Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy
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 chemotherapeuti...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-03-01
|
| Series: | Journal of Nanobiotechnology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12951-024-02314-w |
| _version_ | 1827315781649563648 |
|---|---|
| author | Jinseong Kim Man Kyu Shim Yujeong Moon Jeongrae Kim Hanhee Cho Wan Su Yun Nayeon Shim Joon-Kyung Seong Yonghyun Lee Dong-Kwon Lim Kwangmeyung Kim |
| author_facet | Jinseong Kim Man Kyu Shim Yujeong Moon Jeongrae Kim Hanhee Cho Wan Su Yun Nayeon Shim Joon-Kyung Seong Yonghyun Lee Dong-Kwon Lim Kwangmeyung Kim |
| author_sort | Jinseong Kim |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-04-24T23:03:03Z |
| format | Article |
| id | doaj.art-d7fec239545c4da894e316023dafcba6 |
| institution | Directory Open Access Journal |
| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-04-24T23:03:03Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj.art-d7fec239545c4da894e316023dafcba62024-03-17T12:37:15ZengBMCJournal of Nanobiotechnology1477-31552024-03-0122111910.1186/s12951-024-02314-wCancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapyJinseong Kim0Man Kyu Shim1Yujeong Moon2Jeongrae Kim3Hanhee Cho4Wan Su Yun5Nayeon Shim6Joon-Kyung Seong7Yonghyun Lee8Dong-Kwon Lim9Kwangmeyung Kim10College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans UniversityMedicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST)Medicinal Materials Research Center, Biomedical Research Division, Korea Institute of Science and Technology (KIST)College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans UniversityCollege of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans UniversityCollege of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans UniversityCollege of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans UniversityDepartment of Bioengineering, Korea UniversityCollege of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans UniversityKU-KIST Graduate School of Converging Science and Technology, Korea UniversityCollege of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans UniversityAbstract 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 Abstracthttps://doi.org/10.1186/s12951-024-02314-wAposomesCancer immunotherapyImmune checkpoint blockadePEGylated liposomeImmunogenic cell deathDrug resistance |
| spellingShingle | Jinseong Kim Man Kyu Shim Yujeong Moon Jeongrae Kim Hanhee Cho Wan Su Yun Nayeon Shim Joon-Kyung Seong Yonghyun Lee Dong-Kwon Lim Kwangmeyung Kim Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy Journal of Nanobiotechnology Aposomes Cancer immunotherapy Immune checkpoint blockade PEGylated liposome Immunogenic cell death Drug resistance |
| title | Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy |
| title_full | Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy |
| title_fullStr | Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy |
| title_full_unstemmed | Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy |
| title_short | Cancer cell-specific and pro-apoptotic SMAC peptide-doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy |
| title_sort | cancer cell specific and pro apoptotic smac peptide doxorubicin conjugated prodrug encapsulated aposomes for synergistic cancer immunotherapy |
| topic | Aposomes Cancer immunotherapy Immune checkpoint blockade PEGylated liposome Immunogenic cell death Drug resistance |
| url | https://doi.org/10.1186/s12951-024-02314-w |
| work_keys_str_mv | AT jinseongkim cancercellspecificandproapoptoticsmacpeptidedoxorubicinconjugatedprodrugencapsulatedaposomesforsynergisticcancerimmunotherapy AT mankyushim cancercellspecificandproapoptoticsmacpeptidedoxorubicinconjugatedprodrugencapsulatedaposomesforsynergisticcancerimmunotherapy AT yujeongmoon cancercellspecificandproapoptoticsmacpeptidedoxorubicinconjugatedprodrugencapsulatedaposomesforsynergisticcancerimmunotherapy AT jeongraekim cancercellspecificandproapoptoticsmacpeptidedoxorubicinconjugatedprodrugencapsulatedaposomesforsynergisticcancerimmunotherapy AT hanheecho cancercellspecificandproapoptoticsmacpeptidedoxorubicinconjugatedprodrugencapsulatedaposomesforsynergisticcancerimmunotherapy AT wansuyun cancercellspecificandproapoptoticsmacpeptidedoxorubicinconjugatedprodrugencapsulatedaposomesforsynergisticcancerimmunotherapy AT nayeonshim cancercellspecificandproapoptoticsmacpeptidedoxorubicinconjugatedprodrugencapsulatedaposomesforsynergisticcancerimmunotherapy AT joonkyungseong cancercellspecificandproapoptoticsmacpeptidedoxorubicinconjugatedprodrugencapsulatedaposomesforsynergisticcancerimmunotherapy AT yonghyunlee cancercellspecificandproapoptoticsmacpeptidedoxorubicinconjugatedprodrugencapsulatedaposomesforsynergisticcancerimmunotherapy AT dongkwonlim cancercellspecificandproapoptoticsmacpeptidedoxorubicinconjugatedprodrugencapsulatedaposomesforsynergisticcancerimmunotherapy AT kwangmeyungkim cancercellspecificandproapoptoticsmacpeptidedoxorubicinconjugatedprodrugencapsulatedaposomesforsynergisticcancerimmunotherapy |