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Drug uptake in a rodent sarcoma model after intravenous injection or isolated lung perfusion of free/liposomal doxorubicin ^,

^a Division of Thoracic and Vascular Surgery, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
^b Division of Clinical Pharmacology and Toxicology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
^c Division of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
^d Department of Cardiothoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

*Corresponding author. Service de Chirurgie Thoracique et Vasculaire, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, 1011 Lausanne, Switzerland. Tel.: +41 21 3142408; fax: +41 21 3142358.

E-mail address: hans-beat.ris{at}chuv.ch (H.-B. Ris).

The distribution of free and liposomal doxorubicin (Liporubicin^TM) administered by intravenous injection (IV) or isolated lung perfusion (ILP) was compared in normal and tumor tissues of sarcoma bearing rodent lungs. A single sarcomatous tumor was generated in the left lung of 35 Fischer rats, followed 10 days later by left-sided ILP (n=20) or IV drug administration (n=12), using 100 µg and 400 µg free or liposomal doxorubicin, respectively. The tumor and lung tissue drug concentration was measured by HPLC. Free doxorubicin administered by ILP resulted in a three-fold (100 µg) and 10-fold (400 µg) increase of the drug concentration in the tumor and normal lung tissue compared to IV administration. In contrast, ILP with Liporubicin^TM resulted in a similar drug uptake in the tumor and lung tissue compared to IV injection. For both drug formulations and dosages, ILP resulted in a higher tumor to lung tissue drug ratio but also in a higher spatial heterogeneity of drug distribution within the lung compared to IV administration. ILP resulted in a higher tumor to lung tissue drug ratio and in a more heterogeneous drug distribution within the lung compared to IV drug administration.

Key Words: Isolated lung perfusion; Intravenous drug application; Sarcoma; Chemotherapy; Doxorubicin; Liposomal encapsulation