Nanoparticles for urothelium penetration and delivery of the histone deacetylase inhibitor belinostat for treatment of bladder cancer

Darryl T. Martin, Christopher J. Hoimes, Hristos Z. Kaimakliotis, Christopher J. Cheng, Ke Zhang, Jingchun Liu, Marcia A. Wheeler, W. Kevin Kelly, Greg N. Tew, W. Mark Saltzman, Robert M. Weiss

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Nearly 40% of patients with non-invasive bladder cancer will progress to invasive disease despite locally-directed therapy. Overcoming the bladder permeability barrier (BPB) is a challenge for intravesical drug delivery. Using the fluorophore coumarin (C6), we synthesized C6-loaded poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs), which were surface modified with a novel cell penetrating polymer, poly(guanidinium oxanorbornene) (PGON). Addition of PGON to the NP surface improved tissue penetration by 10-fold in intravesically-treated mouse bladder and ex vivo human ureter. In addition, NP-C6-PGON significantly enhanced intracellular uptake of NPs compared to NPs without PGON. To examine biological activity, we synthesized NPs that were loaded with the histone deacetylase (HDAC) inhibitor belinostat (NP-Bel-PGON). NP-Bel-PGON exhibited a significantly lower IC50 in cultured bladder cancer cells, and sustained hyperacetylation, when compared to unencapsulated belinostat. Xenograft tumors treated with NP-Bel-PGON showed a 70% reduction in volume, and a 2.5-fold higher intratumoral acetyl-H4, when compared to tumors treated with unloaded NP-PGON. From the Clinical Editor: These authors demonstrate that PLGA nanoparticles with PGON surface functionalization result in greatly enhanced cell penetrating capabilities, and present convincing data from a mouse model of bladder cancer for increased chemotherapy efficacy.

Original languageEnglish (US)
Pages (from-to)1124-1134
Number of pages11
JournalNanomedicine: Nanotechnology, Biology, and Medicine
Volume9
Issue number8
DOIs
StatePublished - Nov 1 2013
Externally publishedYes

Keywords

  • Belinostat
  • Bladder cancer
  • Nanoparticle
  • PLGA
  • Poly(guanidinium oxanorbornene)

ASJC Scopus subject areas

  • Bioengineering
  • Medicine (miscellaneous)
  • Molecular Medicine
  • Biomedical Engineering
  • Materials Science(all)
  • Pharmaceutical Science

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  • Cite this

    Martin, D. T., Hoimes, C. J., Kaimakliotis, H. Z., Cheng, C. J., Zhang, K., Liu, J., Wheeler, M. A., Kelly, W. K., Tew, G. N., Saltzman, W. M., & Weiss, R. M. (2013). Nanoparticles for urothelium penetration and delivery of the histone deacetylase inhibitor belinostat for treatment of bladder cancer. Nanomedicine: Nanotechnology, Biology, and Medicine, 9(8), 1124-1134. https://doi.org/10.1016/j.nano.2013.05.017