Dextran-based doxorubicin nanocarriers with improved tumor penetration

Biomacromolecules. 2014 Jan 13;15(1):262-75. doi: 10.1021/bm401526d. Epub 2013 Dec 18.


Drug delivery systems with improved tumor penetration are valuable assets as anticancer agents. A dextran-based nanocarrier system with aldehyde functionalities capable of forming an acid labile linkage with the chemotherapy drug doxorubicin was developed. Aldehyde dextran nanocarriers (ald-dex-dox) demonstrated efficacy as delivery vehicles with an IC50 of ∼300 nM against two-dimensional (2D) SK-N-BE(2) monolayers. Confocal imaging showed that the ald-dex-dox nanocarriers were rapidly internalized by SK-N-BE(2) cells. Fluorescence lifetime imaging microscopy (FLIM) analysis indicated that ald-dex-dox particles were internalized as intact complexes with the majority of the doxorubicin released from the particle four hours post uptake. Accumulation of the ald-dex-dox particles was significantly enhanced by ∼30% in the absence of glucose indicating a role for glucose and its receptors in their endocytosis. However, inhibition of clathrin dependent and independent endocytosis and macropinocytosis as well as membrane cholesterol depletion had no effect on ald-dex-dox particle accumulation. In three-dimensional (3D) SK-N-BE(2) tumor spheroids, which more closely resemble a solid tumor, the ald-dex-dox nanoparticles showed a significant improvement in efficacy over free doxorubicin, as evidenced by decreased spheroid outgrowth. Drug penetration studies in 3D demonstrated the ability of the ald-dex-dox nanocarriers to fully penetrate into a SK-N-BE(2) tumor spheroids, while doxorubicin only penetrates to a maximum distance of 50 μM. The ald-dex-dox nanocarriers represent a promising therapeutic delivery system for the treatment of solid tumors due to their unique enhanced penetration ability combined with their improved efficacy over the parent drug in 3D.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Dextrans / administration & dosage*
  • Dextrans / metabolism
  • Doxorubicin / administration & dosage*
  • Doxorubicin / metabolism
  • Drug Carriers / administration & dosage*
  • Drug Carriers / metabolism
  • Endocytosis / drug effects*
  • Endocytosis / physiology
  • Humans


  • Antineoplastic Agents
  • Dextrans
  • Drug Carriers
  • Doxorubicin