Abstract 3702: A novel nanoparticle-based theranostic agent targeting low-density lipoprotein receptor-related protein-1 enhances the efficacy of neoadjuvant radiotherapy in colorectal cancer

Abstract

Abstract Neoadjuvant radiotherapy is becoming an important therapeutic option for colorectal cancer (CRC) patients, although complete tumor response is observed only in 20 to 30% patients. However, precise biologic mechanisms underlying resistance to radiotherapy remain to be elucidated. In this study, we established a radiotherapy-resistant CRC patient-derived xenograft (PDX) mouse model, and we discovered that low-density lipoprotein receptor-related protein-1 (LRP-1) is increased in radiotherapy-resistant tumors compared with radiotherapy-sensitive tumors. Immunohistochemistry, mRNA and protein expression analyses of radiotherapy-sensitive vs. -refractory CRC patient samples confirmed a statistically significant association between LRP-1 levels and radiotherapy resistance of CRC. We also found that LRP-1 expression is significantly associated with the prognosis of CRC patients by analyzing gene expression data of CRC patients in Gene Expression Omnibus public database. Subsequently, aiming to develop radio-sensitizing nanoparticles targeting LRP-1 for chemotherapeutic drug delivery and in vivo imaging, we screened and identified an LRP-1-binding peptide in a radiotherapy-resistant CRC PDX mouse model using M13 phage display. We next engineered human serum albumin nanoparticles (HSA NPs) containing the LRP-1-binding peptide (for tumor localization), 5-FU (for cytotoxic chemotherapy) and Cy7 fluorophore (for in vivo imaging). When administered in CRC PDX-bearing mice, the LRP-1-targeting HSA NPs accumulated specifically in the CRC tumor tissue and dramatically increased the efficacy of radiotherapy. In addition, whole-body fluorescence imaging of PDX CRC-bearing mice showed that the HSA-NP accumulated only in radiation-treated tumors with high ROI values. In summary, we identified that LRP-1 is a novel signature protein of radiotherapy-resistant CRC, and validated that LRP-1 is closely associated with the progression of CRC. We developed a novel HSA nanoparticle-based theranostic agent loaded with LRP-1-binding peptide, 5-FU and a fluorophore that is applicable to both diagnostic imaging and radio-sensitizing neoadjuvant therapy of CRC. This approach is clinically applicable to improve the effectiveness of neoadjuvant radiotherapy and increase the ratio of complete tumor response in radio-resistant CRC. Citation Format: Kyoung Jin Lee, Serk In Park, Seong-Yun Jeong, Eun Kyung Choi. A novel nanoparticle-based theranostic agent targeting low-density lipoprotein receptor-related protein-1 enhances the efficacy of neoadjuvant radiotherapy in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3702.