Abstract B130: Crossing dimensions: binding and penetration of LyP-1 in 3-D spheroids of pancreatic ductal adenocarcinoma tumors

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related deaths in the United States. The high mortality rates of this form of cancer stem from its tumor microenvironment, which consists of dense desmoplastic stroma, collapsed vasculature, and limited perfusion; all of which have made drug delivery difficult. Novel therapies are being explored through the use of tumor-homing peptides, which have demonstrated significant binding and penetration into PDAC tumor models and can be co-conjugated or co-administered with therapeutic agents to improve targeted drug delivery. One tumor homing peptide, LyP-1, primarily binds to overexpressed p32 receptors on the surfaces of PDAC tumor cells, a characteristic feature of these aggressive tumor phenotypes. This study aims to explore LyP-1 as an alternative to the homing peptide iRGD for PDAC tumors by demonstrating its binding and penetration in pre-clinical tumor models of spheroids. Additionally, with few studies exploring the mechanism of LyP-1, this study seeks to test various proposed mechanistic features of LyP-1 in the spheroid model. Spheroids replicate the 3D architecture and various features of PDAC tumors and, therefore, are advantageous over traditional 2D cell lines. From this study, LyP-1 was found to bind to and penetrate spheroids significantly at concentrations of 750 μM and 900 μM. Thus, this study demonstrated that LyP-1 is internalized into the 3-D in vitro spheroid model and has the therapeutic potential of targeting drugs to these difficult-to-reach tumors. Also, LyP-1 binding to spheroids was significantly decreased when treated with a p32 blocking antibody, demonstrating the significant role that the p32 receptor has on the LyP-1 internalization pathway. Further exploration of the LyP-1 mechanism will offer details on its advantages and disadvantages compared to other tumor-homing peptides.