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Keywords:

  • bisphosphonates;
  • zoledronic acid;
  • docetaxel;
  • polybutyl cyanoacrylate (PBCA) nanoparticles;
  • bone targeting

Abstract

In an attempt to improve tumor localization of docetaxel (DTX)-loaded nanoparticles (NPs), zoledronic acid (ZOL) is used as a ligand to target bone metastasis. DTX-loaded ZOL-conjugated polyethylene glycol (PEG)ylated polybutyl cyanoacrylate (PBCA) NPs are prepared using an anionic polymerization technique. PBCA-PEG-ZOL NPs are subjected to cytotoxic assay in both BO2 and MCF-7 cell lines. Cell cycle arrest and apoptosis induced by the PBCA-PEG-ZOL NPs are studied. Quantitative cellular uptake, NP uptake route characterization, confocal microscopy and IPP/ApppI levels are performed. PBCA-PEG-ZOL NPs show an enhanced cytotoxic effect in both BO2 as well as MCF-7 cell lines due to higher uptake following ZOL-mediated endocytosis. The molecular basis of apoptosis reveals the involvement of a cytoplasmic protein in activating the programmed cell death pathway. Route characterization studies reveal that PBCA-PEG-ZOL NPs uptake is not completely blocked even by using both inhibitors (genistein and phenyl arsinoxide) simultaneously, conferring that uptake is not entirely based upon clathrin or caveolae. PBCA-PEG-ZOL NPs showed 7 and 5.3 times increase in IPP and ApppI production, in comparison to ZOL treatment, and 138 times higher than the control group in MCF-7 cell line. In BO2 cell line, after treatment with NPs, IPP was 5.35 times higher than ZOL solution. No ApppI in BO2 cell line after treatment with NPs and ZOL solution was found. NP distribution in tumor infected bone is also significantly high in comparison to the normal bone at any time point. It is concluded that ZOL-conjugated NPs provide an efficient and targeted delivery of DTX, with synergistic effects. Thus, these NPs present a promising treatment in the near future, by actively targeting metastatic tumor.