Delivery Efficacy Differences of Intravenous and Intraperitoneal Injection of Exosomes: Perspectives from Tracking Dye Labeled and MiRNA Encapsulated Exosomes

Author(s): Xueying Zhou, Zhelong Li, Wenqi Sun, Guodong Yang, Changyang Xing*, Lijun Yuan*

Journal Name: Current Drug Delivery

Volume 17 , Issue 3 , 2020

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Exosomes are cell-derived nanovesicles that play vital roles in intercellular communication. Recently, exosomes are recognized as promising drug delivery vehicles. Up till now, how the in vivo distribution of exosomes is affected by different administration routes has not been fully understood.

Methods: In the present study, in vivo distribution of exosomes following intravenous and intraperitoneal injection approaches was systemically analyzed by tracking the fluorescence-labeled exosomes and qPCR analysis of C. elegans specific miRNA abundance delivered by exosomes in different organs.

Results: The results showed that exosomes administered through tail vein were mostly taken up by the liver, spleen and lungs while exosomes injected intraperitoneally were more dispersedly distributed. Besides the liver, spleen, and lungs, intraperitoneal injection effectively delivered exosomes into the visceral adipose tissue, making it a promising strategy for obesity therapy. Moreover, the results from fluorescence tracking and qPCR were slightly different, which could be explained by systemic errors.

Conclusion: Together, our study reveals that different administration routes cause a significant differential in vivo distribution of exosomes, suggesting that optimization of the delivery route is prerequisite to obtain rational delivery efficiency in detailed organs.

Keywords: Exosomes, in vivo delivery, administration route, efficiency, intraperitoneal injection, intravenous injection.

