Implementing Efficient Peptoid-Mediated Delivery of RNA-Based Therapeutics to the Vocal Folds

Shigeyuki Mukudai, Iv Kraja, Renjie Bing, Danielle M. Nalband, Mallika Tatikola, Nao Hiwatashi, Kent Kirshenbaum, Ryan C. Branski

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: We hypothesize that Smad3 is a master regulator of fibrosis in the vocal folds (VFs) and RNA-based therapeutics targeting Smad3 hold therapeutic promise. Delivery remains challenging. We previously described a novel synthetic peptoid oligomer, lipitoid L0, complexed with siRNA to improve stability and cellular uptake. An advantage of these peptoids, however, is tremendous structural and chemical malleability to optimize transfection efficiency. Modifications of L0 were assayed to optimize siRNA-mediated alteration of gene expression. Methods: In vitro, Smad3 knockdown by various lipitoid variants was evaluated via quantitative real-time polymerase chain reaction in human VF fibroblasts. Cytotoxicity was quantified via colorimetric assays. In vivo, a rabbit model of VF injury was employed to evaluate the temporal dynamics of Smad3 knockdown following injection of the L0-siRNA complex. Results: In vitro, similar reductions in Smad3 expression were established by all lipitoid variants, with one exception. Sequence variants also exhibited similar nontoxic characteristics; no statistically significant differences in cell proliferation were observed. In vivo, Smad3 expression was significantly reduced in injured VFs following injection of L0-complexed Smad3 siRNA at 1 day postinjection. Qualitative suppression of Smad3 expression persisted to 3 days following injury, but did not achieve statistical significance. Conclusions: In spite of the chemical diversity of these peptoid transfection reagents, the sequence variants generally provided consistently efficient reductions in Smad3 expression. L0 yielded effective, yet temporally limited knockdown of Smad3 in vivo. Peptoids may provide a versatile platform for the discovery of siRNA delivery vehicles optimized for clinical application. Level of Evidence: NA.

Original languageEnglish (US)
Pages (from-to)640-644
Number of pages5
JournalLaryngoscope investigative otolaryngology
Volume4
Issue number6
DOIs
StatePublished - Dec 1 2019

Keywords

  • fibrosis
  • lipitoid
  • siRNA
  • Smad3
  • vocal fold
  • Voice

ASJC Scopus subject areas

  • Surgery
  • Otorhinolaryngology

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