Extracellular Vesicles as Drug Delivery System for Cancer Therapy
Abstract
:1. Introduction
2. Discovery and Development of Extracellular Vesicles
2.1. Discovery of Extracellular Vesicles
2.2. Biogenesis and Classification of Extracellular Vesicles
2.3. Absorption/Uptake of Extracellular Vesicles
3. Strategies for Utilizing Extracellular Vesicles as a Drug Delivery System
3.1. Sources of Extracellular Vesicles for Drug Delivery
3.2. Characterization and Purification of Extracellular Vesicles
3.2.1. Characterization of Extracellular Vesicles
3.2.2. Purification of Extracellular Vesicles
3.3. General Methods for Drug Loading into Extracellular Vesicles
3.3.1. Pre-Loading Methods
3.3.2. Post-Loading Methods
Cargo Loading Method | Therapeutic Cargo | Sources of EVs | Cancer Type | Function | Study Type | Year | Ref. |
---|---|---|---|---|---|---|---|
Pre-loding, coincubation | Phthalocyanine chloride tetrasulfonic acid (AlPcS4) | Gastric cancer MGC803 cells | Gastric cancer | Deconstruct exosome for releasing Dox and enable the photodynamics for combination therapy | In vitro and in vivo | 2021 | [148] |
Pre-loding, coincubation | AIE-photosensitizer MBPN-TCyP | Dendritic cells | Breast cancer and colorectal cancer | Synergistic photodynamic immunotherapy elicits dramatic anti-tumor immune responses | In vitro and in vivo | 2022 | [149] |
Pre-loding, coincuba-tion | MTX | Mouse hepatocarcinoma tumour cells H22 | Hepatocarcinoma | Inhibit ascites hepatocarcinoma growth without typical side effects | In vitro and in vivo | 2012 | [80] |
Pre-loding, coincubation | Cisplatin/PTX | Human ovarian cancer tumour cells A2780 | Ovarian cancer | Inhibit human ovarian cancer growth without affecting liver and kidney functions of SCID mice | In vitro and in vivo | 2012 | [80] |
Pre-loding, coincubation | MTX | Mouse fibroblast cells L929 | Glioblastoma | Facilitate extravasation across BBB and inhibit human brain tumor growth | In vitro and in vivo | 2018 | [150] |
Pre-loding, coincubation | MTX | Primary malignant cells that are frequently accompanied by malignant pleural effusion (MPE) in their advanced stages | Lung cancer and colon cancer with MPE | Exhibit clinical activity in killing tumor cells and TAMs and induce antitumor immune responses | In vitro and in vivo | 2019 | [152] |
Pre-loding, coincubation | ICG and PTX | HEK293T | Breast cancer | Increase the anticancer activity through combination of chemo/photothermal/photodynamic therapy | In vitro and in vivo | 2022 | [151] |
Pre-loding, coincubation | PTX | BM-MSCs (SR4987) | Pancreatic adenocarcinoma | Exhibit strong antiproliferative activity on human pancreatic adenocarcinoma cells CFPAC-1 | In vitro | 2014 | [78] |
Pre-loding, transfection | HGF siRNA | HEK293T | Gastric cancer | Suppress proliferation and migration of both cancer cells and vascular cells | In vitro and in vivo | 2018 | [154] |
Pre-loding, electroporat | PTX/miR-16/Penicillin/MCP-1/Cas9-GFP | Differentiated human promyelocytic leukemia cells (dHL-60) and naïve HL-60 | Breast cancer cells (MCF-7)/Colon cancer cells (COLO205)/Jurkat cells | Dhl60 exhibit increased drug loading and production efficiency | In vitro | 2012 | [209] |
Pre-loding, transduction and coincubation | TRAIL and Cabazitaxel (CTX) | MSCs | Oral squamous cell carcinoma | Synergistically inhibit the growth of cancer cells by inhibiting the activation of PI3K/Akt/mTOR pathway and inducing apoptosis | In vitro and in vivo | 2020 | [210] |
