nanoparticle-Mediated Systemic Delivery of siRNA for Treatment of Cancers and Viral Infections

Draz¹,

Fang²,

Zhang³

et al. 2014

Theranostics

206

153

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RNA interference (RNAi) is an endogenous post-transcriptional gene regulatory mechanism, where non-coding, double-stranded RNA molecules interfere with the expression of certain genes in order to silence it. Since its discovery, this phenomenon has evolved as powerful technology to diagnose and treat diseases at cellular and molecular levels. With a lot of attention, short interfering RNA (siRNA) therapeutics has brought a great hope for treatment of various undruggable diseases, including genetic diseases, cancer, and resistant viral infections. However, the challenge of their systemic delivery and on how they are integrated to exhibit the desired properties and functions remains a key bottleneck for realizing its full potential. Nanoparticles are currently well known to exhibit a number of unique properties that could be strategically tailored into new advanced siRNA delivery systems. This review summarizes the various nanoparticulate systems developed so far in the literature for systemic delivery of siRNA, which include silica and silicon-based nanoparticles, metal and metal oxides nanoparticles, carbon nanotubes, graphene, dendrimers, polymers, cyclodextrins, lipids, hydrogels, and semiconductor nanocrystals. Challenges and barriers to the delivery of siRNA and the role of different nanoparticles to surmount these challenges are also included in the review.

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“…As siRNA delivery technology continues to advance, the local delivery to target tissues and systemic delivery are becoming safer and more efficient [7]. The understanding of the siRNA absorption, distribution, metabolism, and excretion (ADME) properties along with the PK parameters in vivo is a necessary step toward developing an RNAi therapeutic.…”

Section: Difficult Isolation From Biomatricesmentioning

confidence: 99%