Endosomolytic Nano-Polyplex Platform Technology for Cytosolic Peptide Delivery to Inhibit Pathological Vasoconstriction

Brian C. Evans, Kyle M. Hocking, Kameron V. Kilchrist, Eric S. Wise, Colleen M. Brophy, Craig L. Duvall

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

A platform technology has been developed and tested for delivery of intracellular-acting peptides through electrostatically complexed nanoparticles, or nano-polyplexes, formulated from an anionic endosomolytic polymer and cationic therapeutic peptides. This delivery platform has been initially tested and optimized for delivery of two unique vasoactive peptides, a phosphomimetic of heat shock protein 20 and an inhibitor of MAPKAP kinase II, to prevent pathological vasoconstriction (i.e., vasospasm) in human vascular tissue. These peptides inhibit vasoconstriction and promote vasorelaxation by modulating actin dynamics in vascular smooth muscle cells. Formulating these peptides into nano-polyplexes significantly enhances peptide uptake and retention, facilitates cytosolic delivery through a pH-dependent endosomal escape mechanism, and enhances peptide bioactivity in vitro as measured by inhibition of F-actin stress fiber formation. In comparison to treatment with the free peptides, which were endowed with cell-penetrating sequences, the nano-polyplexes significantly increased vasorelaxation, inhibited vasoconstriction, and decreased F-actin formation in the human saphenous vein ex vivo. These results suggest that these formulations have significant potential for treatment of conditions such as cerebral vasospasm following subarachnoid hemorrhage. Furthermore, because many therapeutic peptides include cationic cell-penetrating segments, this simple and modular platform technology may have broad applicability as a cost-effective approach for enhancing the efficacy of cytosolically active peptides.

Original languageEnglish (US)
Pages (from-to)5893-5907
Number of pages15
JournalACS nano
Volume9
Issue number6
DOIs
StatePublished - Jun 23 2015

Keywords

  • drug delivery
  • endosomal escape
  • nanoparticle
  • peptide
  • polyplex
  • vasospasm

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