title: Nanoparticles for urothelium penetration and delivery of the histone deacetylase inhibitor belinostat for treatment of bladder cancer.
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.
  
  
  BACKGROUND
  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.
authors.affiliation: Department of Urology, Yale University, New Haven, CT.
authors.forename: Darryl T
authors.initials: DT
authors.lastname: Martin
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hoimes
authors.forename: Hristos Z
authors.initials: HZ
authors.lastname: Kaimakliotis
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Cheng
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Jingchun
authors.initials: J
authors.lastname: Liu
authors.forename: Marcia A
authors.initials: MA
authors.lastname: Wheeler
authors.forename: W Kevin
authors.initials: WK
authors.lastname: Kelly
authors.forename: Greg N
authors.initials: GN
authors.lastname: Tew
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
authors.forename: Robert M
authors.initials: RM
authors.lastname: Weiss
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry* / Q000378:metabolism; D011098:Polyglactin 910 / Q000737:chemistry / Q000378:metabolism; D013449:Sulfonamides / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019459:Urothelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D004337:Drug Carriers; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D013449:Sulfonamides; D011098:Polyglactin 910; C487081:belinostat
keywords: Belinostat; Bladder cancer; Nanoparticle; PLGA; Poly(guanidinium oxanorbornene)