Exosomes and Exosome-Inspired Vesicles for Targeted Drug Delivery
Abstract
:1. Introduction
1.1. Definition, Biogenesis and Main Functions of Extracellular Vesicles (EVs) and Exosomes (EXs)
- (i)
- Apoptotic bodies are released during cell death (apoptosis) and are heterogeneously shaped vesicles with sizes between 50–5000 nm. They are formed from the plasma membrane, and they contain DNA, RNA, histones, and signalling molecules [22]. They usually have high amounts of phosphatidylserine (PS) in their membranes, since the outer membrane of apoptotic cells is enriched in PS.
- (ii)
- Micro vesicles are formed by blebbing of the cell membrane with concurrent incorporation of cytosolic proteins, and their sizes range between 20–1000 nm, depending on the origin cells and the method applied for their isolation from cell media [23]. Their formation can be triggered through Ca2+ influx, phorbol esters, ATP, etc. [24]. Some common biochemical characteristics have been identified between microvesicless from different cells, such as their high membrane levels of PS, and some common surface markers (CD40 ligands, integrins and selectins) [12].
- (iii)
- Finally, exosomes include a more homogeneous (in shape and size) population of vesicles compared to microvesicles, with sizes that range from 50 nm up to 120 nm. Their biogenesis is initiated by inward budding of the plasma membrane which results in the formation of intermediate endosome-vesicles, the multivesicular bodies (MVBs). After that, depending on their composition, MVBs are either degraded after fusion with lysosomes or they fused with the plasma membrane and form exosomess that are released from the cells [25,26,27,28]. Exosomes contain surface proteins unique to the endosomal pathway, which are generally used to characterize exosomes and distinguish them from microvesicles, apoptotic bodies, and other vesicles such as tetraspanin CD9, CD63, CD81 [29], heat shock proteins (Hsc70), lysosomal proteins (Lamp2b), the tumor-sensitive gene 101 (Tsg101), and fusion proteins (CD9, flotillin, and annexin) [30], and incorporate nucleic acids, cytosolic proteins, and receptors. Their lipid composition differs from other extracellular vesicle-types, since they are rich in cholesterol and diacylglycerol. Exosomes are generally considered as transporters of miRNA that regulate specific intracellular mRNA activity [31].
1.2. Current Bottlenecks in Nanoparticle-Assisted Targeted Drug Delivery and Liposomes
2. Similarities and Differences between Exosomes and Liposomes
3. Sources, Methods of Isolation and In Vivo Clearance of Unmodified Exosomes
3.1. Sources of Exosomes
3.2. Isolation Methods
3.2.1. Ultracentrifugation
3.2.2. Immunoaffinity
3.2.3. Other Size-Based Isolation Methods
3.2.4. Precipitation
3.2.5. Yield of Common Isolation Methodologies
3.2.6. Microfluidic Methods for EX/EV Purification
3.3. In Vivo Clearance of Unmodified Exosomes
4. Types of Systems
- The efficient loading of drugs and/or
- Surface-modification/attachment of molecules on their surfaces; such modifications may be required when the in vivo fate (stability and/or pharmacokinetic/biodistribution profile) of the exosomes is not considered to be adequate for the planned drug delivery and/or targeting application. In fact, as analyzed above, in most cases, the clearance of unmodified exosomes after their in vivo administration (especially if iv-injection is used) is rapid, posing a problem for their applicability as targeted drug carriers.
- Artificial Exosome-mimetics, when the starting material is of synthetic or semi-synthetic origin (this category also includes lipids extracted from natural sources, such as cells or extracellular vesicless). In most cases, artificial exosome-mimetics are actually liposomes with or without specific proteins in their membrane (which are inspired from specific types of exosomes with high organotropism).
- Physical-origin exosome-mimetics, when the starting material may be derived from other types of cellular components excluding extracellular vesicles, such as whole cells (in this case the vesicles are names “cellular vesicles”). In this subcategory, again, the starting material is engineered as mentioned above for engineered-exosomes, and the same methodologies apply.