Pre-loding, transduction | miR-379 | MSCs | Breast cancer | Inhibit the growth of breast cancer by downregulating cyclooxygenase (COX-2) | In vitro and in vivo | 2017 | [211] |
Post-loding, coincubation | DOX | Brain endothelial cells | Brain cancer | Mediate drug delivery across the BBB and exert cytotoxic efficacy against brain cancer in zebrafish | In vitro and in vivo | 2015 | [158] |
Post-loding, coincubation | Curcumin | Bovine milk | Multiple cancers (breast, lung and cervical cancer) | Enhance antiproliferative activity against multiple cancer cell lines (breast, lung, and cervical cancer) and e cervical tumor xenograft | In vitro and in vivo | 2017 | [159] |
Post-loding, coincubation | Withaferin A (WFA)/Bilberry-derived anthocyanidins (Anthos)/Curcumin (Cur)/paclitaxel (PTX) and docetaxel (DOC) | Bovine milk | Lung cancer and breast cancer cells | Enhance anti-cancer and anti-inflammatory effects | In vitro | 2016 | [126] |
Post-loding, coincubation for Ce6/electroporation for siRNA | Ce6/PD-L1 siRNA | NK cells | Hepatocellular carcinoma and Colon cancer | Effectively inhibit cancer progression by effective PDT or restoring the immunological surveillance function | In vitro and in vivo | 2022 | [160] |
Post-loding, coincubation | Zinc Phthalocyanine | Metastatic murine melanoma cells (B16F10) | Colon cancer | Increase efficacy and selectivity of PDT | In vitro and in vivo | 2021 | [161] |
Post-loading, coincubation | Zinc Phthalocyanine | M1/M2-like macrophages/B16F10/Milk | Colon cancer | Increase photodynamic therapy and promote immunological memory | In vitro and in vivo | 2022 | [162] |
Post-loading, coincubation | DOX/Cholesterol-modified miRNA 159 | Human monocytes (THP-1) | Triple negative breast cancer (TNBC) | Co-delivering miR159 and Dox by targeted Exo for TNBC therapy | In vitro and in vivo | 2019 | [163] |
Post-loading, coincubation | Cholesterol-modified miRNA 34a | HEK293T | Oral squamous cell carcinoma | Inhibition of oral squamous carcinoma HN6 cell proliferation, migration, and invasion by down regulating SATB2 expression | In vitro | 2022 | [172] |
Post-loading, coincubation | DOX | RAW 264.7 cells pre-treated with hyaluronic acid (HA) and the β-blocker carvedilol (CV) | Breast cancer | Enhance the antitumor effects of DOX | In vitro and in vivo | 2022 | [164] |
Post-loading, coincubation | DOX/Chemosensitizer lonidamine (LND) | Non-small cell lung carcinoma A549 cells | Non-small cell lung carcinoma | Synergistically increase anticancer activity | In vitro and in vivo | 2022 | [165] |
Post-loading, calcium chloride transfection combined with heat shock/electroporation | miR-15a mimic/inhibitor | THP-1 cells | NA | Effectively enhance miRNA loading efficiency to EVs | In vitro | 2017 | [169] |
Post-loading, transfection | miR-335 | Human hepatic stellate cell LX2 | Hepatocellular carcinoma | Inhibit hepatocellular carcinoma growth | In vitro and in vivo | 2018 | [167] |
Post-loading, transfection | VEGF siRNA | Brain endothelial bEND.3 cells | Brain cancer | Mediate siRNA Delivery across the BBB to inhibit brain tumor growth | In vitro and in vivo | 2017 | [168] |
Post-loading, saponin | DOX | Human GBM cell line U87 and U251 cells | Glioblastoma | Eliminate the original cargos of glioblastoma cell-derived small EVs for efficient drug delivery | In vitro and in vivo | 2022 | [212] |
