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서울대학교

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Biomaterials, Volume 277, October 2021, 121105 | https://doi.org/10.1016/j.biomaterials.2021.121105 Caspase-cleavable peptide-doxorubicin conjugate in combination with CD47-antagonizing nanocage therapeutics for immune-mediated elimination of colorectal cancer

Na Kyeong Lee^a,1, Jeong Uk Choi^b,1, Ha Rin Kim^a, Seung Woo Chung^c, Yoon Gun Ko^d, Young Seok Cho^a, Seong Jin Park^a, Eun Jung Lee^e, Sang Yoon Kim^f, In-San Kim^g,h,*, Youngro Byun^a,i,*

^aResearch Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
^bCollege of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea
^cCenter for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA
^dPharosgen, Inc., 2-404 Jangji-dong 892, Songpa-Gu, Seoul, 05852, Republic of Korea
^eDepartment of Chemical Engineering, School of Applied Chemical Engineering, Kyungpook National University, Daegu, 41566, Republic of Korea
^fDepartment of Otolaryngology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
^gBiomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul, 02792, Republic of Korea
^hKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, 02841, Republic of Korea
ⁱDepartment of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea

¹These authors contributed equally to this work as the first author.

^*Corresponding author

Abstract

Here we report a novel combination of a caspase-cleavable peptide-doxorubicin conjugate (MPD-1) with CD47-antagonizing nanocage therapeutics for the treatment of microsatellite-stable (MSS) colorectal cancer (CRC). MPD-1 (i) upregulated markers of immunogenic cell death (ICD) in tumor, and increased co-stimulatory markers on dendritic cells (DCs), (ii) enhanced CD8+ T cell infiltration and antigen presenting cell (APC) activation, and (iii) showed negligible off-target immune-related toxicity compared to free dox. Then, the CD47 antagonist FS nanocage, a SIRPα-expressing ferritin nanocage, was co-administered with MPD-1 that resulted in 95.2% (p < 0.001) tumor growth inhibition in an established CRC model. T cell-mediated elimination of tumors was also confirmed by the tumor-specific activation of T cells detected by IFNγ and tumor-free mice were observed (95%) that bared a memory response when re-challenged. The strategically developed MPD-1 is an ideal adjuvant to immunotherapy and the combination with FS nanocage triggers potent immunity against MSS CRC. In summary, we present an approach to initiate and stimulate immune-mediated eradication of cancer cells using synergistic immunogenic agents targeting the MSS CRC.

논문정보

형식Research article
게재일2021년 10월 (BRIC 등록일 2021-11-18)
연구진국내(교신)+국외 연구진
분야 생명과학 > 노화/암생물학

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