High-quality milk exosomes as oral drug delivery system
Section snippets
Origin and characteristics of exosomes
Exosomes are nano-sized (30–150 nm diameter) extracellular vesicles (EVs) secreted by cells due to environmental stimulation or self-activation [1]. Their membranes have a lipid bilayer structure, and they usually appear as round or cup-shaped under the transmission electron microscope [2,3], as shown in Fig. 1. The shape of the MEs (Fig. 1B) observed by our group under the transmission electron microscope is similar to that of the exosomes reported (Fig. 1A). Exosomes were first found in sheep
Separation and purification of exosomes
Compared with the exosomes secreted by cells in other general studies, milk contains a lot of exosomes. However, milk also contains a large amount of free protein and fat, which affects the extraction, separation and purification of MEs. Impurities such as fat, cell debris and most of the free protein must be removed during the purification of MEs. The purification methods for MEs are similar to the conventional exosome purification methods, and they include differential centrifugation,
Methods for loading drugs into exosomes
As shown in Fig. 6, various methods are utilized for the loading of cargos into exosomes, such as co-incubation, electroporation, sonication, lipofectamine, CaCl2, etc [24,[77], [78], [79], [80]]. The simplest method for drug loading is co-incubation. By passive diffusion, hydrophobic drugs are loaded by co-incubation. Drugs such as paclitaxel, curcumin, withaferin A and docetaxel can be loaded into exosomes via co-incubation in an appropriate buffer. However, co-incubation may lead to the low
Milk-derived exosomes as natural oral drug delivery system
Nanocarriers based on exosomes have three main advantages in drug delivery. 1) The exosomal membrane is comprised of a bilayer of phospholipids, which protects the contents of the exosome from degradation [11,84,85]. 2) The surface of exosomes is studded with transmembrane proteins (CD9, CD63, CD81, etc.) and membrane-bound proteins, which can effectively prolong the circulation time of exosomes in the blood and promote the tissue-targeted delivery of drugs [26,[86], [87], [88], [89], [90], [91]
Bioavailability, biocompatibility and immunogenicity of milk exosomes-based drug delivery system
Oral administration is the preferred route of administration, but the challenge of oral administration is huge. Because of the harsh environment of the gastrointestinal tract, it is difficult for drugs to be completely absorbed by the human body through the wall of the gastrointestinal tract. Therefore, the bioavailability following oral administration is very low [126]. For many years, explorations have been carried out to apply functionalized nanodrug delivery systems to improve drug
The bottleneck in the industrial production of milk exosomes
The industrialization (scale, purity, cost, consistency and standardization) of milk exosome production, like all other exosomes, is currently a major challenge. Besides, MEs may be heterogeneous. The exosomes obtained from different stages in the lifecycle of the same cow, or from different species of cow, may have different characteristics.
Another important issue is the lack of a uniform, standardized separation and purification method. The demands of industrial production are quite different
Declaration of competing interest
The authors have declared that no competing interest exists.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (NSFC) key projects (grant no. 31630027 and 32030060), NSFC International Collaboration key project (grant no. 51861135103) and NSFC-German Research Foundation (DFG) project (grant no. 31761133013). The authors also appreciate the support by “the Beijing-Tianjin-Hebei Basic Research Cooperation Project” (19JCZDJC64100), the National Key Research & Development Program of China (grant no. 2018YFE0117800), and the
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