Assessment of Intratumoral Doxorubicin Penetration after Mild Hyperthermia-Mediated Release from Thermosensitive Liposomes

Marc Derieppe*, Jean-Michel Escoffre, Baudouin Denis de Senneville, Quincy van Houtum, Angelique Barten-van Rijbroek, Kim van der Wurff-Jacobs, Ludwig Dubois, Clemens Bos, Chrit Moonen

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Web of Science)

Abstract

In solid tumors, rapid local intravascular release of anticancer agents, e.g., doxorubicin (DOX), from thermosensitive liposomes (TSLs) can be an option to overcome poor extravasation of drug nanocarriers. The driving force of DOX penetration is the drug concentration gradient between the vascular compartment and the tumor interstitium. In this feasibility study, we used fibered confocal fluorescence microscopy (FCFM) to monitor in real-time DOX penetration in the interstitium of a subcutaneous tumor after its intravascular release from TSLs, Thermodox (R). Cell uptake kinetics of the released DOX was quantified, along with an in-depth assessment of released-DOX penetration using an evolution model. A subcutaneous rat R1 rhabdomyosarcoma xenograft was used. The rodent was positioned in a setup including a water bath, and FCFM identification of functional vessels in the tumor tissue was applied based on AngioSense. The tumor-bearing leg was immersed in the 43 degrees C water for preheating, and TSLs were injected intravenously. Real-time monitoring of intratumoral (i.t.) DOX penetration could be performed, and it showed the progressing DOX wave front via its native fluorescence, labeling successively all cell nuclei. Cell uptake rates (1/k) of 3 minutes were found (n=241cells), and a released-DOX penetration in the range of 2500 mu m(2) s( -1) was found in the tumor extravascular space. This study also showed that not all vessels, identified as functional based on AngioSense, gave rise to local DOX penetration.

Original languageEnglish
Article number2645928
Pages (from-to)1-13
Number of pages13
JournalContrast Media & Molecular Imaging
Volume2019
Early online date2019
DOIs
Publication statusPublished - Mar 2019

Keywords

  • TEMPERATURE-SENSITIVE LIPOSOME
  • TUMOR VASCULAR-PERMEABILITY
  • MACROMOLECULAR THERAPEUTICS
  • NANOPARTICLE EXTRAVASATION
  • DRUG PENETRATION
  • DELIVERY
  • ACCUMULATION
  • MECHANISM

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