Tumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas

Abstract Vestibular schwannoma (VS) is the most common tumor of the cerebellopontine angle, and it typically presents with sensorineural hearing loss. The genomic landscape of schwannoma is complex and many of the molecules implicated in VS pathogenesis represent targets not amenable to antibody-bas...

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Autores principales:	Yin Ren, Jessica E. Sagers, Lukas D. Landegger, Sangeeta N. Bhatia, Konstantina M. Stankovic
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6952ec1c6a8442919fd48a6c5c91cbd6
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spelling	oai:doaj.org-article:6952ec1c6a8442919fd48a6c5c91cbd62021-12-02T15:05:33ZTumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas10.1038/s41598-017-13032-92045-2322https://doaj.org/article/6952ec1c6a8442919fd48a6c5c91cbd62017-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-13032-9https://doaj.org/toc/2045-2322Abstract Vestibular schwannoma (VS) is the most common tumor of the cerebellopontine angle, and it typically presents with sensorineural hearing loss. The genomic landscape of schwannoma is complex and many of the molecules implicated in VS pathogenesis represent targets not amenable to antibody-based or small molecule therapeutics. Tumor-targeted delivery of small interfering RNA (siRNA) therapeutics provides a direct and effective means to interrogate targets while minimizing off-target effects. To establish a preclinical model for therapeutic inhibition of putative targets in VS, archived tumor specimens, fresh tumor cells derived from patients with sporadic VS, and an established schwannoma cell line were screened. Nanoparticles directed by the tumor-homing peptide iRGD were selectively taken up by primary VS cultures in vitro via interactions with αvβ3/β5 integrins and neuropilin-1 (NRP-1). Cellular uptake was inhibited by a neutralizing antibody against αv integrin in a dose-dependent manner. When applied to primary VS cultures, iRGD-targeted nanoparticles delivered siRNA directed against TNFα in a receptor-specific fashion to potently silence gene expression and protein secretion. Taken together, our results provide a proof of principle for tumor-targeted, nanoparticle-mediated delivery of siRNA to VS and establish a novel platform for the development and pre-clinical screening of molecular therapeutics against VS.Yin RenJessica E. SagersLukas D. LandeggerSangeeta N. BhatiaKonstantina M. StankovicNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-16 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yin Ren Jessica E. Sagers Lukas D. Landegger Sangeeta N. Bhatia Konstantina M. Stankovic Tumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas
description	Abstract Vestibular schwannoma (VS) is the most common tumor of the cerebellopontine angle, and it typically presents with sensorineural hearing loss. The genomic landscape of schwannoma is complex and many of the molecules implicated in VS pathogenesis represent targets not amenable to antibody-based or small molecule therapeutics. Tumor-targeted delivery of small interfering RNA (siRNA) therapeutics provides a direct and effective means to interrogate targets while minimizing off-target effects. To establish a preclinical model for therapeutic inhibition of putative targets in VS, archived tumor specimens, fresh tumor cells derived from patients with sporadic VS, and an established schwannoma cell line were screened. Nanoparticles directed by the tumor-homing peptide iRGD were selectively taken up by primary VS cultures in vitro via interactions with αvβ3/β5 integrins and neuropilin-1 (NRP-1). Cellular uptake was inhibited by a neutralizing antibody against αv integrin in a dose-dependent manner. When applied to primary VS cultures, iRGD-targeted nanoparticles delivered siRNA directed against TNFα in a receptor-specific fashion to potently silence gene expression and protein secretion. Taken together, our results provide a proof of principle for tumor-targeted, nanoparticle-mediated delivery of siRNA to VS and establish a novel platform for the development and pre-clinical screening of molecular therapeutics against VS.
format	article
author	Yin Ren Jessica E. Sagers Lukas D. Landegger Sangeeta N. Bhatia Konstantina M. Stankovic
author_facet	Yin Ren Jessica E. Sagers Lukas D. Landegger Sangeeta N. Bhatia Konstantina M. Stankovic
author_sort	Yin Ren
title	Tumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas
title_short	Tumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas
title_full	Tumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas
title_fullStr	Tumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas
title_full_unstemmed	Tumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas
title_sort	tumor-penetrating delivery of sirna against tnfα to human vestibular schwannomas
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/6952ec1c6a8442919fd48a6c5c91cbd6
work_keys_str_mv	AT yinren tumorpenetratingdeliveryofsirnaagainsttnfatohumanvestibularschwannomas AT jessicaesagers tumorpenetratingdeliveryofsirnaagainsttnfatohumanvestibularschwannomas AT lukasdlandegger tumorpenetratingdeliveryofsirnaagainsttnfatohumanvestibularschwannomas AT sangeetanbhatia tumorpenetratingdeliveryofsirnaagainsttnfatohumanvestibularschwannomas AT konstantinamstankovic tumorpenetratingdeliveryofsirnaagainsttnfatohumanvestibularschwannomas
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Tumor-Penetrating Delivery of siRNA against TNFα to Human Vestibular Schwannomas

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