Co-delivery of peptide-modified cisplatin and doxorubicin via mucoadhesive nanocapsules for potential synergistic intravesical chemotherapy of non-muscle-invasive bladder cancer

Synergistic effect against UMUC3 bladder cancer cells was demonstrated via a two-in-one combination of doxorubicin (Dox) and peptide-modified cisplatin (Pt-ALy) loaded in positively charged mucoadhesive chitosan-polymethacrylic acid (CM) nanocapsules. The in vitro killing efficacy of the dual drug-loaded nanocapsules (CM-Dox-PtALy) against UMUC3 cells after 4 h-and 72 h-treatment is much higher (with 5-16 times lower IC50) than either Dox- or Pt-ALy-loaded nanocapsules, resulting in combination indexes of much less than 1 (i.e. obvious synergism) at fractions of affected cells ranging from 0.2 to 0.8. The dose reduction index of Pt-ALy for 72 h-treatment is higher than for 4 h-treatment, suggesting that Dox in CM-Dox-PtALy played a more significant role in the synergy in the former. The drug-loaded CM nanocapsules are readily taken in by the cells as shown by flow cytometry, confocal laser scanning microscopy and inductively coupled plasma mass spectrometry. Microscopy observations indicate that CM nanocapsules attach strongly on the luminal surface of the bladder with no obvious damage of the urothelium, supporting our objective of prolonging the dwell time of the drug-loaded nanocapsules for intravesical applications. Our study indicates that the mucoadhesive CM-Dox-PtALy nanocapsules have a high drug loading and a sustained release profile, and thus, are promising for synergistic intravesical chemotherapy of non-muscle-invasive bladder cancers. (C) 2016 Elsevier B.V. All rights reserved.