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

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 EditorThese 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.

Graphical AbstractPLGA nanoparticles surface-modified with an amidine-based polymer poly(guanidinium oxanorbornene) (PGON) were shown to increase transurothelial migration and tumor cell uptake. PGON-modified nanoparticles increased the cytotoxicity of belinostat, a histone deacetylase inhibitor, which has been shown to be a promising therapeutic agent for cancer. Further, treatment with belinostat-encapsulated PGON-modified nanoparticles led to prolonged HDAC inhibition compared to unencapsulated drug and flank tumor regression in a mouse xenograft bladder cancer model. Our results suggest that PGON nanoparticles encapsulated with belinostat have the potential to be an effective intravesical delivery system for the adjuvant treatment of non-invasive urothelial cancers.Figure optionsDownload high-quality image (137 K)Download as PowerPoint slide