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PDL1-binding peptide/anti-miRNA21 conjugate as a therapeutic modality for PD-L1high tumors and TAMs

Authors
Kim, E.H.Lee, J.Kwak, G.Jang, H.Kim, H.Cho, H.Jang, Y.Choi, J.Chi, S.-G.Kim, K.Kwon, I.C.Yang, Y.Kim, S.H.
Issue Date
5월-2022
Publisher
Elsevier B.V.
Keywords
anti-miRNA delivery; B16 melanoma; miR-21; PD-L1; Tumor-associated macrophage
Citation
Journal of Controlled Release, v.345, pp.62 - 74
Indexed
SCIE
SCOPUS
Journal Title
Journal of Controlled Release
Volume
345
Start Page
62
End Page
74
URI
https://scholar.korea.ac.kr/handle/2021.sw.korea/140178
DOI
10.1016/j.jconrel.2022.02.031
ISSN
0168-3659
Abstract
Upregulation of oncogenic miRNA21 (miR-21) plays a pivotal role in proliferation, migration and invasion of cancer cells. In addition to cancer cells, tumor-associated macrophages (TAMs) also have high abundance of miR-21, which accelerates malignant progression of tumors in the late stages of carcinogenesis. Despite of the pro-tumorigenic functions of miR-21 in TAMs and cancer cells, reliable therapeutic strategies to simultaneously inhibit miR-21 activity in both types of cell have not yet been developed. In this study, we designed a dual-targeting drug delivery system of miR-21 inhibitors that could bind to both tumor cells and macrophages with overexpressed PD-L1 receptors. This peptide-oligonucleotide conjugate (Pep-21) consists of a PDL1-binding peptide covalently linked with an anti-miR-21 inhibitor via click chemistry. Pep-21 was preferentially internalized in both cell types, consequently depleting endogenous miR-21. Our studies found that Pep-21 treatment reduced tumor cell migration, reprogrammed immunosuppressive M2-type TAMs into M1-type macrophages, and restrained tumor progression. Collectively, neutralization of miR-21 activity in both cancer cells and TAMs can be a promising strategy for effective antitumor responses. © 2022 Elsevier B.V.
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