한빛사 논문
Wooram Uma, Hyewon Kob, Dong Gil Youb, Seungho Limc, Gijung Kwakc,d, Man Kyu Shimc, Suah Yangc,d, Jeongjin Leea, Yeari Songb, Kwangmeyung Kimc,d, and Jae Hyung Parka,b,e,*
aDepartment of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul 06351, Republic of Korea
bSchool of Chemical Engineering, College of Engineering, Sungkyunkwan University, Suwon 16419, Republic of Korea
cCenter for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
dKU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea
eBiomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, Suwon 16419, Republic of Korea
W.U. and H.K. contributed equally to this work.
*To whom correspondence should be addressed.
Abstract
Necroptosis, caspase‐independent programmed necrosis, has emerged as a therapeutic target to make dying cancer cells stimulants for antitumor immune responses. The clinical translations exploiting necroptosis, however, have been limited since most cancer cells downregulate receptor‐interacting protein kinase 3 (RIPK3) as a key enzyme for necroptosis. Herein, nanobubbles (NBs) that can trigger RIPK3‐independent necroptosis, facilitating cell‐membrane rupture via the acoustic cavitation effect are reported. The NBs, imbibing perfluoropentane as the gas precursor, are prepared using an amphiphilic polymer conjugate, composed of PEGylated carboxymethyl dextran as the hydrophilic backbone and chlorin e6 as the hydrophobic sonosensitizer. When exposed to ultrasound, the NBs efficiently promote the release of biologically active damage‐associated molecular patterns by inducing burst‐mediated cell‐membrane disintegration. Consequently, the necroptosis‐inducible NBs significantly improve antitumor immunity by maturation of dendritic cells and activation of CD8+ cytotoxic T cells both in vitro and in vivo. In addition, the combination of NBs and immune checkpoint blockade leads to complete regression of the primary tumor and beneficial therapeutic activity against metastatic tumors in an RIPK3‐deficient CT26 tumor‐bearing mouse model. Overall, the innovative NB that causes immunogenic cell death of cancer via RIPK3‐independent necroptosis is a promising enhancer for cancer immunotherapy.
Keywords : damage‐associated molecular patterns, immune checkpoint blockade, necroptosis, reactive oxygen species, sonodynamic therapy
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