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울산대학교 의과대학, 서울아산병원

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Biomaterials, Available online 27 May 2020, 120151 | https://doi.org/10.1016/j.biomaterials.2020.120151 A novel nanoparticle-based theranostic agent targeting LRP-1 enhances the efficacy of neoadjuvant radiotherapy in colorectal cancer

Kyoung Jin Lee^a,b,h, Eun Jung Ko^a,b, Yun-Yong Park^a,b,c, Seok Soon Park^a,b, Eun Jin Ju^a,b, Jin Park^a,b, Seol Hwa Shin^a,b, Young-Ah Suh^b,d, Seung-Mo Hong^d, In Ja Park^e, Kyu-pyo Kim^f, Jung Jin Hwang^a,b,c, Se Jin Jang^b,d, Jung Shin Lee^f, Si Yeol Song^b,g, Seong-Yun Jeong^a,b,c,*, Eun Kyung Choi^b,g,*

^aAsan Institute for Life Sciences, South Korea
^bCenter for Advancing Cancer Therapeutics, South Korea
^cDepartment of Convergence Medicine, South Korea
^dDepartment of Pathology, South Korea
^eDepartment of Colon and Rectal Surgery, South Korea
^fDepartment of Oncology, South Korea
^gDepartment of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, South Korea
^hDepartment of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul, 02841, South Korea

^*Corresponding author

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.

Keywords : Colorectal cancer (CRC); Neoadjuvant radiotherapy; Radio-resistant; Low-density lipoprotein receptor-related protein-1 (LRP-1)

논문정보

형식Research article
게재일2020년 05월 (BRIC 등록일 2020-06-05)
연구진국내 연구진
분야 의약학 > 종양의학

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