[1]
Mathieu, M.; Martin-Jaular, L.; Lavieu, G.; Théry, C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat. Cell Biol., 2019, 21(1), 9-17.
[http://dx.doi.org/10.1038/s41556-018-0250-9] [PMID: 30602770]
[2]
Anel, A.; Gallego-Lleyda, A.; de Miguel, D.; Naval, J.; Martínez-Lostao, L. Role of exosomes in the regulation of T-cell mediated immune responses and in autoimmune disease. Cells, 2019, 8(2)E154
[http://dx.doi.org/10.3390/cells8020154] [PMID: 30759880]
[3]
Chan, B.D.; Wong, W.Y.; Lee, M.M.; Cho, W.C.; Yee, B.K.; Kwan, Y.W.; Tai, W.C. Exosomes in inflammation and inflammatory disease. Proteomics, 2019, 19(8)e1800149
[http://dx.doi.org/10.1002/pmic.201800149] [PMID: 30758141]
[4]
Li, G.; Liu, H.; Ma, C.; Chen, Y.; Wang, J.; Yang, Y. Exosomes are the novel players involved in the beneficial effects of exercise on type 2 diabetes. J. Cell. Physiol., 2019. Epub ahead of print
[http://dx.doi.org/10.1002/jcp.28319] [PMID: 30756380]
[5]
Barile, L.; Moccetti, T.; Marbán, E.; Vassalli, G. Roles of exosomes in cardioprotection. Eur. Heart J., 2017, 38(18), 1372-1379.
[PMID: 27443883]
[6]
Vilaça-Faria, H.; Salgado, A.J.; Teixeira, F.G. Mesenchymal stem cells-derived exosomes: A new possible therapeutic strategy for parkinson’s disease? Cells, 2019, 8(2)E118
[http://dx.doi.org/10.3390/cells8020118] [PMID: 30717429]
[7]
Budnik, V.; Ruiz-Cañada, C.; Wendler, F. Extracellular vesicles round off communication in the nervous system. Nat. Rev. Neurosci., 2016, 17(3), 160-172.
[http://dx.doi.org/10.1038/nrn.2015.29] [PMID: 26891626]
[8]
Becker, A.; Thakur, B.K.; Weiss, J.M.; Kim, H.S.; Peinado, H.; Lyden, D. Extracellular vesicles in cancer: Cell-to-cell mediators of metastasis. Cancer Cell, 2016, 30(6), 836-848.
[http://dx.doi.org/10.1016/j.ccell.2016.10.009] [PMID: 27960084]
[9]
Sun, X.; Shan, A.; Wei, Z.; Xu, B. Intravenous mesenchymal stem cell-derived exosomes ameliorate myocardial inflammation in the dilated cardiomyopathy. Biochem. Biophys. Res. Commun., 2018, 503(4), 2611-2618.
[http://dx.doi.org/10.1016/j.bbrc.2018.08.012] [PMID: 30126637]
[10]
Sun, Y.; Shi, H.; Yin, S.; Ji, C.; Zhang, X.; Zhang, B.; Wu, P.; Shi, Y.; Mao, F.; Yan, Y.; Xu, W.; Qian, H. Human mesenchymal stem cell derived exosomes alleviate type 2 diabetes mellitus by reversing peripheral insulin resistance and relieving β-cell destruction. ACS Nano, 2018, 12(8), 7613-7628.
[http://dx.doi.org/10.1021/acsnano.7b07643] [PMID: 30052036]
[11]
Lapchak, P.A.; Boitano, P.D.; de Couto, G.; Marbán, E. Intravenous xenogeneic human cardiosphere-derived cell extracellular vesicles (exosomes) improves behavioral function in small-clot embolized rabbits. Exp. Neurol., 2018, 307, 109-117.
[http://dx.doi.org/10.1016/j.expneurol.2018.06.007] [PMID: 29908146]
[12]
Braun, R.K.; Chetty, C.; Balasubramaniam, V.; Centanni, R.; Haraldsdottir, K.; Hematti, P.; Eldridge, M.W. Intraperitoneal injection of MSC-derived exosomes prevent experimental bronchopulmonary dysplasia. Biochem. Biophys. Res. Commun., 2018, 503(4), 2653-2658.
[http://dx.doi.org/10.1016/j.bbrc.2018.08.019] [PMID: 30093115]
[13]
Rager, T.M.; Olson, J.K.; Zhou, Y.; Wang, Y.; Besner, G.E. Exosomes secreted from bone marrow-derived mesenchymal stem cells protect the intestines from experimental necrotizing enterocolitis. J. Pediatr. Surg., 2016, 51(6), 942-947.
[http://dx.doi.org/10.1016/j.jpedsurg.2016.02.061] [PMID: 27015901]
[14]
Zhao, H.; Shang, Q.; Pan, Z.; Bai, Y.; Li, Z.; Zhang, H.; Zhang, Q.; Guo, C.; Zhang, L.; Wang, Q. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and beiging in white adipose tissue. Diabetes, 2018, 67(2), 235-247.
[http://dx.doi.org/10.2337/db17-0356] [PMID: 29133512]
[15]
Li, Z.; Zhou, X.; Wei, M.; Gao, X.; Zhao, L.; Shi, R.; Sun, W.; Duan, Y.; Yang, G.; Yuan, L. In vitro and in vivo RNA inhibition by CD9-HuR functionalized exosomes encapsulated with miRNA or CRISPR/dCas9. Nano Lett., 2019, 19(1), 19-28.
[PMID: 30517011]
[16]
Wiklander, O.P.; Nordin, J.Z.; O’Loughlin, A.; Gustafsson, Y.; Corso, G.; Mäger, I.; Vader, P.; Lee, Y.; Sork, H.; Seow, Y.; Heldring, N.; Alvarez-Erviti, L.; Smith, C.I.; Le Blanc, K.; Macchiarini, P.; Jungebluth, P.; Wood, M.J.; Andaloussi, S.E. Extracellular vesicle in vivo biodistribution is determined by cell source, route of administration and targeting. J. Extracell. Vesicles, 2015, 4, 26316.
[http://dx.doi.org/10.3402/jev.v4.26316] [PMID: 25899407]
[17]
Deng, G.; Qu, J.; Zhang, Y.; Che, X.; Cheng, Y.; Fan, Y.; Zhang, S.; Na, D.; Liu, Y.; Qu, X. Gastric cancer-derived exosomes promote peritoneal metastasis by destroying the mesothelial barrier. FEBS Lett., 2017, 591(14), 2167-2179.
