Delivery of siRNA Therapeutics: Barriers and Carriers

Wang, Jie; Lu, Ze; Wientjes, M. Guillaume; Au, Jessie L.-S.

doi:10.1208/s12248-010-9210-4

Cited by 673 publications

(619 citation statements)

References 97 publications

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“…Encapsulation of siRNAs within nanoparticles offers numerous delivery benefits, including protection from degradation by ubiquitous nucleases, passive and active targeting, and evasion of endosomal Toll-like receptors (1)(2)(3). To date, several polymeric, lipid, and dendritic nanoparticles have been developed for the encapsulation and delivery of siRNAs (4)(5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery

Alabi

Love

Sahay

et al. 2013

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

143

110

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Nanoparticle-mediated siRNA delivery is a complex process that requires transport across numerous extracellular and intracellular barriers. As such, the development of nanoparticles for efficient delivery would benefit from an understanding of how parameters associated with these barriers relate to the physicochemical properties of nanoparticles. Here, we use a multiparametric approach for the evaluation of lipid nanoparticles (LNPs) to identify relationships between structure, biological function, and biological activity. Our results indicate that evaluation of multiple parameters associated with barriers to delivery such as siRNA entrapment, pK a , LNP stability, and cell uptake as a collective may serve as a useful prescreening tool for the advancement of LNPs in vivo. This multiparametric approach complements the use of in vitro efficacy results alone for prescreening and improves in vitro-in vivo translation by minimizing false negatives. For the LNPs used in this work, the evaluation of multiple parameters enabled the identification of LNP pK a as one of the key determinants of LNP function and activity both in vitro and in vivo. It is anticipated that this type of analysis can aid in the identification of meaningful structure-functionactivity relationships, improve the in vitro screening process of nanoparticles before in vivo use, and facilitate the future design of potent nanocarriers.RNAi | thiol-yne | gene silencing | drug carrier

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mentioning

confidence: 99%

Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery

Alabi

Love

Sahay

et al. 2013

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

143

110

View full text Add to dashboard Cite

show abstract

“…82 However, RNA therapeutics face considerable hurdles, including development of reliable delivery systems, dosage regimes and techniques to ameliorate off-target effects. 113,114 In addition, targeting transcripts the size of lncRNAs may seem like a daunting task; one must screen more small-interfering RNAs compared with mRNAs, possibly because of the extensive secondary structures in lncRNAs. Furthermore, few examples of transgenic models of lncRNA have been published to date.…”

Section: Discussionmentioning

confidence: 99%

The long non-coding RNAs, a new cancer diagnostic and therapeutic gold mine

2013

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The conventional view of gene regulation in biology has centered around protein-coding genes via the central dogma of DNA-mRNA-protein. The discovery of thousands of long non-coding RNAs (lncRNAs) has certainly changed our view of the complexity of mammalian genomes and transcriptomes, as well as many other aspects of biology including transcriptional and posttranscriptional regulation of gene expression. Accumulating reports of misregulated lncRNA expression across numerous cancer types suggest that aberrant lncRNA expression may be a major contributor to tumorigenesis. Here, we summarize recent data about the biological characteristics of lncRNAs in cancer pathways. These include examples with a wide range of molecular mechanisms involved in gene regulation. We also consider the medical implications, and discuss how lncRNAs can be used for cancer diagnosis and prognosis, and serve as potential therapeutic targets. As more examples of regulation by lncRNA are uncovered, one might predict that the large transcripts will eventually rival small RNAs and proteins in their versatility as regulators of genetic information.

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“…[79] Similarly, cyclodextrins undergo unspecific (clathrin independent) uptake [80] but also serve to improve water-solubility and biodistribution of the cargo due to their cyclic oligosaccharide nature. [81] In the case of CPPs, uptake may occur either through transitory micelle formation, endocytosis in its four variants, or direct penetration driven by penetratin or TAT (GRKKR-RQRRR) domains, [82] which explains their documented high transfection efficiencies. [76] Overall, dendrimers, cyclodextrins, and CPPs offer extensive versatility in their structure and associated phys-chem properties, ultimately allowing the formation of the complexes to occur through charge adsorption or physical encapsulation; research in adapting and optimizing these vectors for miRNA delivery will undoubtedly impact the application of miRNA therapeutics in RM.…”

Section: Nonviral Vectorsmentioning

confidence: 99%

Scaffold‐Based microRNA Therapies in Regenerative Medicine and Cancer

Curtin

Castaño

O’Brien

2017

Adv Healthcare Materials

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The field of "regenerative medicine" (RM) was conceptually developed to aid the body's natural capacity to self-repair, a capacity which is impaired with age and in cases of disease or injury. [1] RM is a vast and multifaceted area of medicine, often microRNA-based therapies are an advantageous strategy with applications in both regenerative medicine (RM) and cancer treatments. microRNAs (miRNAs) are an evolutionary conserved class of small RNA molecules that modulate up to one third of the human nonprotein coding genome. Thus, synthetic miRNA activators and inhibitors hold immense potential to finely balance gene expression and reestablish tissue health. Ongoing industrysponsored clinical trials inspire a new miRNA therapeutics era, but progress largely relies on the development of safe and efficient delivery systems. The emerging application of biomaterial scaffolds for this purpose offers spatiotemporal control and circumvents biological and mechanical barriers that impede successful miRNA delivery. The nascent research in scaffold-mediated miRNA therapies translates know-how learnt from studies in antitumoral and genetic disorders as well as work on plasmid (p)DNA/siRNA delivery to expand the miRNA therapies arena. In this progress report, the state of the art methods of regulating miRNAs are reviewed. Relevant miRNA delivery vectors and scaffold systems applied to-date for RM and cancer treatment applications are discussed, as well as the challenges involved in their design. Overall, this progress report demonstrates the opportunity that exists for the application of miRNA-activated scaffolds in the future of RM and cancer treatments.Regenerative Medicine

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Delivery of siRNA Therapeutics: Barriers and Carriers

Cited by 673 publications

References 97 publications

Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery

Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery

The long non-coding RNAs, a new cancer diagnostic and therapeutic gold mine

Scaffold‐Based microRNA Therapies in Regenerative Medicine and Cancer

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