울산의대 / 이경진, 정성윤*, 최은경*
Abstract
Neoadjuvant radiotherapy has become an important therapeutic option for colorectal cancer (CRC) patients, whereas complete tumor response is observed only in 20-30% patients. Therefore, the development of diagnostic probe for radio-resistance is important to decide an optimal treatment timing and strategy for radiotherapy-resistant CRC patients. In this study, using the patient-derived xenograft (PDX) mouse model established with a radio-resistant CRC tumor tissue, we found low-density lipoprotein receptor-related protein-1 (LRP-1) as a radio-resistant marker protein induced by initial-dose radiation in radio-resistant CRC tumors. Simultaneously, we discovered a LRP-1 targeting peptide in a radio-resistant CRC PDX through in vivo peptide screening. We next engineered the theranostic agent made of human serum albumin nanoparticles (HSA NPs) containing 5-FU for chemo-radiotherapy and decorating LRP-1-targeting peptide for tumor localization, Cy7 fluorophore for diagnostic imaging. The nanoparticle-based theranostic agent accurately targeted the tumor designated by LRP-1 responding radiation and showed dramatically improved therapeutic efficacy in the radio-resistant PDX model. In conclusion, we have identified LRP-1 as a signature protein of radio-resistant CRC and successfully developed LRP-1-targeting HSA-NP containing 5-FU that is a novel theranostic tool for both diagnostic imaging and neoadjuvant therapy of CRC patients. This approach is clinically applicable to improve the effectiveness of neo-adjuvant radiotherapy and increase the ratio of complete tumor response in radio-resistant CRC.
Affiliations
Kyoung Jin Lee 1 , Eun Jung Ko 2 , Yun-Yong Park 3 , Seok Soon Park 2 , Eun Jin Ju 2 , Jin Park 2 , Seol Hwa Shin 2 , Young-Ah Suh 4 , Seung-Mo Hong 5 , In Ja Park 6 , Kyu-Pyo Kim 7 , Jung Jin Hwang 3 , Se Jin Jang 4 , Jung Shin Lee 7 , Si Yeol Song 8 , Seong-Yun Jeong 9 , Eun Kyung Choi 10
1 Asan Institute for Life Sciences, , Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea; Center for Advancing Cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea; Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, 02841, South Korea.
2 Asan Institute for Life Sciences, , Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea; Center for Advancing Cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
3 Asan Institute for Life Sciences, , Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea; Center for Advancing Cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea; Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
4 Center for Advancing Cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea; Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
5 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
6 Department of Colon and Rectal Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
7 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
8 Center for Advancing Cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea; Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea.
9 Asan Institute for Life Sciences, , Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea; Center for Advancing Cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea; Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea. Electronic address: syj@amc.seoul.kr.
10 Center for Advancing Cancer Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea; Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea. Electronic address: ekchoi@amc.seoul.kr.