Polymer nanoparticles encapsulating siRNA for treatment of HSV-2 genital infection

Steinbach, Jill M.; Weller, Caroline E.; Booth, Carmen J.; Saltzman, W. Mark

doi:10.1016/j.jconrel.2012.06.008

Cited by 97 publications

(70 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, NP treatment is controlled for siRNA loading and the total siRNA payload delivered by the two types of NPs over the course of the experiment (4 d) is the same (same cumulative fraction of the total dose is released). We also measured the hydrodynamic diameter (283 nm) and zeta potential (−23 mV) of the siBCR-ABLwob loaded PLGA particles; these measurements were consistent with previous studies (24).…”

Section: Robust and Specific Leukemic Cell Death Can Be Achieved Using Asupporting

confidence: 90%

“…We do notice a small apparent increase in viability in U87 cells treated with siRNAloaded NPs compared with untreated cells. We believe this is due to the PLGA NP delivery vehicle, because we sometimes observe an apparent increase in cell viability upon treatment with blank or spermidine-only PLGA NPs (24,25).…”

Section: Robust and Specific Leukemic Cell Death Can Be Achieved Using Amentioning

confidence: 97%

See 1 more Smart Citation

Enhancing potency of siRNA targeting fusion genes by optimization outside of target sequence

Gavrilov

Seo

Tietjen

et al. 2015

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

Self Cite

View full text Add to dashboard Cite

Canonical siRNA design algorithms have become remarkably effective at predicting favorable binding regions within a target mRNA, but in some cases (e.g., a fusion junction site) region choice is restricted. In these instances, alternative approaches are necessary to obtain a highly potent silencing molecule. Here we focus on strategies for rational optimization of two siRNAs that target the junction sites of fusion oncogenes BCR-ABL and TMPRSS2-ERG. We demonstrate that modifying the termini of these siRNAs with a terminal G-U wobble pair or a carefully selected pair of terminal asymmetry-enhancing mismatches can result in an increase in potency at low doses. Importantly, we observed that improvements in silencing at the mRNA level do not necessarily translate to reductions in protein level and/or cell death. Decline in protein level is also heavily influenced by targeted protein half-life, and delivery vehicle toxicity can confound measures of cell death due to silencing. Therefore, for BCR-ABL, which has a long protein halflife that is difficult to overcome using siRNA, we also developed a nontoxic transfection vector: poly(lactic-coglycolic acid) nanoparticles that release siRNA over many days. We show that this system can achieve effective killing of leukemic cells. These findings provide insights into the implications of siRNA sequence for potency and suggest strategies for the design of more effective therapeutic siRNA molecules. Furthermore, this work points to the importance of integrating studies of siRNA design and delivery, while heeding and addressing potential limitations such as restricted targetable mRNA regions, long protein half-lives, and nonspecific toxicities.drug delivery | RNA interference | leukemia | BCR-Abl | TMPRSS2-ERG

show abstract

Section: Robust and Specific Leukemic Cell Death Can Be Achieved Using Asupporting

confidence: 90%

Section: Robust and Specific Leukemic Cell Death Can Be Achieved Using Amentioning

confidence: 97%

Enhancing potency of siRNA targeting fusion genes by optimization outside of target sequence

Gavrilov

Seo

Tietjen

et al. 2015

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Woodrow et al [50,52] have provided significant evidence that siRNA complexes could be successfully delivered by PLGA-NPs, providing sustained gene silencing in the female reproductive tract. Later, Steinbach et al [50,53] have showed that siRNA delivery via PLGA-NPs could provide protection against vaginal infection. Furthermore, these results are further evidence that siRNA-loaded PLGA-NPs may provide vaginal protection from sexually transmitted infections with improved safety compared to conventional siRNA delivery vehicles.…”

