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Research Article

Gene editing particle system as a therapeutic approach for drug-resistant colorectal cancer

Jee-Yeon Ryu1, You Jung Choi2, Eun-Jeong Won1, Emmanuel Hui3, Ho-Shik Kim2, Young-Seok Cho2( ), Tae-Jong Yoon1( )
Laboratory of Nanopharmacy, College of Pharmacy, Research Institute of Pharmaceutical Science and Technology (RIPST), Ajou University, Suwon 16499, Republic of Korea
Division of Gastroenterology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
Moogene Medi Co., Ltd., Seongnam 13488, Republic of Korea
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Abstract

The epidermal growth factor receptor (EGFR) pathway plays an important role in the progression of colorectal cancer (CRC). Anti-EGFR drugs based on antibodies have been widely used for treating CRC through inducing the cell death pathway. However, the majority of CRC patients will inevitably develop drug-resistance during anti-EGFR drug treatment, which is mainly caused by a point mutation in the KRAS oncogene. We developed a nanoliposomal (NL) particle containing the Cas9 protein and a single-guide RNA (sgRNA) complex (Cas9-RNP), for genomic editing of the KRAS mutation. The NL particle is composed of bio-compatible lipid compounds that can effectively encapsulate Cas9-RNP. By modifying the NL particle to include the appropriate antibody, it can specifically recognize EGFR expressing CRC and effectively deliver the gene-editing complexes. The conditions of NL treatment were optimized using a KRAS mutated CRC in vivo mouse model. Mice with KRAS-mutated CRC showed drug resistance against cetuximab, a therapeutic antibody drug. After treating the mice with the KRAS gene-editing NL particles, the implanted tumors showed a dramatic decrease in size. Our results demonstrated that this genomic editing complex has great potential as a therapeutic carrier system for the treatment of drug-resistant cancer caused by a point mutation.

Keywords

nanoliposomeclustered regularly interspaced short palindromic repeat and associated Cas9 nuclease (CRISPR/Cas9)KRAS mutationdrug-resistancecolorectal cancer

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Nano Research
Volume 13 Issue 6,
June 2020
Pages 1576-1585
DOI: 10.1007/s12274-020-2773-1
Cite this article:
Ryu J-Y, Jung Choi Y, Won E-J, et al. Gene editing particle system as a therapeutic approach for drug-resistant colorectal cancer. Nano Research, 2020, 13(6): 1576-1585. https://doi.org/10.1007/s12274-020-2773-1
Topics:
Antibodies Cell death Drug therapyGenesMammals

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Received: 30 November 2019
Revised: 27 February 2020
Accepted: 23 March 2020
Published: 04 April 2020
© Tsinghua University Press and Springer-Verlag GmbH Germany, part of Springer Nature 2020
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