View : 136 Download: 0
Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy
- Title
- Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy
- Authors
- Kim; Jinseong; Shim; Man Kyu; Moon; Yujeong; Jeongrae; Cho; Hanhee; Yun; Wan Su; Nayeon; Seong; Joon-Kyung; Lee; Yonghyun; Lim; Dong-Kwon; Kwangmeyung
- Ewha Authors
- 김진성; 이용현; 김광명
- SCOPUS Author ID
- 김진성; 이용현; 김광명
- Issue Date
- 2024
- Journal Title
- Journal of Nanobiotechnology
- ISSN
- 1477-3155
- Citation
- Journal of Nanobiotechnology vol. 22, no. 1
- Keywords
- Aposomes; Cancer immunotherapy; Drug resistance; Immune checkpoint blockade; Immunogenic cell death; PEGylated liposome
- Publisher
- BioMed Central Ltd
- Indexed
- SCIE; SCOPUS
- Document Type
- Article
- 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. Graphical Abstract: (Figure presented.). © The Author(s) 2024.
- DOI
- 10.1186/s12951-024-02314-w
- Appears in Collections:
- 연구기관 > 약학연구소 > Journal papers
- Files in This Item:
There are no files associated with this item.
- Export
- RIS (EndNote)
- XLS (Excel)
- XML