Abstract 4507: Utilizing the targeting properties of elastin-like polypeptide to safely deliver a potent doxorubicin derivative.

Abstract

Abstract N-butyldiacetate doxorubicin (NBD) is a derivative of a common chemotherapeutic agent that is three to four orders of magnitude more potent that the its parent compound. Targeting such a potent drug to the tumor, relies on an effective tumor targeting strategy. For this purpose, we have developed a hypothermic approach and developed a new macromolecular conjugate by coupling NBD to elastin-like polypeptide (ELP), a macromolecule that is soluble at normal physiological temperature but aggregates in the presence of heat (40-42 °C). Attaching NBD to ELP holds the promise of accumulating NBD effectively in the tumor while sparing healthy tissue. ELP is a macromolecule that is soluble at normal physiological temperature but aggregates in the presence of heat (40-42 °C). The ELP delivery system, SynB1-ELP-NBD, consists of 3 parts: a) a cell-penetrating peptide to facilitate entry through the cell membrane, b) ELP to allow thermal targeting, and c) an acid-sensitive derivative of doxorubicin, NBD. Preliminary results in the S2013 pancreatic cancer cell line have been promising. The IC50 of free doxorubicin is ∼9 μM, while the IC50 of SynB1-ELP-NBD is 1 nM. Very little is known about the mechanism of NBD inside the cell. Using flow cytometry, we compared apoptosis, cell cycle arrest, and generation of reactive oxygen species of SynB1-ELP, SynB1-ELP-NBD, and free NBD. While SynB1-ELP had very little effect on the cell cycle, generation of ROS, and less than 10% apoptotic cells, SynB1-ELP-NBD and free NBD were more active during the S phase at the expense of G1, generated 6× more ROS compared to control cells, and 80% of cells were apoptotic or necrotic after 72 h treatment. In vitro, SynB1-ELP-NBD works very similarly to free NBD, but safe delivery is the goal. In a maximum tolerated dose study, the animals were able to tolerate 2.5 times more NBD when it was attached to ELP compared to free NBD. This delivery system makes it possible to deliver larger amounts of a highly potent doxorubicin derivative to tumor-bearing animals and a comparative in vivo study in a pancreatic cancer mouse model is ongoing. Citation Format: Leslie R. Walker, Eddie Perkins, Khalid Abu Ajaj, Felix Kratz, Drazen Raucher. Utilizing the targeting properties of elastin-like polypeptide to safely deliver a potent doxorubicin derivative. [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 4507. doi:10.1158/1538-7445.AM2013-4507