Hyaluronate-coated perfluoroalkyl polyamine prodrugs as bioactive siRNA delivery systems for the treatment of peritoneal cancers

Ao Yu, Siyuan Tang, Ling Ding, Jackson Foley, Weimin Tang, Huizhen Jia, Sudipta Panja, Cassandra E. Holbert, Yu Hang, Tracy Murray Stewart, Lynette M. Smith, Diptesh Sil, Robert A. Casero, David Oupický

Research output: Contribution to journalArticlepeer-review

Abstract

RNA interference (RNAi) is an emerging therapeutic modality for cancer, which remains in critical need of effective delivery vectors due to the unfavorable biopharmaceutical properties of small RNAs. Polyamines are essential for functioning of mammalian cells. Dysregulated polyamine metabolism is found in many cancers and has been an attractive therapeutic target in combination therapies. Combination therapies based on drugs that affect polyamine metabolism and nucleic acids promise to enhance anticancer activity due to a cooperative effect on multiple oncogenic pathways. Here, we report bioactive polycationic prodrug (F-PaP) based on an anticancer polyamine analogue bisethylnorspermine (BENSpm) modified with perfluoroalkyl moieties. Following encapsulation of siRNA, F-PaP/siRNA nanoparticles were coated with hyaluronic acid (HA) to form ternary nanoparticles HA@F-PaP/siRNA. The presence of perfluoroalkyl moieties and HA reduced cell membrane toxicity and improved stability of the particles with cooperatively enhanced siRNA delivery in pancreatic and colon cancer cell lines. We then tested a therapeutic hypothesis that combining BENSpm with siRNA silencing of polo-like kinase 1 (PLK1) would result in cooperative cancer cell killing. HA@F-PaP/siPLK1 induced polyamine catabolism and cell cycle arrest, leading to enhanced apoptosis in the tested cell lines. The HA-coated nanoparticles facilitated tumor accumulation and contributed to strong tumor inhibition and favorable modulation of the immune tumor microenvironment in orthotopic pancreatic cancer model.

Original languageEnglish (US)
Article number212755
JournalBiomaterials Advances
Volume136
DOIs
StatePublished - May 2022

Keywords

  • Combination cancer therapy
  • Hyaluronic acid
  • Perfluoroalkyls
  • Polyamines
  • siRNA delivery

ASJC Scopus subject areas

  • Biomedical Engineering
  • Biomaterials
  • Bioengineering

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