Bimodal tumor-targeting from microenvironment responsive hyaluronan layer-by-layer (LbL) nanoparticles

ACS Nano. 2014 Aug 26;8(8):8374-82. doi: 10.1021/nn502861t. Epub 2014 Aug 11.


Active targeting of nanoscale drug carriers can improve tumor-specific delivery; however, cellular heterogeneity both within and among tumor sites is a fundamental barrier to their success. Here, we describe a tumor microenvironment-responsive layer-by-layer (LbL) polymer drug carrier that actively targets tumors based on two independent mechanisms: pH-dependent cellular uptake at hypoxic tumor pH and hyaluronan-directed targeting of cell-surface CD44 receptor, a well-characterized biomarker for breast and ovarian cancer stem cells. Hypoxic pH-induced structural reorganization of hyaluronan-LbL nanoparticles was a direct result of the nature of the LbL electrostatic complex, and led to targeted cellular delivery in vitro and in vivo, with effective tumor penetration and uptake. The nanoscale drug carriers selectively bound CD44 and diminished cancer cell migration in vitro, while co-localizing with the CD44 receptor in vivo. Multimodal targeting of LbL nanoparticles is a powerful strategy for tumor-specific cancer diagnostics and therapy that can be accomplished using a single bilayer of polyamine and hyaluronan that, when assembled, produce a dynamic and responsive cell-particle interface.

Keywords: controlled delivery; nanomaterials; nanomedicine; polymer engineering; self-assembly.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biological Transport
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Transformation, Neoplastic
  • Drug Carriers / chemistry*
  • Drug Carriers / metabolism*
  • Hyaluronan Receptors / metabolism
  • Hyaluronic Acid / chemistry*
  • Hyaluronic Acid / metabolism*
  • Hydrogen-Ion Concentration
  • Mice
  • Nanoparticles*
  • Polylysine / chemistry
  • Tumor Microenvironment*


  • Drug Carriers
  • Hyaluronan Receptors
  • Polylysine
  • Hyaluronic Acid