4.1. Engineered-Exosomes or Extracellular Vesicles
4.2. Exosome (or Extracellular Vesicle)-Mimetics
4.2.1. Artificial Extracellular Vesicle-Mimetics
4.2.2. Physical-Origin Extracellular Vesicle-Mimetics
4.2.3. Other Types of Extracellular Vesicle-Mimetic Systems
5. Methods of Preparation and Engineering of Engineered Exosomes and Exosome-Mimetics
5.1. Drug Loading Methodologies
5.1.1. Pre-Loading Methods
Treatment of Parental Cells with Drugs
Parental Cell Engineering
5.1.2. Post-Loading Methods
Incubation with Drug
Electroporation
Sonication
Extrusion
Freeze/Thaw Cycle Method
Saponin-Assisted Loading
5.1.3. Comparison of Different Loading Methods
5.2. Surface Modification Methods
5.3. Microfluidic Methods for Engineering of Exosomes and Exosome-Mimetics
6. Potential Clinical Applications of EXs and EXs-Mimetics
6.1. Current Status
6.2. Challenges and Future Perspectives
Acknowledgments
Conflicts of Interest
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Method | Advantages | Disadvantages | Drug Loaded/Application |
---|---|---|---|
Treatment of parental cells with drug | Relatively simple Does not require addition of drug into the system | Low loading efficiency Drugs may be cytotoxic to cells | Paclitaxel (Ptx) [104] Hydrophobic sensitizers (model drug) [141] |
Incubation with drug | Simplest method Do not require extra equipement | Low loading efficiency | Curcumin [92,107]; si RNAs [116]; Porphyrins [111]; Catalase [108]; PTX [105]; DOX [129] |
Electroporation | Loading with large molecules possible | Disrupts EX integrity siRNA aggregation Low loading efficiency (hydrophobic drugs) | siRNA [112,114]; Porphyrins [111]; DOX [109]; Dextran macromolecules [110]; PTX [105] |
Sonication | Increased loading efficiency (compared to other methods) Applicable for small RNAs | Potential deformation of membrane Not efficient for hydrophobic drugs | PTX [105]; Catalase [108]; siRNA, miRNA, ssDNA [114,149] |
Extrusion | High drug loading efficiency | Potential deformation of membrane | Porphyrins [111]; Catalase [108] |
Freeze/thaw method | Medium loading Fusion of membranes possible [54] | Exosomes may aggregate Low loading Efficiency | Catalase [108]; DOX [129] |
Saponin-assisted loading | High drug loading, compared to the other methods used in early reports | Generates pores in EXs Haemolysis/Toxicity concerns [150] Saponin conc. Control & Washing required | Catalase [108]; Porphyrins [111]; DOX [129] |
Status | Study Title | Conditions | Interventions | Phase | NCT Number |
---|---|---|---|---|---|
Not yet recruiting | Allogenic Mesenchymal Stem Cell Derived Exosome in Patients With Acute Ischemic Stroke | Cerebrovascular Disorders | Biological: exosome | Phase 1 Phase 2 | 03384433 |
Enrolling by invitation | Effect of Plasma Derived Exosomes on Cutaneous Wound Healing | Ulcer | Other: plasma-derived exosomes | Early Phase 1 | 02565264 |
Active, not recruiting | Study Investigating the Ability of Plant Exosomes to Deliver Curcumin to Normal and Colon Cancer Tissue | Colon Cancer | curcumin Curcumin conjugated with plant exosomes | Phase 1 | 01294072 |
Recruiting | Dendritic Cells-Derived Exosomes in Human Sepsis | Sepsis | Drug: Antibiotics | 02957279 | |
Not yet recruiting | Plant Exosomes and Patients Diagnosed With Polycystic Ovary Syndrome (PCOS) 17 | Polycystic Ovary Syndrome | Ginger exosomes Aloe exosomes Placebo | Not Applicable | 03493984 |
Unknown | Effect of Microvesicles and Exosomes Therapy on β-cell Mass in Type I Diabetes Mellitus (T1DM) | Diabetes Mellitus Type 1 | Biological: MSC exosomes. | Phase 2 Phase 3 | 02138331 |
Not yet recruiting | iExosomes in Treating Participants With Metastatic Pancreas Cancer With KrasG12D Mutation | KRAS NP_004976.2:p.G12D Metastatic Pancreatic Adenocarcinoma | Drug: Mesenchymal Stromal Cells-derived Exosomes with KRAS G12D siRNA | Phase 1 | 03608631 |
Recruiting | MSC-Exos Promote Healing of MHs | Macular Holes | Biological: exosomes derived from mesenchymal stem cells (MSC-Exo) | Early Phase 1 | 03437759 |
Active, not recruiting | Edible Plant Exosome Ability to Prevent Oral Mucositis Associated With Chemoradiation Treatment of Head and Neck Cancer | Head and Neck Cancer Oral Mucositis | Dietary Supplement: Grape extract Drug: Lortab, Fentanyl patch, mouthwash | Phase 1 | 01668849 |
Completed | Trial of a Vaccination With Tumor Antigen-loaded Dendritic Cell-derived Exosomes | Non Small Cell Lung Cancer | Biological: Dex2 | Phase 2 | 01159288 |
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Antimisiaris, S.G.; Mourtas, S.; Marazioti, A. Exosomes and Exosome-Inspired Vesicles for Targeted Drug Delivery. Pharmaceutics 2018, 10, 218. https://doi.org/10.3390/pharmaceutics10040218
Antimisiaris SG, Mourtas S, Marazioti A. Exosomes and Exosome-Inspired Vesicles for Targeted Drug Delivery. Pharmaceutics. 2018; 10(4):218. https://doi.org/10.3390/pharmaceutics10040218
Chicago/Turabian StyleAntimisiaris, Sophia G., Spyridon Mourtas, and Antonia Marazioti. 2018. "Exosomes and Exosome-Inspired Vesicles for Targeted Drug Delivery" Pharmaceutics 10, no. 4: 218. https://doi.org/10.3390/pharmaceutics10040218