Abstract
Recently, exosomes have been emerged as promising drug delivery carriers, while certain tissues are intrinsically resistant to exosomes. Therapeutically improving the drug delivery efficiency in these tissues/organs would certainly broaden the potential application of exosomes in future. Ultrasound-targeted microbubble destruction (UTMD) is a promising technique for non-invasive, targeted drug delivery. In this study, we explore the possibility that UTMD assists exosome delivery in these intrinsically resistant tissues. Mice were subjected to tail vein injection of DiR-labeled exosomes together with/without UTMD of SonoVueTM, followed by in vivo and ex vivo tracking of the exosomes. As expected, heart, adipose tissue, and skeletal muscle were found reluctant to exosomes from different origins. Targeted destruction of the ultrasound microbubbles (SonoVueTM) in the heart and adipose tissue region significantly increased the exosome infiltration and endocytosis there, as revealed by fluorescence imaging and confocal laser scanning microscope (CLSM). UTMD treatment 1 h prior to exosome injection failed to facilitate the exosome endocytosis in the targeted region, indicating that the transient promoting effects of UTMD. Moreover, increases of UTMD (numerous pulses) did not linearly enhance the exosome delivery. Together, our study here has established a novel strategy for targeted delivery of exosomes in the reluctant tissues, by combining the advantages of ultrasound microbubbles and exosomes in drug delivery.
Highlights
In the medicine field, gene therapy is the therapeutic delivery of nucleic acid into a patient’s cells as a drug to treat disease
Mice were anesthetized with 2% isoflurane, and 100 mL SonoVueTM microbubble solution was infused into the tail vein slowly
Our study here revealed that the clinically available diagnostic microbubble SonoVueTM significantly increased the endocytosis of exosomes in the refractory heart and adipose tissues
Summary
Gene therapy is the therapeutic delivery of nucleic acid into a patient’s cells as a drug to treat disease. One of the biggest hurdles of gene therapy is the challenge to non-invasively and locally deliver the gene drugs (Haussecker, 2014). Exosomes, which are cell-derived vesicles of 30–150 nm in diameter, are emerging as a promising drug carrier (Contreras-Naranjo et al, 2017). The nucleic acids of interest could be either loaded by electroporation in the isolated exosomes or encapsulated during exosome biogenesis in the donor cells (Alvarez-Erviti et al, 2011; Barile & Vassalli, 2017). Increasing the exosomes delivery rate in these intrinsically refractory organs would certainly broaden the putative application of exosomes
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