TY - JOUR
T1 - Assessment of Intratumoral Doxorubicin Penetration after Mild Hyperthermia-Mediated Release from Thermosensitive Liposomes
AU - Derieppe, Marc
AU - Escoffre, Jean-Michel
AU - de Senneville, Baudouin Denis
AU - van Houtum, Quincy
AU - Barten-van Rijbroek, Angelique
AU - van der Wurff-Jacobs, Kim
AU - Dubois, Ludwig
AU - Bos, Clemens
AU - Moonen, Chrit
N1 - Funding Information:
-is study was funded by the ERC project 268906 “Sound Pharma” (Prof C. Moonen). -e authors are grateful to Burcin Ozbakir (Pharmaceutical Sciences Institute, University of Utrecht, Utrecht, the Netherlands) and Dr. Noboru Sasaki (Image Sciences Institute, University Medical Center Utrecht, Utrecht, the Netherlands) for their technical support. -e authors also thank Prof. Gert Storm for fruitful discussions (Pharmaceutical Sciences Institute, University of Utrecht, Utrecht, the Netherlands).
Publisher Copyright:
© 2019 Marc Derieppe et al.
PY - 2019/3
Y1 - 2019/3
N2 - 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.
AB - 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.
KW - TEMPERATURE-SENSITIVE LIPOSOME
KW - TUMOR VASCULAR-PERMEABILITY
KW - MACROMOLECULAR THERAPEUTICS
KW - NANOPARTICLE EXTRAVASATION
KW - DRUG PENETRATION
KW - DELIVERY
KW - ACCUMULATION
KW - MECHANISM
U2 - 10.1155/2019/2645928
DO - 10.1155/2019/2645928
M3 - Article
C2 - 30956626
SN - 1555-4309
VL - 2019
SP - 1
EP - 13
JO - Contrast Media & Molecular Imaging
JF - Contrast Media & Molecular Imaging
M1 - 2645928
ER -