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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.
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1 Eaton Peabody Laboratories, Massachusetts Eye and Ear, Boston, MA, USA; Department of Otolaryngology, Massachusetts Eye and Ear, Boston, MA, USA; Department of Otolaryngology, Harvard Medical School, Boston, MA, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
2 Eaton Peabody Laboratories, Massachusetts Eye and Ear, Boston, MA, USA; Department of Otolaryngology, Massachusetts Eye and Ear, Boston, MA, USA; Harvard Program in Speech and Hearing Bioscience and Technology, Boston, MA, USA
3 Eaton Peabody Laboratories, Massachusetts Eye and Ear, Boston, MA, USA; Department of Otolaryngology, Massachusetts Eye and Ear, Boston, MA, USA; Department of Otolaryngology, Harvard Medical School, Boston, MA, USA; Department of Otolaryngology, Medical University of Vienna, Vienna, Austria
4 Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Institute for Medical Engineering and Science, Cambridge, MA, USA; Department of Electrical Engineering and Computer Science, Cambridge, MA, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA
5 Eaton Peabody Laboratories, Massachusetts Eye and Ear, Boston, MA, USA; Department of Otolaryngology, Massachusetts Eye and Ear, Boston, MA, USA; Department of Otolaryngology, Harvard Medical School, Boston, MA, USA; Harvard Program in Speech and Hearing Bioscience and Technology, Boston, MA, USA