Journal
NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE
Volume 9, Issue 8, Pages 1124-1134Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.nano.2013.05.017
Keywords
PLGA; Nanoparticle; Poly(guanidinium oxanorbornene); Bladder cancer; Belinostat
Funding
- National Institutes of Health (NIH) [5RC1DK087015, UL1 RR0204139, R01 EB000487]
- Department of Defense (DOD) [W81XWH-10-1-0295]
- National Science Foundation [CHE-0910963]
- Direct For Mathematical & Physical Scien
- Division Of Materials Research [1308123] Funding Source: National Science Foundation
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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. (C) 2013 Elsevier Inc. All rights reserved.
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