Extracellular Vesicle-Based Therapeutics: Preclinical and Clinical Investigations
Abstract
:1. Introduction
2. Implications Related to Biological Activity Inherited from EV Origin
3. Improving Functional Heterogenicity and Yields of EVs Nanocarriers
4. Loading EVs with Therapeutic Cargo
4.1. Exogenous Loading of EVs
4.1.1. Co-Incubation
4.1.2. Sonication
4.1.3. Electroporation
4.1.4. Transient Permeabilization with Saponin
4.1.5. Freeze-Thaw and Extrusion Cycles
4.2. Exogenous Loading of Parent Cells
5. Challenges of Insufficient Targeting Efficiency of EVs Formulations to Disease Tissues
6. EV-Based Drug Formulations in Clinic
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Disease | Source of EVs | Therapeutic Cargo/Drug | Loading Method | Ref. |
---|---|---|---|---|
Inflammatory-related diseases | Neutrophil-derived EVs | Piceatannol | Co-incubation | [95] |
Cancer | Bioinspired EV-mimetic nanovesicles | Doxorubicin | Co-incubation | [54] |
Inflammatory-related diseases | EL-4 Cells | Curcumin | Co-incubation | [41] |
Brain inflammatory-related diseases | Brain inflammation disease cells | Curcumin | Co-incubation | [102] |
Cerebral diseases | Endothelial cells | Curcumin | Co-incubation | [103] |
Cancer | Immature dendritic cells | Doxorubicin | Co-incubation | [104] |
Prostate Cancer | PC-3 cells | Paclitaxel | Co-incubation | [106] |
Parkinson’s Disease | Blood | Dopamine | Co-incubation | [108] |
Melanoma | Me 30966 | Acridine Orange | Co-incubation | [110] |
Cardiotoxicity | Liposomes | Doxorubicin | Co-incubation | [119] |
Brain inflammatory-related diseases | Macrophages | Brain derived neurotrophic factor (BDNF) | Co-incubation | [45] |
Pancreatic Cancer | Autologous EVs | Gemcitabine | Co-incubation and probe sonification | [109] |
Triple Negative Breast Cancer | Macrophages | Paclitaxel and Doxorubicin | Probe sonification | [112] |
Cancer | BT-474 tumor cells/SK-N-MC tumor cells | Doxorubicin | Probe sonification | [113] |
MDR Cancer | Macrophages | Paclitaxel | Sonification | [107] |
Cancer | Hybrid EVs (EVs from macrophage hybridized with synthetic liposome) | Doxorubicin | Water bath sonification | [97] |
Pulmonary metastases | Macrophages | Paclitaxel | Probe sonification and Electroporation | [111] |
Brain-related diseases | Macrophages | TPP1 | Water bath sonification and permeabilization with saponin | [44] |
Brain-related diseases | DC-derived EVs | siRNA | Electroporation | [114] |
Breast Cancer | EVs targeted to EGFR-expressing cells | miRNA | Electroporation | [115] |
Lung Cancer | EVs | Doxorubicin | Electroporation | [116] |
Ovarian Cancer | Fibroblasts-derived EVs | Tumor suppressor miRNA | Electroporation | [120] |
Lung diseases | Serum-derived EVs | siRNA | Permeabilization with saponin | [121] |
Parkinson’s Disease | EVs secreted by monocytes and macrophages | Catalase | Co-incubation, probe sonification, permeabilization with saponin, freeze-thaw cycles, and extrusion | [43] |
Disease | Source of EVs | Therapeutic Cargo/Drug | Loading Method | Ref. |
---|---|---|---|---|
Cancer | Bioinspired EV-mimetic nanovesicles | Dox | Loading of parent cells with therapeutic agent | [54] |
Parkinson’s disease | EVs secreted by monocytes and macrophages | Catalase | Loading of parent cells with therapeutic agent | [43] |
Pancreatic Cancer | PANC-1 cells | Curcumin | Loading of parent cells with therapeutic agent | [130] |
Cancer | MSC-derived EVs | Paclitaxel | Loading of parent cells with therapeutic agent | [131] |
Carcinoma | HepG2 cells | Paclitaxel, Etoposide, Carboplatin, Irinotecan, Epirubicin, Mitoxanthrone | Loading of parent cells with therapeutic agent | [132] |
Neurodegene- rative diseases | Bone marrow-derived macrophages | Catalase | Loading of parent cells with therapeutic agent | [133] |
