Mechanisms and optimization of in vivo delivery of lipophilic siRNAs

Wolfrum, Christian; Shi, Shuanping; Jayaprakash, K. N.; Jayaraman, Muthusamy; Wang, Gang; Pandey, Rajendra K.; Rajeev, Kallanthottathil G.; Nakayama, Tomoko; Charrise, Klaus; Ndungo, Esther; Zimmermann, Tracy; Koteliansky, Victor; Manoharan, Muthiah; Stoffel, Markus

doi:10.1038/nbt1339

Cited by 867 publications

(842 citation statements)

References 25 publications

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“…The cholesterol moiety enhances retention of the conjugated siRNA in the circulation by binding to albumin, low-density lipoprotein and highdensity lipoprotein particles, as well as uptake in hepatocytes by binding to low-density lipoprotein receptors and uptake in the liver, gut, kidney and steroidogenic organs by binding to the scavenger receptor class B, type I receptors, which take up high-density lipoprotein. 40 Conjugation of cholesterol, as well as a-tocopherol, 41 lithocholic acid or lauric acid 42 to ApoB-siRNAs reduces serum cholesterol and ApoB mRNA levels in the liver after intravenous injection. Another example of this approach is 'siRNA dynamic polyconjugates' .…”

Section: Introductionmentioning

confidence: 99%

Special delivery: targeted therapy with small RNAs

2011

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Harnessing RNA interference using small RNA-based drugs has great potential to develop drugs designed to knock down expression of any disease-causing gene, thereby greatly expanding the universe of possible drug targets. However, delivering small RNAs into specific tissues and cells is still a hurdle. Here, we review recent progress in overcoming systemic, local and cellular barriers to RNA drug delivery, focusing on strategies for targeted uptake.

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Section: Introductionmentioning

confidence: 99%

Special delivery: targeted therapy with small RNAs

2011

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“…The most typical derivatization is with long-chain fatty acids, whereas derivatization with cholesterol has been little explored (57). However, a recent report on the comparative efficacy in vivo of intravenously administered lipophilic derivatives of siRNA showed that derivatization with cholesterol and related molecules gave the highest biological activity (58). Therefore, we investigated whether derivatization with cholesterol, in addition to providing improved antiviral potency, also extends the half-life of the peptide in vivo.…”

Section: Effect Of Lipid Derivatization On the Pharmacokinetics Of C3mentioning

confidence: 99%

Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency

Ingallinella

Bianchi

Ladwa

et al. 2009

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

185

247

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Peptides derived from the heptad repeat 2 (HR2) region of the HIV fusogenic protein gp41 are potent inhibitors of viral infection, and one of them, enfuvirtide, is used for the treatment of therapyexperienced AIDS patients. The mechanism of action of these peptides is binding to a critical intermediate along the virus-cell fusion pathway, and accordingly, increasing the affinity for the intermediate yields more potent inhibitors. We took a different approach, namely to increase the potency of the HR2 peptide inhibitor C34 by targeting it to the cell compartment where fusion occurs, and we show here that a simple, yet powerful way to accomplish this is attachment of a cholesterol group. C34 derivatized with cholesterol (C34-Chol) shows dramatically increased antiviral potency on a panel of primary isolates, with IC 90 values 15-to 300-fold lower than enfuvirtide and the second-generation inhibitor T1249, making C34-Chol the most potent HIV fusion inhibitor to date. Consistent with its anticipated mechanism of action, the antiviral activity of C34-Chol is unusually persistent: washing target cells after incubation with C34-Chol, but before triggering fusion, increases IC 50 only 7-fold, relative to a 400-fold increase observed for C34. Moreover, derivatization with cholesterol extends the half-life of the peptide in vivo. In the mouse, s.c. administration of 3.5 mg/kg C34-Chol yields a plasma concentration 24 h after injection >300-fold higher than the measured IC 90 values. Because the fusion machinery targeted by C34-Chol is similar in several other enveloped viruses, we believe that these findings may be of general utility. antiretroviral drug ͉ enveloped viruses ͉ lipid rafts ͉ peptide therapeutic

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“…Wolfrum et al [111] demonstrated that cholesterol-conjugated siRNA is taken up in murine models by a lipoprotein-dependent mechanism. Delivery of the siRNA conjugates depended upon interactions with lipoprotein particles, lipoprotein receptors and transmembrane proteins.…”

Section: "Ad" System -Based Deliverymentioning

confidence: 99%

Therapeutic targeting in the silent era: advances in non-viral siRNA delivery

et al. 2010

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Access to the full text of the published version may require a subscription. Rights AbstractGene silencing using RNA-interference, first described in mammalian systems almost a decade ago, is revolutionizing therapeutic target validation efforts both in vitro and in vivo. Moreover, the potential for using short interfering RNA (siRNA) as a therapy in its own right is also progressing at a significant pace. However, the widespread use of such approaches is contingent on having appropriate delivery systems to achieve clinically appropriate, safe, and efficient delivery of siRNA. There are many physicochemical and biological barriers to such delivery, and a growing emphasis on the design and characterisation of non-viral technologies that will overcome these barriers and expedite targeted delivery. This review discusses the considerations and challenges associated with use of siRNA-based therapeutics, including stability and off-target effects. Speculation is made on the properties of an ideal delivery system and the non-viral delivery approaches used to date, both in vitro and in vivo, are classified and discussed. Moreover, the ability of cyclodextrin-based delivery vectors to fulfil many of the criteria of an ideal delivery construct is also elaborated.3 Introduction:

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Mechanisms and optimization of in vivo delivery of lipophilic siRNAs

Cited by 867 publications

References 25 publications

Special delivery: targeted therapy with small RNAs

Special delivery: targeted therapy with small RNAs

Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency

Therapeutic targeting in the silent era: advances in non-viral siRNA delivery

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