Recent Progress in Extracellular Vesicle-Based Carriers for Targeted Drug Delivery in Cancer Therapy
Abstract
:1. Introduction
2. Classification of Evs
2.1. Biogenesis of Exosomes
2.2. Biogenesis of Microvesicles
2.3. Biogenesis of Apoptosis Bodies
3. EV Isolation Methods
3.1. Ultracentrifugation
3.2. Density-Gradient Ultracentrifugation
3.3. Co-Precipitation
3.4. Size-Exclusion Chromatography
3.5. Ultrafiltration
3.6. Immunoaffinity Enrichment
3.7. Field Flow Fractionation
4. Drug Loading of EVs
4.1. Pre-Loading
4.2. Post-Loading
5. Functionalization of EVs
5.1. Pre-Functionalization
5.1.1. Gene Engineering
5.1.2. Metabolic Engineering
5.1.3. Source Cell Alteration Engineering
5.2. Post-Isolation
5.2.1. Physical Modification
5.2.2. Chemical Modification
6. EVs as Drug Delivery Nanovectors
6.1. Small-Molecule Drugs
6.1.1. Chemotherapy Drugs
6.1.2. Immune Small-Molecule Drugs
6.2. Nucleic Acids
6.2.1. miRNA
6.2.2. siRNA
6.2.3. mRNA
6.2.4. CRISPR-Cas9
6.2.5. ASO
6.3. Protein
6.4. Others
6.4.1. Photothermal Therapy
6.4.2. Sonodynamic Therapy
6.4.3. Combination Therapy
7. Conclusions and Prospects
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Isolation Methods | Working Principle | Advantage | Drawback | Ref. |
---|---|---|---|---|
Ultracentrifugation | Based on the size of EVs. Large ones precipitate earlier, while small ones require greater centrifugal force to precipitate easily. | The most commonly used method; Less reagent consumption; EVs can be isolated from a large number of samples. | High equipment cost; Time-consuming; High- speed centrifugation may damage EVs. | [49] |
Density-gradient ultracentrifugation | Based on EV density. | High purity; Good to maintain the activity of EVs. | Complexity; Time-consuming. | [50,51] |
Co-Precipitation | Polymer-based precipitators bind to hydrophobic proteins and lipid molecules for co-precipitation to separate EVs. | Easy and simple to handle; Low time requirement. | Low purity and recovery; More heteroprotein; Produces polymers that are difficult to remove. | [52] |
Size-Exclusion Chromatography | Based on the size of EV molecules, a porous gel matrix causes separation. | High purity. | Needs special equipment; Time-consuming and laborious. | [53] |
Ultrafiltration | Relative division using different interceptions; a sub-mass ultrafiltration membrane is used for selective separation of samples. | Simple and efficient; No sample size limitation; Does not affect EVs’ biological activity. | Low yields; Protein contamination; Deformation of vesicles. | [54] |
Immunoaffinity Enrichment | EV surface-specific marker, coated with corresponding antibody; EVs can be isolated by incubating the magnetic beads with EVs. | Simple operation; Does not affect EVs’ morphological integrity; High specificity. | Low efficiency; Not suitable for large quantities; Antibodies are expensive. | [55] |
Field-flow fractionation | Macromolecules flow through flat channels, applying force fields perpendicular to the sample flow to achieve separation based on different sizes and molecular weights. | Broad separation range; Wide variety of eluents. | Lengthy duration; Requires fractionation equipment. | [56] |
Cargo Types | Specific Substances | Extracellular Vesicles Source | Type of Extracellular Vesicles | Loading Method | Effect | Cancer Types | Ref. | |
---|---|---|---|---|---|---|---|---|
Small-Molecule Drugs | Chemotherapy drugs | Doxorubicin | MSC | Exosome | Electroporation | Inhibits tumor growth | Colorectal cancer | [103] |
Paclitaxel | PC-3 | Exosome Microvesicle | Co-incubation | Enhances the cytotoxicity of paclitaxel in autologous prostate cancer cells | Prostate cancer | [23] | ||
Cisplatin | Macrophage cell | Exosome | Co-incubation | Reverses cisplatin resistance, Inhibits tumor growth | Ovarian cancer | [104] | ||
Curcumin | PANC-1 | Exosome | Co-incubation | Induces apoptosis in cancer cells. | Pancreatic cancer | [105] | ||
Temozolomide | Glioma cells | Exosome | Co-incubation | Reverses TMZ resistance, Inhibits tumor growth | GBM | [106] | ||
Camptothecin | 4T1 | Apoptotic bodies | Co-incubation | Enhances tumor growth suppression and antimetastatic ability | Breast cancer | [82] | ||
Immune small-molecule drugs | TGFβRI kinase inhibitor and TLR7/8 agonist | FBS | Exosome | Electroporation | Inhibits tumor growth | Melanoma and Prostate cancer | [107] | |
MHC, CD86, αCD3 Ab, and αEGFR Ab | DC | Exosome | Co-incubation | Activates T cells and increases their killing ability, Inhibits tumor growth | B16-OVA melanoma | [108] | ||
