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Development of exosome-mimetic nanovesicles as novel drug delivery systems

Development of exosome-mimetic nanovesicles as novel drug delivery systems
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Targeted delivery with drug delivery systems is a method of delivering therapeutic agents to specific disease regions rather than other parts of body for minimizing the adverse effects and for maximizing the therapeutic efficacy of therapeutic agents. For the targeted delivery of drugs, various types of the nano-sized delivery systems such as liposomes, nanoparticles, and polymeric particles have been developed with their own strengths. However, there are concerns in mass production, conjugation, and immunogenicity of delivery systems. Recently, exosomes, the endogenous nanocarriers that can deliver biological information between cells, were introduced as new kind of drug delivery system. Because of natural origin, exosomes have low immunogenicity and easily achieve the targeted delivery using cell-derived proteins. However, mammalian cells release relatively low quantities of exosomes and purification of exosomes is difficult. Here, bioinspired exosome-mimetic nanovesicles that deliver therapeutics to the target cells or organs including tumor tissue after systemic administration were developed. The therapeutics-loaded nanovesicles were produced by the breakdown of monocytes or macrophages using a serial extrusion through filters with diminishing pore sizes. These cell-derived nanovesicles have similar characteristics with the exosomes, but have 100-folds higher production yield. Furthermore, the nanovesicles have natural targeting ability of cells by maintaining the topology of plasma membrane proteins. Chemotherapeutic drug-loaded nanovesicles induced TNF-α-stimulated endothelial cell death in a dose-dependent manner in vitro, traffic to tumor tissue and reduce tumor growth without the adverse effects that observed with equipotent free drug in vivo. When compared with doxorubicin-loaded exosomes, doxorubicin-loaded nanovesicles showed similar in vivo anti-tumor activity. However, doxorubicin-loaded liposomes that did not carry targeting proteins were inefficient in reducing tumor growth. The nanovesicles also delivered the siRNA to the TNF-α-stimulated endothelial cell and inhibit the target mRNAs and proteins in vitro. In addition, chemotherapeutic drug-loaded nanovesicles were optimized by modulation of size and modification of surface with polyethylenglycol. These modification efficiently reduced the non-specific uptake and increased efficacy of chemotherapeutic drug-loaded nanovesicles. Taken together, these studies suggest that the bioengineered nanovesicles can serve as novel exosome-mimetics to deliver therapeutics effectively.
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