Post-loading, saponin/electroporation/extrusion/dialysis | Porphyrins | HMSCs/HUVECs/MDA-MB-231 cells | Breast cancer MDA-MB-231 cells | Induce a stronger phototoxic effect than free drug in a cancer cell model | In vitro | 2015 | [175] |
Post-loading, saponin/sonication/extrusion/freeze-thaw cycles | Catalase | Raw 264.7 | Neuronal cells PC12 | Exhibit high loading efficiency, sustained release, and catalase preservation against proteases degradation and provide significant neuroprotective effects | In vitro and in vivo | 2015 | [174] |
Post-loding, electroporation | DOX | HEK293F/B16F10 | Metastatic murine melanoma B16F10 cells | Optimized electroporation improves the loading of EVs with DOX | In vitro | 2022 | [179] |
Post-loding, electroporation | ASOs/Cas9 mRNA and gRNA | Red blood cells (RBCs) | Leukemia/breast cancer | Exhibit highly robust microRNA inhibition and CRISPR–Cas9 genome editing | In vitro and in vivo | 2018 | [122] |
Post-loding, electroporation for siRNA; Pre-loading, co-incubation for DOX | KRASG12D siRNA/DOX | Human umbilical cord mesenchymal stromal cells (UC-MSCs) | Pancreatic ductal adenocarcinoma (PDAC) | Co-delivery KRASG12D siRNA and DOX to PDAC cells to inhibit the cancer progression | In vitro | 2023 | [181] |
Post-loding, electroporation | ITGB6 siRNAs | Prostate cancer cells (DU145 and PC3) | Prostate cancer | Delivery of siRNAs targeting the ITGB6 to inhibit adhesion and migration of recipient prostate cancer cells | In vitro | 2022 | [180] |
Post-loding, sonication | HER2 siRNA | HEK293T/MCF-7 | Breast cancer | Knockdown of HER2, a therapeutic target that is overexpressed in numerous cancers | In vitro | 2016 | [185] |
Post-loding, soni-cation | DOX | RAW 264.7 | TNBC | Significantly inhibit TNBC tumor growth | In vitro and in vivo | 2020 | [97] |
Post-loding, sonication | PTX | RAW 264.7 macrophages | Lung cancer | Inhibit growth of pulmonary metastases and overcome MDR in Cancer cell | In vitro and in vivo | 2016 | [186] |
Post-loding, sonication | Erastin/Rose Bengal | HEK293T | Hepatocellular carcinoma | Induce obvious ferroptosis in HCC with minimized toxicity in liver and kidney | In vitro and in vivo | 2021 | [187] |
Post-loding, extrusion | PTX | Mesenchymal stem cells (MSCs) | Breast cancer | Exhibit therapeutically efficient for the treatment of breast cancer | In vitro and in vivo | 2018 | [193] |
Post-loding, extrusion for DOX/electroporation for P-gp siRNA | DOX/P-gp siRNA | Normal ovarian epithelial Iose80 cells | Ovary cancer | Target delivery of chemotherapeutics to overcome drug resistance of ovarian cancer | In vitro and in vivo | 2023 | [194] |
Post-loding, extrusion | DOX | HT1080/Hela | Fibrosarcoma | Tumor cell-derived exosomes preferentially targeted their cell of origin | In vitro and in vivo | 2020 | [195] |
Post-loding, freeze-thaw cycles | Liposome | Mouse fibroblast sarcoma-derived CMS7-wt/CMS7-HE (HER2 overexpression)/Raw 264.7 | HeLa cells | Develop hybrid exosomes by fusing the membranes of exosomes with liposomes for loading therapeutic agents into exosomes | In vitro | 2016 | [199] |
Post-loding, freeze-thaw cycles/extrusion,/sonication | DOX | Platelets | Breast cancer | Efficiently load DOX and kill breast cancer cells | In vitro | 2023 | [201] |
Post-loding, freeze-thaw cycles | Folate-modified Liposomes with or without PTX | Mesenchymal stem cells (MSCs) | Colon carcinoma cell line CT26/Mouse melanoma cell line B16/Human ovarian cancer cell line A2780 | Increase therapeutic potential of PTX for cancer therapy | In vitro and in vivo | 2024 | [202] |
