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Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Research Article

Construction and Evaluation of Liraglutide Delivery System based on Milk Exosomes: A New Idea for Oral Peptide Delivery

Author(s): Yanan Shi*, Shiqi Guo, Yanzi Liang, Lanze Liu, Aiping Wang, Kaoxiang Sun and Youxin Li*

Volume 23, Issue 8, 2022

Published on: 20 August, 2021

Page: [1072 - 1079] Pages: 8

DOI: 10.2174/1389201022666210820114236

Price: $65

Abstract

Background: Increasing the bioavailability of peptide or protein drugs have always been an important topic in the field of pharmacy. Milk exosomes as a carrier for oral drug delivery systems have begun to attract attention in recent years. The application of oral milk exosomes carriers to peptide drugs, such as liraglutide, is worth trying.

Objectives: Milk-derived exosomes are used in this study to try to encapsulate the GLP-1 receptor agonist liraglutide and the feasibility of using this drug delivery system for oral biomolecules delivery in the future is explored.

Methods: The size and morphology of milk exosomes were characterized. The gastrointestinal stability of milk exosomes was evaluated in a dialysis bag. The cellular uptake of milk exosomes in the intestinal cells was observed. Six drug loading methods have been evaluated and compared preliminarily and they are incubation method, sonication method, extrusion method, freeze-thaw cycles method, saponin-assisted method and electroporation method.

Results: As demonstrated in this study, milk exosomes showed significant stability in the gastrointestinal environment and excellent affinity with intestinal cells, indicating their unique benefits used for drug oral delivery. Effective drug loading method for exosomes is challenging. Among the six drug loading methods used in this study, the liraglutide-Exo prepared by the extrusion method obtained the largest drug load, which was 2.45 times the direct incubation method. The liraglutide-Exo obtained by the freeze-thaw cycles method has the smallest morphological change.

Conclusion: The study showed that milk exosome-based oral drug delivery systems are promising.

Keywords: Milk exosomes, liraglutide, oral delivery system, nanovesicle, peptide-carrying exosomes, dialysis bag.

