Thermally-triggered 'off-on-off' response of gadolinium-hydrogel-lipid hybrid nanoparticles defines a customizable temperature window for non-invasive magnetic resonance imaging thermometry

J Control Release. 2012 Feb 10;157(3):478-84. doi: 10.1016/j.jconrel.2011.09.061. Epub 2011 Sep 10.


For effective and safe thermotherapy, real-time, accurate, three-dimensional tissue thermometry is required. Magnetic resonance imaging (MRI)-based thermometry in combination with current temperature responsive contrast agents only provides an 'off-on' signal at a certain temperature, not indicating temperature increases beyond the desired therapeutic levels. To overcome this limitation, a novel Gd-chelated hydrogel-lipid hybrid nanoparticle (HLN) formulation was developed that provides an 'off-on-off' signal defining a thermometric window for MR thermometry. Novel thermally responsive poly(N-isopropylacrylamide-co-acrylamide) (NIPAM-co-AM) hydrogel nanoparticles (<15 nm) with bisallylamidodiethylenetriaminetriacetic acid, a novel crosslinker with Gd(3+) chelation functionality, were synthesized. The Gd-hydrogel nanoparticles were encapsulated in a solid lipid nanoparticle matrix that prevented T(1)-weighted contrast signal enhancement. Melting of the matrix lipid freed the Gd-hydrogel nanoparticles into the bulk water and an 'off-on' contrast signal enhancement occurred. As the temperature was further increased to temperatures greater than, the volume phase transition temperature of the hydrogel nanoparticles, they collapsed and provided an 'on-off' signal diminution. Both the 'off-on' and the 'on-off' transition temperature could be tailored by changing the lipid matrix and altering the NIPAM/AM ratio in the hydrogel, respectively. This allowed MRI thermometry of different temperature windows using the Gd-HLN system.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetates / chemical synthesis
  • Acetates / chemistry
  • Acrylic Resins / chemistry
  • Chelating Agents / chemical synthesis
  • Chelating Agents / chemistry
  • Contrast Media / chemistry*
  • Drug Carriers / chemistry*
  • Gadolinium / chemistry*
  • Hot Temperature
  • Hydrogels / chemistry*
  • Magnetic Resonance Imaging
  • Nanoparticles / chemistry*
  • Polyethylene Glycols / chemistry


  • Acetates
  • Acrylic Resins
  • Chelating Agents
  • Contrast Media
  • Drug Carriers
  • Hydrogels
  • poly(N-isopropylacrylamide-co-acrylamide)
  • Polyethylene Glycols
  • polyethylene glycol monostearate
  • Gadolinium