Anti-CD3/CD28 single-chain variable fragments (scFvs) | HEK293T | Exosome | Transfection | Activates T cells and increase their killing ability | Gastric cancer | [109] | ||
Lapatinib | MCF10 A | Exosome | Electroporation | Activates T cells and increases their killing ability | Breast cancer | [110] | ||
A33Ab | LIM1215 | Exosome | Co-incubation | Improves tumor-targeting capabilities | Colorectal cancer | [111] | ||
CpG | EL4 | Apoptotic body | Co-incubation | Prevents tumor metastasis and recurrence | lymphoma | [112] | ||
cGAMP | Breast cancer cell | Apoptotic body | Active loading | Enhances STING activation and an improves tumor-specific antigen presentation ability | Breast cancer | [113] | ||
Nucleic Acids | miRNA | miR-138-5p | ADSCs | Exosome | Lentivirus infection | Inhibits tumor growth | Bladder cancer | [114] |
miRNA-497 | HEK293T | Exosome | Chemical transfection | Regulates the growth, migration, and angiogenesis of tumors | Lung cancer | [115] | ||
miR-199a | AMSC | Exosome | Lentivirus infection | Improves the sensitivity of tumor cells to DOX | HCC | [116] | ||
miR-146b | MSC | Exosome | Electroporation | Inhibits tumor growth | GBM | [117] | ||
miRNA-21 | HEK293T | Exosome | Electroporation | Inhibits tumor growth | GBM | [118] | ||
siRNA | siS100A4 | Auto logous breast cancer cells | Exosome | Co-incubation and Extrusion | Inhibits tumor growth | Breast cancer | [119] | |
siRNA | HEK293T | Exosome | Chemical transfection | Significant tumor growth regression | NSCLC | [120] | ||
siSTAT3 | RAW | Exosome | Ultrasonication and Incubation | Inhibits tumor growth | GBM | [121] | ||
siCDK1 | Sk-hep1 | EVs | Electroporation | Inhibits tumor growth | HCC | [98] | ||
mRNA | PTEN | MEFs and DCs | Exosome | Cellular-nanoporation | Inhibits tumor growth | Glioma | [122] | |
5-FC and yCD::UPRT mRNA | HEK-293T | Microvesicle | Co-incubation | Inhibits tumor growth | Glioma | [123] | ||
CRISPR-Cas9 | CRISPR-Cas9 | HEK293/SKOV3 | Exosome | Electroporation | Induces apoptosis in ovarian cancer. Enhances chemosensitivity to cisplatin. | Ovarian cancer | [124] | |
CRISPR-Cas9 | HEK293T | EVs | Sonication | Inhibits tumor growth | Liver cancer | [125] | ||
ASO | ASO-STAT6 | HEK293/M2 macrophages | Exosome | Mixing | Inhibits tumor growth | Colorectal cancer and HCC | [126] | |
Proteins | Transferrin receptor-binding peptide | MDA-MB-231 | Exosome | Mixing | Inhibits tumor growth | Breast cancer | [118] | |
Tlyp-1 | M1macrophage | Exosome | Co-incubation; Electroporation | Inhibits tumor growth | Breast cancer | [127] | ||
αCD3/αEGFR | M1macrophage | EVs | Electroporation | Inhibits tumor growth | Breast cancer | [128] | ||
Transferrin receptor-binding peptide | HEK293T | Exosome | Transfection | Improves tumor-targeting capabilities | GBM | [118] | ||
Combination Therapy | CPPO/Ce6/Dox-EMCH | THLG-293T/LG-293T | EVs | Electroporation | Reverses drug resistance in colon cancer. | Colon cancer | [129] | |
miR-21/5-FU | HEK293T | Exosome | Co-incubation | Inhibits tumor growth | Breast cancer | [130] | ||
Dox/Cho-miR-159 | THP-15 | Exosome | Co-incubation | Powerful ferroptosis promotion in GBM. Inhibits tumor growth | GBM | [131] | ||
siGPX4/Fe3O4@mSiO2 | HEK293T | Exosome | Co-incubation | Inhibits tumor growth | Triple-negative Breast cancer | [132] | ||
CPT-SS-PR104A | Tumor cell | Apoptotic bodies | Active loading | Inhibits tumor growth | Breast cancer | [82] |
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Tang, Y.; Liu, X.; Sun, M.; Xiong, S.; Xiao, N.; Li, J.; He, X.; Xie, J. Recent Progress in Extracellular Vesicle-Based Carriers for Targeted Drug Delivery in Cancer Therapy. Pharmaceutics 2023, 15, 1902. https://doi.org/10.3390/pharmaceutics15071902
Tang Y, Liu X, Sun M, Xiong S, Xiao N, Li J, He X, Xie J. Recent Progress in Extracellular Vesicle-Based Carriers for Targeted Drug Delivery in Cancer Therapy. Pharmaceutics. 2023; 15(7):1902. https://doi.org/10.3390/pharmaceutics15071902
Chicago/Turabian StyleTang, Yaqin, Xingyou Liu, Meng Sun, Su Xiong, Nianting Xiao, Jianchao Li, Xiao He, and Jing Xie. 2023. "Recent Progress in Extracellular Vesicle-Based Carriers for Targeted Drug Delivery in Cancer Therapy" Pharmaceutics 15, no. 7: 1902. https://doi.org/10.3390/pharmaceutics15071902
APA StyleTang, Y., Liu, X., Sun, M., Xiong, S., Xiao, N., Li, J., He, X., & Xie, J. (2023). Recent Progress in Extracellular Vesicle-Based Carriers for Targeted Drug Delivery in Cancer Therapy. Pharmaceutics, 15(7), 1902. https://doi.org/10.3390/pharmaceutics15071902