Parkinson’s disease | GDNF-transfected macrophages | Catalase | Loading of parent cells with therapeutic agent and Transfection of parent cells | [134] |
Glioblastomas | Isolated EVs from CD-UPRT-treated cells | Therapeutic CD-UPRT | Transfection of parent cells | [135] |
Breast Cancer | Isolated EVs from EGCG-treated 4T1 cells | EGCG | Transfection of parent cells | [136] |
Cancer | Isolated EVs from OVAC1C2-treated cells | OVAC1C2 | Transfection of parent cells | [137] |
Neurodegene-rative diseases | Transfected macrophages | Catalase | Transfection of parent cells | [138] |
Adeno-associated virus | VEVs | AAV vectors | Transfection of parent cells | [139] |
EVs Source | Condition | Drug | Administration Route | Dose Reported | Phase | Study Identifier |
---|---|---|---|---|---|---|
MSCs | Cerebrovascular disorders/stroke | miR-124 | i.v. | 200 µg protein | 1/2 | NCT03384433 |
MSCss | Alzheimer Disease | no | nasal drip | 5 μg–20 μg | 1/2 | NCT04388982 |
MSCs | Periodontitis | no | local | not reported | early 1 | NCT04270006 |
MSCs | Neuralgia | no | i.v. epineurally | 45 mg, 15 mg | n/a | NCT04202783 |
MSCs | Depression | no | i.v. | 21 million cells | n/a | NCT04202770 |
MSCs | Diabetes Mellitus Type 1 | no | i.v. | 1.2 × 1010 –1.51 × 1010 particles/kg | 2/3 | NCT02138331 |
MSCs | Chronic Ulcer | no | topical | not reported | 1 | NCT04134676 |
Plasma | Ulcer | no | topical | not reported | Early 1 | NCT02565264 |
MSC | Dystrophic Epidermolysis Bullosa | no | topical | not reported | 1/2 | NCT04173650 |
MSCs | Multiple Organ Failure | no | i.v. | 150 mg once a day for 14 times | n/a | NCT04356300 |
MSCs | Healthy | no | inhalation | 2 × 108–20 × 108 particles/3 ml | 1 | NCT04313647 |
Plant | Colon Cancer | curcumin | oral | not reported | 1 | NCT01294072 |
Plant | Polycystic Ovary Syndrome | no | oral | not reported | n/a | NCT03493984 |
Grape | Head and Neck Cancer Oral Mucositis | no | oral | not reported | 1 | NCT01668849 |
DCs | Non Small Cell Lung Cancer | MHC class I- class II- cancer antigens | i.v. | 53–2422 μg protein/injection | 2 | NCT01159288 |
MSCs | Pancreatic Adenocarcinoma | KRAS G12D siRNA | i.v. | days 1, 4, and 10 (dose not reported) | 1 | NCT03608631 |
MSCs | SARS-CoV-2 pneumonia | no | inhalation | 2 × 108 particles/3 mL | 1 | NCT04276987 |
MSCs | SARS-CoV-2 pneumonia | no | inhalation | 0.5 × 1010–2 × 1010 particles/3 ml | 1/2 | NCT04491240 |
Bone marrow | SARS-CoV-2 pneumonia | no | i.v. | not reported | 2 | NCT04493242 |
Human amniotic fluid | SARS-CoV-2 pneumonia | no | i.v. | 2 × 1010 –5 × 1010 particles | 1/2 | NCT04384445 |
MSCs | Dry Eye | no | eye drop | 10 µg/drop | 1/2 | NCT04213248 |
MSCs | Macular Holes | no | drop | 50 μg or 20 μg | early 1 | NCT03437759 |
COVID-19 Specific T Cells | SARS-CoV-2 pneumonia | no | inhalation | 2 × 1018 particles/3 mL | 1 | NCT04389385 |
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Klyachko, N.L.; Arzt, C.J.; Li, S.M.; Gololobova, O.A.; Batrakova, E.V. Extracellular Vesicle-Based Therapeutics: Preclinical and Clinical Investigations. Pharmaceutics 2020, 12, 1171. https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12121171
Klyachko NL, Arzt CJ, Li SM, Gololobova OA, Batrakova EV. Extracellular Vesicle-Based Therapeutics: Preclinical and Clinical Investigations. Pharmaceutics. 2020; 12(12):1171. https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12121171
Chicago/Turabian StyleKlyachko, Natalia L., Camryn J. Arzt, Samuel M. Li, Olesia A. Gololobova, and Elena V. Batrakova. 2020. "Extracellular Vesicle-Based Therapeutics: Preclinical and Clinical Investigations" Pharmaceutics 12, no. 12: 1171. https://0-doi-org.brum.beds.ac.uk/10.3390/pharmaceutics12121171