Fused expression with tetraspanin CD63 | OVA | 293F cells | Immune cells | Significantly inhibit tumor growth by induce DNA vaccine-specific CD8+ T cell responses | In vitro and in vivo | 2017 | [206] |
Fused expression with CD9 (CIBN and CRY interaction system) | Proteins: mCherry/luciferase/Bax/super repressor IκB (srIκB)/Cre recombinase | HEK293T | HeLa cells/Rat embryonic primary neurons/Neuronal cells | Significantly increase intracellular levels of cargo proteins and their function in recipient cells | In vitro and in vivo | 2016 | [207] |
Fused expression with CD63 (FRB/FKBP heterodimerization system) | Proteins: Diphtheria toxin A (DTA) | DTA-resistant HT1080 cells | HT1080 cells | Efficient system enables to load any protein-based therapeutics into EVs | In vitro | 2023 | [208] |
4. Extracellular Vesicles Modification for Targeted Anti-Cancer Drug Delivery
4.1. Genetic Target Engineering
4.1.1. Genetic Target Engineering by Fusion Expression with LAMP-2B
4.1.2. Genetic Target Engineering by Fusion Expression with PDGFR TM Domain
4.1.3. Genetic Target Engineering by Fusion Expression with Lactadherin C1–C2 Domain
4.1.4. Genetic Target Engineering by Fusion Expression with the Tetraspanin Superfamily Proteins
4.1.5. Genetic Target Engineering by Fusion Expression with the CD47
4.1.6. Genetic Target Engineering by Fusion Expression with Glycosylphosphatidylinositol (GPI)-Anchor Signal Peptides
Targeting Ligand | Transmembrane Protein on EVs | Therapeutic Cargo | Cargo Loading Method | Cell Sources of EVs | Cancer Type and Targets | Function | Study Type | Year | Ref. |
---|---|---|---|---|---|---|---|---|---|
iRGD | LAMP-2B | DOX | Electroporation | immature dendritic cells | Breast cancer cells | Inhibit tumor growth without overt toxicity | In vitro and in vivo | 2014 | [99] |
iRGD | LAMP-2B | DOX; GAPDH siRNA | Electroporation; Transfection | HEK293FT | Glioblastoma cells | Increase the drug internalization via across BBB | In vitro | 2022 | [218] |
iRGD | LAMP-2B | KRAS siRNA | Transfection | HEK293T | Lung cancer cells | Target oncogenic KRAS | In vitro and in vivo | 2019 | [219] |
iRGD | LAMP-2B | CPT1A siRNA | Transfection | HEK293T | Colon cancer cells | Target silencing CPT1A to inhibit FAO; reverse oxaliplatin resistance and inhibit tumour growth | In vitro and in vivo | 2021 | [220] |
iRGD | LAMP-2B | BCL6 siRNA | Electroporation | immature dendritic cells | Diffuse large B-cell lymphoma cells (DLBCL) | Target silencing BLC6 to inhibit DLBCL tumor growth | In vitro and in vivo | 2022 | [221] |
iRGD | LAMP-2B | miR-484 | Electroporation | HEK293T | Ovarian cancer cells; tumor vascular endothelial cells | Inhibit angiogenesis and sensitize the cancer to chemotherapy | In vitro and in vivo | 2022 | [217] |
tLyP-1 | LAMP-2B | SOX2 siRNA | Electroporation | HEK293T | Lung cancer and cancer stem cells | Target silencing SOX2 expression of NSCLC cells and reducing the stemness of NSCLC stem cells | In vitro | 2020 | [224] |
fragment of Interleukin 3 | LAMP-2B | Imatinib; BCR-ABL siRNA | Direct incubation; Transfection | HEK293T | Chronic myeloid leukemia (CML) cells | Target delivery of Imatinib or BCR-ABL siRNA to CML cells | In vitro and in vivo | 2017 | [227] |
