Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood‒brain barrier
Glioblastoma (GBM) is the most aggressive malignant brain tumor and has a high mortality rate. Photodynamic therapy (PDT) has emerged as a promising approach for the treatment of malignant brain tumors. However, the use of PDT for the treatment of GBM has been limited by its low blood‒brain barrier...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-09-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383523001132 |
| _version_ | 1797690215137017856 |
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| author | Thuy Giang Nguyen Cao Ji Hee Kang Su Jin Kang Quan Truong Hoang Han Chang Kang Won Jong Rhee Yu Shrike Zhang Young Tag Ko Min Suk Shim |
| author_facet | Thuy Giang Nguyen Cao Ji Hee Kang Su Jin Kang Quan Truong Hoang Han Chang Kang Won Jong Rhee Yu Shrike Zhang Young Tag Ko Min Suk Shim |
| author_sort | Thuy Giang Nguyen Cao |
| collection | DOAJ |
| description | Glioblastoma (GBM) is the most aggressive malignant brain tumor and has a high mortality rate. Photodynamic therapy (PDT) has emerged as a promising approach for the treatment of malignant brain tumors. However, the use of PDT for the treatment of GBM has been limited by its low blood‒brain barrier (BBB) permeability and lack of cancer-targeting ability. Herein, brain endothelial cell-derived extracellular vesicles (bEVs) were used as a biocompatible nanoplatform to transport photosensitizers into brain tumors across the BBB. To enhance PDT efficacy, the photosensitizer chlorin e6 (Ce6) was linked to mitochondria-targeting triphenylphosphonium (TPP) and entrapped into bEVs. TPP-conjugated Ce6 (TPP-Ce6) selectively accumulated in the mitochondria, which rendered brain tumor cells more susceptible to reactive oxygen species-induced apoptosis under light irradiation. Moreover, the encapsulation of TPP-Ce6 into bEVs markedly improved the aqueous stability and cellular internalization of TPP-Ce6, leading to significantly enhanced PDT efficacy in U87MG GBM cells. An in vivo biodistribution study using orthotopic GBM-xenografted mice showed that bEVs containing TPP-Ce6 [bEV(TPP-Ce6)] substantially accumulated in brain tumors after BBB penetration via transferrin receptor-mediated transcytosis. As such, bEV(TPP-Ce6)-mediated PDT considerably inhibited the growth of GBM without causing adverse systemic toxicity, suggesting that mitochondria are an effective target for photodynamic GBM therapy. |
| first_indexed | 2024-03-12T01:56:20Z |
| format | Article |
| id | doaj.art-94638c77ed2a4643aa5fadc0d3e4f8e6 |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-03-12T01:56:20Z |
| publishDate | 2023-09-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-94638c77ed2a4643aa5fadc0d3e4f8e62023-09-08T04:33:17ZengElsevierActa Pharmaceutica Sinica B2211-38352023-09-0113938343848Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood‒brain barrierThuy Giang Nguyen Cao0Ji Hee Kang1Su Jin Kang2Quan Truong Hoang3Han Chang Kang4Won Jong Rhee5Yu Shrike Zhang6Young Tag Ko7Min Suk Shim8Division of Bioengineering, Incheon National University, Incheon 22012, Republic of KoreaCollege of Pharmacy, Gachon University, Incheon 21936, Republic of KoreaDivision of Bioengineering, Incheon National University, Incheon 22012, Republic of KoreaDivision of Bioengineering, Incheon National University, Incheon 22012, Republic of KoreaDepartment of Pharmacy, Integrated Research Institute of Pharmaceutical Sciences, and BK21 PLUS Team for Creative Leader Program for Pharmacomics-based Future Pharmacy, College of Pharmacy, the Catholic University of Korea, Gyeonggi-do 14662, Republic of KoreaDivision of Bioengineering, Incheon National University, Incheon 22012, Republic of Korea; Research Center for Bio Materials & Process Development, Incheon National University, Incheon 22012, Republic of Korea; Corresponding authors.Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Cambridge, MA 02139, USA; Corresponding authors.College of Pharmacy, Gachon University, Incheon 21936, Republic of Korea; Corresponding authors.Division of Bioengineering, Incheon National University, Incheon 22012, Republic of Korea; Corresponding authors.Glioblastoma (GBM) is the most aggressive malignant brain tumor and has a high mortality rate. Photodynamic therapy (PDT) has emerged as a promising approach for the treatment of malignant brain tumors. However, the use of PDT for the treatment of GBM has been limited by its low blood‒brain barrier (BBB) permeability and lack of cancer-targeting ability. Herein, brain endothelial cell-derived extracellular vesicles (bEVs) were used as a biocompatible nanoplatform to transport photosensitizers into brain tumors across the BBB. To enhance PDT efficacy, the photosensitizer chlorin e6 (Ce6) was linked to mitochondria-targeting triphenylphosphonium (TPP) and entrapped into bEVs. TPP-conjugated Ce6 (TPP-Ce6) selectively accumulated in the mitochondria, which rendered brain tumor cells more susceptible to reactive oxygen species-induced apoptosis under light irradiation. Moreover, the encapsulation of TPP-Ce6 into bEVs markedly improved the aqueous stability and cellular internalization of TPP-Ce6, leading to significantly enhanced PDT efficacy in U87MG GBM cells. An in vivo biodistribution study using orthotopic GBM-xenografted mice showed that bEVs containing TPP-Ce6 [bEV(TPP-Ce6)] substantially accumulated in brain tumors after BBB penetration via transferrin receptor-mediated transcytosis. As such, bEV(TPP-Ce6)-mediated PDT considerably inhibited the growth of GBM without causing adverse systemic toxicity, suggesting that mitochondria are an effective target for photodynamic GBM therapy.http://www.sciencedirect.com/science/article/pii/S2211383523001132Extracellular vesicleChlorin e6TriphenylphosphoniumMitochondria-targeting photosensitizerPhotodynamic therapyBlood‒brain barrier |
| spellingShingle | Thuy Giang Nguyen Cao Ji Hee Kang Su Jin Kang Quan Truong Hoang Han Chang Kang Won Jong Rhee Yu Shrike Zhang Young Tag Ko Min Suk Shim Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood‒brain barrier Acta Pharmaceutica Sinica B Extracellular vesicle Chlorin e6 Triphenylphosphonium Mitochondria-targeting photosensitizer Photodynamic therapy Blood‒brain barrier |
| title | Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood‒brain barrier |
| title_full | Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood‒brain barrier |
| title_fullStr | Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood‒brain barrier |
| title_full_unstemmed | Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood‒brain barrier |
| title_short | Brain endothelial cell-derived extracellular vesicles with a mitochondria-targeting photosensitizer effectively treat glioblastoma by hijacking the blood‒brain barrier |
| title_sort | brain endothelial cell derived extracellular vesicles with a mitochondria targeting photosensitizer effectively treat glioblastoma by hijacking the blood brain barrier |
| topic | Extracellular vesicle Chlorin e6 Triphenylphosphonium Mitochondria-targeting photosensitizer Photodynamic therapy Blood‒brain barrier |
| url | http://www.sciencedirect.com/science/article/pii/S2211383523001132 |
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