한빛사논문
- 조회432
이화여자대학교, 고려대학교
Jinseong Kim1,2†, Man Kyu Shim3†, Yujeong Moon3,4, Jeongrae Kim1,2, Hanhee Cho1, Wan Su Yun1,2, Nayeon Shim1, Joon‑Kyung Seong4, Yonghyun Lee1, Dong‑Kwon Lim2 and Kwangmeyung Kim1*
1College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
2KU‑KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea.
3Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
4Department of Bioengineering, Korea University, Seoul 02841, Republic of Korea.
†Jinseong Kim and Man Kyu Shim have authors contributed equally to this work.
*Correspondence: Kwangmeyung Kim
Abstract
Background: Immunogenic cell death (ICD) is a crucial approach to turn immunosuppressive tumor microenvironment (ITM) into immune-responsive milieu and improve the response rate of immune checkpoint blockade (ICB) therapy. However, cancer cells show resistance to ICD-inducing chemotherapeutic drugs, and non-specific toxicity of those drugs against immune cells reduce the immunotherapy efficiency.
Methods: Herein, we propose cancer cell-specific and pro-apoptotic liposomes (Aposomes) encapsulating second mitochondria-derived activator of caspases mimetic peptide (SMAC-P)-doxorubicin (DOX) conjugated prodrug to potentiate combinational ICB therapy with ICD. The SMAC-P (AVPIAQ) with cathepsin B-cleavable peptide (FRRG) was directly conjugated to DOX, and the resulting SMAC-P-FRRG-DOX prodrug was encapsulated into PEGylated liposomes.
Results: The SMAC-P-FRRG-DOX encapsulated PEGylated liposomes (Aposomes) form a stable nanostructure with an average diameter of 109.1 ± 5.14 nm and promote the apoptotic cell death mainly in cathepsin B-overexpressed cancer cells. Therefore, Aposomes induce a potent ICD in targeted cancer cells in synergy of SMAC-P with DOX in cultured cells. In colon tumor models, Aposomes efficiently accumulate in targeted tumor tissues via enhanced permeability and retention (EPR) effect and release the encapsulated prodrug of SMAC-P-FRRG-DOX, which is subsequently cleaved to SMAC-P and DOX in cancer cells. Importantly, the synergistic activity of inhibitors of apoptosis proteins (IAPs)-inhibitory SMAC-P sensitizing the effects of DOX induces a potent ICD in the cancer cells to promote dendritic cell (DC) maturation and stimulate T cell proliferation and activation, turning ITM into immune-responsive milieu.
Conclusions: Eventually, the combination of Aposomes with anti-PD-L1 antibody results in a high rate of complete tumor regression (CR: 80%) and also prevent the tumor recurrence by immunological memory established during treatments.
논문정보
- Research article
- 2024년 03월 (BRIC 등록일 2024-04-03)
- 국내 연구진
- 바이오·의료융합 > 바이오센싱 및 나노바이오물질
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