HER2-binding affibody zHER | LAMP-2B | 5-FU and miRNA-21 inhibitor | Electroporation | HEK293T | Her2 expressing colorectal cancer cells | Effectively reverse drug resistance and significantly enhanced the cytotoxicity in 5-FU-resistant colon cancer cells | In vitro and in vivo | 2020 | [183] |
HER2-specific DARPin | LAMP-2B | TPD52 siRNA | Electroporation | HEK293T | HER2-positive breast cancer cells | Target silencing the TPD52 of Her2 positive cancer cells | In vitro | 2019 | [155] |
HER2-specific DARPin | LAMP-2B | DOX | Electroporation | BM-MSCs | HER2-positive breast cancer cells | Specifically inhibit Her2 positive tumor growth | In vitro and in vivo | 2019 | [232] |
HER2-specific DARPin | LAMP-2B | 99mTc | Chemical modification | HEK293T | HER2-positive ovarian cancer cells | In vivo HER2-positive tumor imaging | In vitro and in vivo | 2020 | [233] |
GE11/EGF | PDGFR-TM | let-7a miRNA | Transfection | HEK293T | EGFR-positive breast cancer cells | Target delivery miRNAs to EGFR expressing cancer cells | In vitro and in vivo | 2013 | [237] |
αCD3/αEGFR | PDGFR-TM | αCD3/αEGFR | Transfection | Expi293F cells | T cell and EGFR-expressing breast cancer cells | Induce cross-linking of T cells and EGFR-expressing breast cancer cells and elicit potent antitumor immunity. | In vitro and in vivo | 2018 | [240] |
anti-HER2 scFv antibody (ML39) | Lactadherin C1-C2 domain | CNOB and HCHrR6 mRNA | Electroporation | HEK293 | HER2-overexpressing breast cancer cells | Delivery of functional exogenous mRNA to tumors | In vitro and in vivo | 2018 | [243] |
anti-HER2 scFvs with different affinity | Lactadherin C1-C2 domain | CFSE | Chemical modification | HEK293 | HER2-overexpressing cancer cells | Monitor the target delivery of antiHER2-scFvs modified exosomes | In vitro and in vivo | 2018 | [239] |
Two copies of the HER2 ligand | Lactadherin C1-C2 domain | HER2 miRNA | Transfection | HEK293 | HER2-overexpressing cancer cells | Specifically inhibit Her2 expressing tumor growth | In vitro and in vivo | 2020 | [244] |
Anti-EGFR nanobodies | GPI-anchor Signal peptides | CellTracker Deep Red | Chemical modification | Neuro2A | EGFR-overexpressing cancer cells | Specifically target EGFR expression cells | In vitro | 2016 | [256] |
Apo-A1 | CD63 | miRNA-26a | Electroporation | HEK293T | Hepatocellular Carcinoma (HepG2 | Inhibit tumor cell migration and proliferation | In vitro | 2018 | [252] |
CDX peptide/CREKA | CD47 | PTEN mRNA | Cellular nanoporation biochip (CNP) | bone marrow-derived dendritic cells (BMDCs) | PTEN-deficient human U87 and mouse GL216 glioblastoma cells | Specifically inhibit PTEN-deficient glioblastoma | In vitro and in vivo | 2019 | [253] |
4.2. Chemical Modification of Extracellular Vesicles
4.2.1. Click Chemistry Method for Direct Modification
4.2.2. Hydrophobic Insertion Mediated Modification
Targeting Ligand | Ligand Labeling Method | Therapeutic Cargo | Cargo Loading Method | Cell Sources of EVs | Cancer Type and Targets | Function | Study Type | Year | Ref. |
---|---|---|---|---|---|---|---|---|---|
RGE | Copper catalyzed click chemistry | Curcumin and SPION | Electroporation | Mouse macrophage cell line Raw264.7 | Glioma | Simultaneous target imaging and therapy of glioma | In vitro and in vivo | 2018 | [258] |
c(RGDyk) | Copper free click chemistry | Curcumin | Incubation | BM-MSCs | Integrin αvβ3 overexpressing cells (U87 glioblastoma cells and vascular endothelial cells) | Increase the drug internalization via across BBB and target delivery drugs to integrin αvβ3 overexpressing cells | In vitro | 2017 | [259] |
