Low-Dose Vascular Photodynamic Therapy Decreases Tumor Interstitial Fluid Pressure, which Promotes Liposomal Doxorubicin Distribution in a Murine Sarcoma Metastasis Model.
BACKGROUND
Solid tumors are known to have an abnormal vasculature that limits the distribution of chemotherapy. We have recently shown that tumor vessel modulation by low-dose photodynamic therapy (L-PDT) could improve the uptake of macromolecular chemotherapeutic agents such as liposomal doxorubicin (Liporubicin) administered subsequently. However, how this occurs is unknown. Convection, the main mechanism for drug transport between the intravascular and extravascular spaces, is mostly related to interstitial fluid pressure (IFP) and tumor blood flow (TBF). Here, we determined the changes of tumor and surrounding lung IFP and TBF before, during, and after vascular L-PDT. We also evaluated the effect of these changes on the distribution of Liporubicin administered intravenously (IV) in a lung sarcoma metastasis model.


METHODS
A syngeneic methylcholanthrene-induced sarcoma cell line was implanted subpleurally in the lung of Fischer rats. Tumor/surrounding lung IFP and TBF changes induced by L-PDT were determined using the wick-in-needle technique and laser Doppler flowmetry, respectively. The spatial distribution of Liporubicin in tumor and lung tissues following IV drug administration was then assessed in L-PDT-pretreated animals and controls (no L-PDT) by epifluorescence microscopy.


RESULTS
L-PDT significantly decreased tumor but not lung IFP compared to controls (no L-PDT) without affecting TBF. These conditions were associated with a significant improvement in Liporubicin distribution in tumor tissues compared to controls (P < .05).


CONCLUSIONS
L-PDT specifically enhanced convection in blood vessels of tumor but not of normal lung tissue, which was associated with a significant improvement of Liporubicin distribution in tumors compared to controls.
Division of Thoracic and Vascular Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Electronic address: jean.perentes@chuv.ch.
Jean Yannis
JY
Perentes
Division of Thoracic and Vascular Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Yabo
Y
Wang
Division of Thoracic and Vascular Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Xingyu
X
Wang
Division of Thoracic and Vascular Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Etienne
E
Abdelnour
Division of Thoracic and Vascular Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Michel
M
Gonzalez
Department of Clinical Pharmacology and Toxicology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Laurent
L
Decosterd
Laboratory of Organometallic and Medicinal Chemistry, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland.
Georges
G
Wagnieres
Laboratory of Organometallic and Medicinal Chemistry, Ecole Polytechnique Federale de Lausanne (EPFL), Lausanne, Switzerland.
Hubert
H
van den Bergh
Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Solange
S
Peters
Division of Thoracic and Vascular Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Hans-Beat
HB
Ris
Division of Thoracic and Vascular Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. Electronic address: thorsten.krueger@chuv.ch.
Thorsten
T
Krueger