Abstract 5129: Cell-penetrating doxorubicin released from Elastin-like polypeptide kills doxorubicin-resistant cancer cells

A drug-releasing system facilitated by external stimuli could be used to deliver cytotoxic chemotherapy agents to tumor sites selectively and safely. Among many suggested strategies, elastin-like polypeptide (ELP) exploits its characteristic of phase transitioning in response to changes in ambient temperature. This unique property permits selective targeting of the polymer to hyperthermic tumors by aggregating as it transitions. ELP therefore can be used as a thermosensitive vector for the delivery of chemotherapy agents and therapeutic peptides, resulting in a rise in drug concentration exclusively in tumors. This novel strategy introduces unprecedented options for treating cancer, with fewer concerns about indiscriminate side effects from the chemotherapy. In this study, the ELP-drug conjugate was further modified with incorporation of an enzyme-specific cleavable linker in order to trigger drug release within tumors. The suggested system is composed of ELP, a matrix metalloproteinase (MMP) substrate, a cell penetrating peptide (CPP), and 6-maleimidocaproyl amide derivative of doxorubicin (Dox). Rationale for this design is that this construct may be initially targeted to the tumor site by local application of mild heat. When the construct reaches tumor site, it is cleaved by MMP, releasing CPP conjugated Dox, which is able to more efficiently infiltrate tumor tissues and penetrate cancer cell membranes. This strategy shows up to 4-fold increase in cell penetration up to four times and results more cell death in breast cancer cells than the ELP-doxorubicin complex. Even in doxorubicin-resistant cancer cells (NCI/ADR and MES/ADR), ELP-released, cell-penetrating doxorubicin demonstrated better membrane penetration (two fold), leading to at least twice killing of the resistant cancer cells than ELP-Dox and free Dox. Citation Format: Jung Su Ryu, Drazen Raucher. Cell-penetrating doxorubicin released from Elastin-like polypeptide kills doxorubicin-resistant cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5129. doi:10.1158/1538-7445.AM2017-5129