[http://dx.doi.org/10.1002/1873-3468.12722] [PMID: 28643334]
[18]
Shandilya, S.; Rani, P.; Onteru, S.K.; Singh, D. Small interfering RNA in milk exosomes is resistant to digestion and crosses the intestinal barrier in vitro. J. Agric. Food Chem., 2017, 65(43), 9506-9513.
[http://dx.doi.org/10.1021/acs.jafc.7b03123] [PMID: 28967249]
[19]
Yang, T.; Martin, P.; Fogarty, B.; Brown, A.; Schurman, K.; Phipps, R.; Yin, V.P.; Lockman, P.; Bai, S. Exosome delivered anticancer drugs across the blood-brain barrier for brain cancer therapy in Danio rerio. Pharm. Res., 2015, 32(6), 2003-2014.
[http://dx.doi.org/10.1007/s11095-014-1593-y] [PMID: 25609010]
[20]
Shi, R.; Zhao, L.; Cai, W.; Wei, M.; Zhou, X.; Yang, G.; Yuan, L. Maternal exosomes in diabetes contribute to the cardiac development deficiency. Biochem. Biophys. Res. Commun., 2017, 483(1), 602-608.
[http://dx.doi.org/10.1016/j.bbrc.2016.12.097] [PMID: 27998767]
[21]
Coscia, C.; Parolini, I.; Sanchez, M.; Biffoni, M.; Boussadia, Z.; Zanetti, C.; Fiani, M.L.; Sargiacomo, M. Generation, quantification, and tracing of metabolically labeled fluorescent exosomes. Methods Mol. Biol., 2016, 1448, 217-235.
[http://dx.doi.org/10.1007/978-1-4939-3753-0_16] [PMID: 27317184]
[22]
Pomatto, M.A.C.; Bussolati, B.; D’Antico, S.; Ghiotto, S.; Tetta, C.; Brizzi, M.F.; Camussi, G. Improved loading of plasma-derived extracellular vesicles to encapsulate antitumor miRNAs. Mol. Ther. Methods Clin. Dev., 2019, 13, 133-144.
[http://dx.doi.org/10.1016/j.omtm.2019.01.001] [PMID: 30788382]
[23]
Gangadaran, P.; Hong, C.M.; Ahn, B.C. An update on in vivo imaging of extracellular vesicles as drug delivery vehicles. Front. Pharmacol., 2018, 9, 169.
[http://dx.doi.org/10.3389/fphar.2018.00169] [PMID: 29541030]
[24]
Gangadaran, P.; Hong, C.M.; Ahn, B.C. Current perspectives on in vivo noninvasive tracking of extracellular vesicles with molecular imaging. BioMed Res. Int., 2017, 20179158319
[http://dx.doi.org/10.1155/2017/9158319] [PMID: 28246609]
[25]
Di Rocco, G.; Baldari, S.; Toietta, G. Towards therapeutic delivery of extracellular vesicles: Strategies for in vivo tracking and biodistribution analysis. Stem Cells Int., 2016, 20165029619
[http://dx.doi.org/10.1155/2016/5029619] [PMID: 27994623]
[26]
Lai, C.P.; Mardini, O.; Ericsson, M.; Prabhakar, S.; Maguire, C.; Chen, J.W.; Tannous, B.A.; Breakefield, X.O. Dynamic biodistribution of extracellular vesicles in vivo using a multimodal imaging reporter. ACS Nano, 2014, 8(1), 483-494.
[http://dx.doi.org/10.1021/nn404945r] [PMID: 24383518]
[27]
Watson, D.C.; Bayik, D.; Srivatsan, A.; Bergamaschi, C.; Valentin, A.; Niu, G.; Bear, J.; Monninger, M.; Sun, M.; Morales-Kastresana, A.; Jones, J.C.; Felber, B.K.; Chen, X.; Gursel, I.; Pavlakis, G.N. Efficient production and enhanced tumor delivery of engineered extracellular vesicles. Biomaterials, 2016, 105, 195-205.
[http://dx.doi.org/10.1016/j.biomaterials.2016.07.003] [PMID: 27522254]
[28]
Grange, C.; Tapparo, M.; Bruno, S.; Chatterjee, D.; Quesenberry, P.J.; Tetta, C.; Camussi, G. Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging. Int. J. Mol. Med., 2014, 33(5), 1055-1063.
[http://dx.doi.org/10.3892/ijmm.2014.1663] [PMID: 24573178]
[29]
Sun, W.; Li, Z.; Zhou, X.; Yang, G.; Yuan, L. Efficient exosome delivery in refractory tissues assisted by ultrasound-targeted microbubble destruction. Drug Deliv., 2019, 26(1), 45-50.
[http://dx.doi.org/10.1080/10717544.2018.1534898] [PMID: 30744440]
[30]
Smyth, T.; Kullberg, M.; Malik, N.; Smith-Jones, P.; Graner, M.W.; Anchordoquy, T.J. Biodistribution and delivery efficiency of unmodified tumor-derived exosomes. J. Control. Release, 2015, 199, 145-155.
[31]
Thomou, T.; Mori, M.A.; Dreyfuss, J.M.; Konishi, M.; Sakaguchi, M.; Wolfrum, C.; Rao, T.N.; Winnay, J.N.; Garcia-Martin, R.; Grinspoon, S.K.; Gorden, P.; Kahn, C.R. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature, 2017, 542(7642), 450-455.
[http://dx.doi.org/10.1038/nature21365] [PMID: 28199304]
[32]
Sun, D.; Zhuang, X.; Xiang, X.; Liu, Y.; Zhang, S.; Liu, C.; Barnes, S.; Grizzle, W.; Miller, D.; Zhang, H.G. A novel nanoparticle drug delivery system: the anti-inflammatory activity of curcumin is enhanced when encapsulated in exosomes. Mol. Ther., 2010, 18(9), 1606-1614.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 17
ISSUE: 3
Year: 2020
Page: [186 - 194]
Pages: 9
DOI: 10.2174/1567201817666200122163251
Price: $65

Article Metrics

PDF: 32
HTML: 2