RGD | DSPE-PEG-RGD | V2C Quantum Dots | Electroporation | MCF-7 cells | Integrin αvβ3-poitive breast cancer MCF-7 cells | Target delivery photothermal agents to integrin expressing cells | In vitro and in vivo | 2019 | [261] |
Folic acid (FA) | DSPE-PEG-FA | Human hyaluronidase (PH20); DOX | Transfection; Electroporation | HEK293T | Folate receptor overexpressing cancer cells | Reduce hyaluronidase-induced metastasis and enhance target delivery of chemotherapy | In vitro and in vivo | 2021 | [262] |
Folic acid (FA) | DSPE-PEG-FA | Erastin | Sonication | Human fetal lung fibroblasts HFL-1 | Folate receptor overexpressing cancer cells | Induce ferroptosis of folate receptor overexpression TNBC cells | In vitro | 2019 | [207] |
Folic acid (FA) | DSPE-PEG-FA | DOX/P-gp siRNA | Extrusion; Electroporation | Normal ovarian epithelial Iose80 cells | Folate receptor overexpressing ovary cancer cells | Target delivery of chemotherapeutics to overcome drug resistance of ovarian can-cer | In vitro and in vivo | 2023 | [194] |
Aminoethylanisamide (AA) | DSPE-PEG-AA | PTX | Sonication | Mouse macrophage cell line Raw264.7 | Sigma receptor overexpressing lung cancer cells | Improve drug circulation and inhibit lung cancer metastases | In vitro and in vivo | 2017 | [263] |
AS1411 aptamer | Cholesterol-polypeptides | Let-7 miRNA/VEGF siRNA | Electroporation | BMDCs | Nucleolin overexpressing breast cancer cells | Target delivery siRNAs/miRNAs to nucleolin positive cancer cells | In vitro and in vivo | 2017 | [265] |
AS1411 aptamer | Cholesterol-PEG2000 | PTX | Sonication | BMDCs | Nucleolin overexpressing breast cancer cells | Target delivery paclitaxel to nucleolin positive cancer cells | In vitro and in vivo | 2018 | [115] |
PSMA RNA aptamer; EGFR RNA aptamer; Folic acid | Cholesterol-RNA nanoparticles | Survivin siRNA | Transfection | HEK293T | prostate cancer; breast cancer and colorectal cancer cells | Mediate RNA nanoparticles on EV memebrane | In vitro and in vivo | 2017 | [266] |
LDL peptide | ApoA-I mimetic peptide | methotrexate, KLA (Lys-Leu-Ala) | Co-incubation | Mouse fibroblast L929 cells | LDLR overexpressing glioblastoma cells | Target treatment of LDLR overexpressing glioblastoma cells | In vitro and in vivo | 2018 | [150] |
Aptamer sgc8 | Diacylipid-(PEG)2 | DOX | Electroporation | Immature dendritic cells (imDC) | Leukemia cells that overexpressed PTK7 | Target delivery of therapeutics to PTK7 overexpressing cancer cells | In vitro | 2019 | [259] |
5. Conclusion and Future Perspective
Author Contributions
Funding
Conflicts of Interest
References
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Wang, J.; Yin, B.; Lian, J.; Wang, X. Extracellular Vesicles as Drug Delivery System for Cancer Therapy. Pharmaceutics 2024, 16, 1029. https://doi.org/10.3390/pharmaceutics16081029
Wang J, Yin B, Lian J, Wang X. Extracellular Vesicles as Drug Delivery System for Cancer Therapy. Pharmaceutics. 2024; 16(8):1029. https://doi.org/10.3390/pharmaceutics16081029
Chicago/Turabian StyleWang, Jin, Bohang Yin, Jiabing Lian, and Xia Wang. 2024. "Extracellular Vesicles as Drug Delivery System for Cancer Therapy" Pharmaceutics 16, no. 8: 1029. https://doi.org/10.3390/pharmaceutics16081029
APA StyleWang, J., Yin, B., Lian, J., & Wang, X. (2024). Extracellular Vesicles as Drug Delivery System for Cancer Therapy. Pharmaceutics, 16(8), 1029. https://doi.org/10.3390/pharmaceutics16081029