Intracellular Degradable Hydrogel Cubes and Spheres for Anti-Cancer Drug Delivery

ACS Appl Mater Interfaces. 2015 Jun 24;7(24):13633-44. doi: 10.1021/acsami.5b03360. Epub 2015 Jun 9.


Shape and responsiveness of nanoengineered delivery carriers are crucial characteristics for rapid and efficient delivery of therapeutics. We report on a novel type of micrometer-sized hydrogel particles of controlled shape with dual pH- and redox-sensitivity for intracellular delivery of anticancer drugs. The cubical and spherical poly(methacrylic acid) (PMAA) networks with disulfide links are obtained by cross-linking PMAA with cystamine within hydrogen-bonded multilayers of PMAA/poly(vinylpyrrolidone) (PMAA/PVPON) on sacrificial mesoporous templates. The pH-triggered hydrogel swelling/shrinkage not only affords effective doxorubicin entrapment but also efficient endosomal/lysosomal escape, and redox-triggered degradation provides drug release into the cytosolic space. The hydrogels degrade rapidly to low molecular weight chains in the presence of the typical intracellular concentration of glutathione, which should ensure a rapid renal clearance in vivo. Particle shape is found to affect internalization at the initial step of cell-particle interactions. Drug-loaded spherical particles are found to be 12% more cytotoxic than the corresponding cubes within the first 10 h of cell incubation suggesting more rapid internalization of spheres. Both doxorubicin-loaded hydrogel cubes and spheres demonstrate 50% and 90% cytotoxicity when incubated with HeLa cancer cells for 24 and 48 h, respectively. The presented approach integrates the advantages of pH-sensitivity, enzymatic degradation, and shape-regulated internalization for novel types of "intelligent" three-dimensional networks with programmable behavior for use in controlled delivery of therapeutics.

Keywords: intracellular degradable; multilayer hydrogel; pH-responsive; particle shape; poly(methacrylic acid).

Publication types

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

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / pharmacology
  • Cell Survival / drug effects
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacokinetics
  • Drug Carriers / chemistry*
  • HeLa Cells
  • Humans
  • Hydrogel, Polyethylene Glycol Dimethacrylate / chemistry*
  • Hydrogen-Ion Concentration
  • Intracellular Space / metabolism*
  • Particle Size
  • Polymethacrylic Acids / chemistry


  • Antineoplastic Agents
  • Drug Carriers
  • Polymethacrylic Acids
  • Hydrogel, Polyethylene Glycol Dimethacrylate
  • Doxorubicin