Redox Sensitive Shell and Core Crosslinked Hyaluronic Acid Nanocarriers for Tumor-Targeted Drug Delivery

J Biomed Nanotechnol. 2016 Aug;12(8):1641-53. doi: 10.1166/jbn.2016.2279.


The purpose of the present study was to develop a robust and redox-sensitive nanocarrier based on amphiphilic hyaluronic acid nanoparticles, in which the hydrophobic core was crosslinked by photo-crosslinking and the hyaluronic acid shell was crosslinked via a bioreducible disulfide linkage. Dynamic light scattering showed that the shell and core crosslinked nanocarriers were obviously more stable than core crosslinked or non-crosslinked nanoparticles. Moreover, the particle size changed as the glutathione concentration was altered, exhibiting obvious redox sensitivity. Transmission electron microscopy showed that the nanoparticle structure was denser after crosslinking. Additionally, methotrexate was effectively encapsulated into nanoparticles with high drug-loading efficiency. In vitro methotrexate release assays showed that the methotrexate-loaded bioreducible hyaluronic acid nanoparticles greatly suppressed drug release in phosphate-buffered saline (pH 7.4) without or with 20 μM glutathione. In contrast, in phosphate-buffered saline (pH 7.4) with higher glutathione concentrations (2, 5, or 10 mM), methotrexate was released more rapidly and completely from the nanocarriers in 24 h. Furthermore, methotrexate was released completely and rapidly from the nanoparticles under simulated tumor cell conditions (pH 5.0 with 10 mM glutathione), suggesting potential applications in tumor-specific drug release. In vitro anticancer activity tests showed that the inhibition rate of methotrexate-loaded nanoparticles in HeLa cells reached 94%. However, excess hyaluronic acid decreased cell toxicity. Cellular uptake studies suggested that the prepared nanoparticles were probably internalized into the cancer cells via receptor-mediated endocytosis. Overall, our data demonstrated that the bio-reducible shell and core crosslinked nanoparticles could be used as a potential carrier for cancer therapy.

Keywords: Hyaluronic Acid; Methotrexate; Crosslink; Glutathione; Redox; Nanoparticle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacokinetics
  • Antineoplastic Agents* / pharmacology
  • Cell Proliferation / drug effects
  • Cross-Linking Reagents
  • Drug Carriers / chemistry*
  • Glutathione / chemistry
  • HeLa Cells
  • Humans
  • Hyaluronic Acid / chemistry*
  • Hydrophobic and Hydrophilic Interactions
  • Methotrexate / chemistry
  • Methotrexate / pharmacokinetics
  • Methotrexate / pharmacology
  • Nanoparticles / chemistry*
  • Oxidation-Reduction
  • Particle Size


  • Antineoplastic Agents
  • Cross-Linking Reagents
  • Drug Carriers
  • Hyaluronic Acid
  • Glutathione
  • Methotrexate