Section: Rectal and Vaginal Route Of Drug Deliverymentioning

confidence: 99%

Synthetic Polymer-Based Nanoparticles: Intelligent Drug Delivery Systems

Andonova¹

2017

Acrylic Polymers in Healthcare

View full text Add to dashboard Cite

One of the most promising strategies to improve the bioavailability of active pharmaceutical ingredients is based on the association of the drug with colloidal carriers, for example, polymeric nanoparticles, which are stable in biological environment, protective for encapsulated substances and able to modulate physicochemical characteristics, drug release and biological behaviour. The synthetic polymers possess unique properties due to their chemical structure. Some of them are characterized with mucoadhesiveness; another can facilitate the penetration through mucous layers; or to be stimuli responsive, providing controlled drug release at the target organ, tissues or cells; and all of them are biocompatible and versatile. These are suitable vehicles of nucleic acids, oligonucleotides, DNA, peptides and proteins. This chapter aims to look at the 'hot spots' in the design of synthetic polymer nanoparticles as an intelligent drug delivery system in terms of biopharmaceutical challenges and in relation to the route of their administration: the non-invasive-oral, transdermal, transmucosal (nasal, buccal/sublingual, vaginal, rectal and ocular) and inhalation routes-and the invasive parenteral route.

show abstract

“…The hypotoxicity and low drug dose makes the vagina an excellent site for siRNA delivery to target viral genes or host genes. Nanoparticle-based gene delivery systems, such as positively charged liposomes, 4 lipid-like molecules, 5,6 and polymer nanoparticles 7,8 have been evaluated in vaginal siRNA delivery because they show sustained release behavior and cellular targeting properties. Intravaginal administration with biodegradable poly (lactic-coglycolic acid) nanoparticles encapsulating siRNA showed efficient epithelial uptake and sustained gene silencing, 7 improving survival of the mice after herpes simplex virus 2 infection.…”

Section: Introductionmentioning

confidence: 99%

“…Intravaginal administration with biodegradable poly (lactic-coglycolic acid) nanoparticles encapsulating siRNA showed efficient epithelial uptake and sustained gene silencing, 7 improving survival of the mice after herpes simplex virus 2 infection. 8 However, delivery of siRNA to the vaginal epithelium has been significantly impeded by the mucus layer covering the vaginal wall. 9 Densely crosslinked mucin fibers with a woven mesh-like structure 10 function as a molecular sieve; this restricts foreign particles that fail to fit through the mesh pores.…”

Section: Introductionmentioning

confidence: 99%

Spray-dried powders enhance vaginal siRNA delivery by potentially modulating the mucus molecular sieve structure

Wu¹,

Zhang²,

Li³

et al. 2015

IJN

View full text Add to dashboard Cite

Vaginal small interfering RNA (siRNA) delivery provides a promising strategy for the prevention and treatment of vaginal diseases. However, the densely cross-linked mucus layer on the vaginal wall severely restricts nanoparticle-mediated siRNA delivery to the vaginal epithelium. In order to overcome this barrier and enhance vaginal mucus penetration, we prepared spray-dried powders containing siRNA-loaded nanoparticles. Powders with Pluronic F127 (F127), hydroxypropyl methyl cellulose (HPMC), and mannitol as carriers were obtained using an ultrasound-assisted spray-drying technique. Highly dispersed dry powders with diameters of 5–15 μm were produced. These powders showed effective siRNA protection and sustained release. The mucus-penetrating properties of the powders differed depending on their compositions. They exhibited different potential of opening mesh size of molecular sieve in simulated vaginal mucus system. A powder formulation with 0.6% F127 and 0.1% HPMC produced the maximum increase in the pore size of the model gel used to simulate vaginal mucus by rapidly extracting water from the gel and interacting with the gel; the resulting modulation of the molecular sieve effect achieved a 17.8-fold improvement of siRNA delivery in vaginal tract and effective siRNA delivery to the epithelium. This study suggests that powder formulations with optimized compositions have the potential to alter the steric barrier posed by mucus and hold promise for effective vaginal siRNA delivery.

show abstract

Polymer nanoparticles encapsulating siRNA for treatment of HSV-2 genital infection

Cited by 97 publications

References 33 publications

Enhancing potency of siRNA targeting fusion genes by optimization outside of target sequence

Enhancing potency of siRNA targeting fusion genes by optimization outside of target sequence

Synthetic Polymer-Based Nanoparticles: Intelligent Drug Delivery Systems

Spray-dried powders enhance vaginal siRNA delivery by potentially modulating the mucus molecular sieve structure

Contact Info

Product

Resources

About