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Biomaterials, Available online 5 August 2021, 121058. DOI 10.1016/j.biomaterials.2021.121058 Repurposing macitentan with nanoparticle modulates tumor microenvironment to potentiate immune checkpoint blockade

Soyoung Son^a,b,1, Jung Min Shin^b,c,1, Sol Shin^a, Chan Ho Kim^b, Jae Ah Lee^b, Hyewon Ko^d, Eun Sook Lee^a, Jae Min Jung^b, Jeongyun Kim^b, Jae Hyung Park^a,b,e,*

^aDepartment of Health Sciences and Technology, SAIHST, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
^bSchool of Chemical Engineering, College of Engineering, Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
^cDepartment of Genetic Resources, National Marine Biodiversity Institute of Korea (MABIK), 75 Jangsan-ro 101-gil, Janghang-eup, Seocheon, 33662, Republic of Korea
^dBionanotechnology Research Center, Korea Research Institute of Bioscience & Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea
^eBiomedical Institute for Convergence at SKKU (BICS), Sungkyunkwan University, 2066 Seobu-ro, Jangan-gu, Suwon, 16419, Republic of Korea
¹These authors contributed equally to this work.
^*Corresponding author.

Abstract

Immune checkpoint therapy (ICT), which reinvigorates cytotoxic T cells, provides clinical benefits as an alternative to conventional cancer therapies. However, its clinical response rate is too low to treat an immune-excluded tumor, owing to the presence of abundant stromal elements impeding the penetration of immune cells. Here, we report that macitentan, a dual endothelin receptor antagonist approved by the FDA to treat pulmonary arterial hypertension, can be repositioned to modulate the desmoplastic tumor microenvironment (TME). In the 4T1 orthotopic tumor model, the polymeric nanoparticles bearing macitentan (M-NPs) prevent fibrotic progression by regulating the function of cancer-associated fibroblasts, attenuate the biogenesis of cancer cell-derived exosomes, and modulate the T cell subsets and distribution in TME. These results demonstrate that the M-NPs effectively reorganize the immunosuppressive TME by targeting the endothelin-1 axis and consequently exhibit synergistic antitumor effects in combination with ICT.

논문정보

형식Research article
게재일2021년 08월 (BRIC 등록일 2021-08-19)
연구진국내 연구진
분야 바이오·의료융합 > 바이오소재

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