Abstract 2986: Novel vascular targeting strategy using pegylated liposomal doxorubicin to increase drug accumulation to tumor site and therapeutic efficacy

Abstract

Abstract Although pegylated liposomal doxorubicin (PLD) can be advantageous over free doxorubicin because of accumulation of PLD to tumors utilizing the enhanced permeation and retention (EPR) effect, the increase in overall survival in patients treated with PLD has been modest. These clinical data indicate the benefit of the EPR effect can vary among the patients. Therefore developing novel strategies to increase the EPR effect for enhanced PLD accumulation to tumor shall improve therapeutic outcome. When tumor endothelial cells are damaged by PLD, the vascular permeability for macromolecules can be increased by large pores and the discontinuity of the endothelial cell layer. This endothelial cell damage and increased vascular permeability (i.e., increased EPR effect) will be eventually restored by angiogenic reaction of the vessels. Therefore, we hypothesized that PLD, injected subsequently during the time window when the vascular permeability is increased by initial therapy, shall extravasate and accumulate more into tumor (Vascular Targeting Strategy: VTS) as compared to the PLD injected after the recovery of tumor vessels (Standard Strategy: SS). The mice bearing 4T1 murine breast cancer growing in the mammary fat pad was injected intravenously with PLD. To evaluate the effect of PLD on the EPR effect, pegylated FITC-Liposomes (PFL) was injected, before, 1, 2, 3, 5, 7, or 10 days after the PLD injection. The mice at the each time point were sacrificed six hours after the injection of PFL, and the amount of PFL extravasation and accumulation into the tumor as well as uninvolved organs were evaluated by immunofluorescence imaging of the tissues. The amount of PFL in the tumor increased from day 1 as compared to those in the mice without PLD injection. The amount reached maximum at 2 days after the injection and returned to baseline at day 7. These data suggest that the EPR effect was changed over time after the PLD injection. Interestingly, these effects were found only in the tumors, but not in the uninvolved normal organs. Then, the tumor bearing mice were randomized to the therapy groups, (1) Control group; injection of PBS every 10 days, (2) SS group; injection of PLD (6mg/kg) every 10 days, (3) VTS group; injection of PLD (6mg/kg) on day 0 and Day 2. The therapeutic cycle consists with 20 days and total amount of PLD given during the cycle was same between the mice in the SS and VTS group. 4T1 tumor growth was fastest in the control mice. PLD given by SS showed delay in tumor growth as compared to control. The mice treated by VTS showed statistically best anti-tumor effect among the three treatment groups. Pharmacokinetic analysis showed that plasma C max as well as AUC in SS and VTS group mice were 18.0, 23.9 μg/ml and 97.3, 102.9 μg•hr/ml, respectively. There was no obvious side effect identified in these mice. These data suggests VTS can be a better therapeutic regimen as compared to SS to increase therapeutic efficacy. Citation Format: Kenji Yokoi, Tomonori Tanei, Yuki Saito, Mauro Ferrari. Novel vascular targeting strategy using pegylated liposomal doxorubicin to increase drug accumulation to tumor site and therapeutic efficacy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2986. doi:10.1158/1538-7445.AM2014-2986