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

Published

Journal Article

UNLABELLED: 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.

Full Text

Duke Authors

Cited Authors

  • Martin, DT; Hoimes, CJ; Kaimakliotis, HZ; Cheng, CJ; Zhang, K; Liu, J; Wheeler, MA; Kelly, WK; Tew, GN; Saltzman, WM; Weiss, RM

Published Date

  • November 2013

Published In

Volume / Issue

  • 9 / 8

Start / End Page

  • 1124 - 1134

PubMed ID

  • 23764660

Pubmed Central ID

  • 23764660

Electronic International Standard Serial Number (EISSN)

  • 1549-9642

Digital Object Identifier (DOI)

  • 10.1016/j.nano.2013.05.017

Language

  • eng

Conference Location

  • United States