Abstract 4973: Tumor type and organ type dependent differences of vascular permeability to pegylated liposomal doxorubicin.
Authors: Yokoi Kenji , Tanei Tomonori , Godin Biana , van de Ven Anne , Alexander Jenolyn , Ferrari Mauro 
Published: August 2014

Abstract
Pegylated liposomal doxorubicin (PLD) for cancer therapy is advantageous over conventional chemotherapy with doxorubicin, because of the preferential delivery of drugs to tumors owing to the enhanced permeation and retention (EPR) effect. The biological barriers include abnormal structure of tumor vessels in heterogeneous tumor microenvironments shall influence the EPR effect and result in heterogeneous tumor perfusion of PLD and therapeutic efficacy.
Although 4T1, murine breast cancer cells and 3LL, murine lung cancer cells had similar sensitivity to PLD in vitro, only 4T1 tumors responded to therapy with PLD in vivo. There were no significant differences of the microvessel density and blood perfusion in these tumors. In contrast, PLD extravasated and accumulated into 4T1 tumors significantly more than 3LL tumors, indicating vascular permeability was higher in 4T1 tumors. Coverage of endothelial cells by collagen type IV, which constitutes basement membrane of the vessels, was significantly lower in 4T1 tumors as compared to those in 3LL tumors. Differential analysis of protein expression by 4T1 and 3LL cells in vitro revealed that MMP-9 (collagenase) production was significantly higher in 4T1 cells as compared to 3LL cells. MMP-9 expression was also higher in 4T1 tumors as well as in sera of mice bearing 4T1 tumors as compared to 3LL tumors and sera of mice bearing 3LL tumors and normal mice respectively. Batimastat, MMPs inhibitor, injected in vivo increased the coverage of endothelial cells by basement membrane and abrogated the accumulation of PLD into the 4T1 tumors, indicating MMP-9 can play a pivotal role in controlling the vascular permeability. Interestingly, 4T1 tumors were accumulated with PLD only when tumors were growing in the brain and mammary fat pad, but not in the liver. Coverage of the endothelial cells by basement membrane was significantly higher in the tumors growing in the liver as compared to the other two locations. The levels of TIMP-1, endogenous inhibitor of MMPs, were significantly higher in the mice bearing 4T1 in the liver as compared to the mice bearing the tumors in the other locations. These data indicate the levels as well as balance between MMP-9 and TIMP-1 can determine the vascular permeability to PLD. Therefore the these enzymes in the circulation can serve as surrogate markers for the vascular permeability to PLD and there is a possibility to personalize the therapy by selecting patients who will likely accumulated with PLD into tumors to increase clinical outcome.
Citation Format: Kenji Yokoi, Tomonori Tanei, Biana Godin, Anne van de Ven, Jenolyn Alexander, Mauro Ferrari. Tumor type and organ type dependent differences of vascular permeability to pegylated liposomal doxorubicin. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4973. doi:10.1158/1538-7445.AM2013-4973