Graphical Abstract
[1]
Pan, Bin Tao Johnstone, R. M. J. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: Selective externalization of the receptor. Cell, 1983, 33(3), 967-978.
[2]
Haney, M.J.; Klyachko, N.L.; Zhao, Y.; Gupta, R.; Plotnikova, E.G.; He, Z.; Patel, T.; Piroyan, A.; Sokolsky, M.; Kabanov, A.V.; Batrakova, E.V. Exosomes as drug delivery vehicles for Parkinson’s disease therapy. J. Control. Release, 2015, 207, 18-30.
[http://dx.doi.org/10.1016/j.jconrel.2015.03.033] [PMID: 25836593]
[3]
Johnstone, R.M. The jeanne manery-fisher memorial lecture 1991. Maturation of reticulocytes: Formation of exosomes as a mechanism for shedding membrane proteins. Biochem. Cell Biol., 1992, 70(3-4), 179-190.
[http://dx.doi.org/10.1139/o92-028] [PMID: 1515120]
[4]
Harding, C.; Stahl, P. Transferrin recycling in reticulocytes: pH and iron are important determinants of ligand binding and processing. Biochem. Biophys. Res. Commun., 1983, 113(2), 650-658.
[5]
Yang, Z.; Xie, J.; Zhu, J.; Kang, C.; Chiang, C.; Wang, X.; Wang, X.; Kuang, T.; Chen, F.; Chen, Z.; Zhang, A.; Yu, B.; Lee, R.J.; Teng, L.; Lee, L.J. Functional exosome-mimic for delivery of siRNA to cancer: In vitro and in vivo evaluation. J. Control. Release, 2016, 243, 160-171.
[http://dx.doi.org/10.1016/j.jconrel.2016.10.008] [PMID: 27742443]
[6]
Théry, C.; Ostrowski, M.; Segura, E. Membrane vesicles as conveyors of immune responses. Nat. Rev. Immunol., 2009, 9(8), 581-593.
[http://dx.doi.org/10.1038/nri2567] [PMID: 19498381]
[7]
Kim, M.S.; Haney, M.J.; Zhao, Y.; Yuan, D.; Deygen, I.; Klyachko, N.L.; Kabanov, A.V.; Batrakova, E.V. Engineering macrophage-derived exosomes for targeted paclitaxel delivery to pulmonary metastases: In vitro and in vivo evaluations. Nanomedicine (Lond.), 2018, 14(1), 195-204.
[http://dx.doi.org/10.1016/j.nano.2017.09.011] [PMID: 28982587]
[8]
Ha, D.; Yang, N.; Nadithe, V. Exosomes as therapeutic drug carriers and delivery vehicles across biological membranes: Current perspectives and future challenges. Acta Pharm. Sin. B, 2016, 6(4), 287-296.
[http://dx.doi.org/10.1016/j.apsb.2016.02.001] [PMID: 27471669]
[9]
Vashisht, M.; Rani, P.; Onteru, S.K.; Singh, D. Curcumin Encapsulated in Milk exosomes resists human digestion and possesses enhanced intestinal permeability in vitro. Appl. Biochem. Biotechnol., 2017, 183(3), 993-1007.
[http://dx.doi.org/10.1007/s12010-017-2478-4] [PMID: 28466459]
[10]
Wang; Li, DeWei; Wang, YanHuan; Li, MengLu; Fang, XingTang; Chen, Hong; Zhang, ChunLei The landscape of circular RNAs and mRNAs in bovine milk exosomes. J. Food Compos. Anal., 2019, 76, 33-38.
[11]
de la Torre Gomez, C.; Goreham, R.V.; Bech Serra, J.J.; Nann, T.; Kussmann, M. “Exosomics”-a review of biophysics, biology and biochemistry of exosomes with a focus on human breast milk. Front. Genet., 2018, 9, 92.
[http://dx.doi.org/10.3389/fgene.2018.00092] [PMID: 29636770]
[12]
Aqil, F.; Munagala, R.; Jeyabalan, J.; Agrawal, A.K.; Kyakulaga, A.H.; Wilcher, S.A.; Gupta, R.C. Milk exosomes - Natural nanoparticles for siRNA delivery. Cancer Lett., 2019, 449, 186-195.
[http://dx.doi.org/10.1016/j.canlet.2019.02.011] [PMID: 30771430]
[13]
Betker, J.L.; Angle, B.M.; Graner, M.W.; Anchordoquy, T.J. The potential of exosomes from cow milk for oral delivery. J. Pharm. Sci., 2019, 108(4), 1496-1505.
[http://dx.doi.org/10.1016/j.xphs.2018.11.022] [PMID: 30468828]
[14]
Yamauchi, M.; Shimizu, K.; Rahman, M.; Ishikawa, H.; Takase, H.; Ugawa, S.; Okada, A.; Inoshima, Y. Efficient method for isolation of exosomes from raw bovine milk. Drug Dev. Ind. Pharm., 2019, 45(3), 359-364.
[http://dx.doi.org/10.1080/03639045.2018.1539743] [PMID: 30366501]
[15]
Munagala, R.; Aqil, F.; Jeyabalan, J.; Gupta, R.C. Bovine milk-derived exosomes for drug delivery. Cancer Lett., 2016, 371(1), 48-61.
[http://dx.doi.org/10.1016/j.canlet.2015.10.020] [PMID: 26604130]
[16]
Kusuma, R.J.; Manca, S.; Friemel, T.; Sukreet, S.; Nguyen, C.; Zempleni, J. Human vascular endothelial cells transport foreign exosomes from cow’s milk by endocytosis. Am. J. Physiol. Cell Physiol., 2016, 310(10), C800-C807.
[http://dx.doi.org/10.1152/ajpcell.00169.2015] [PMID: 26984735]
[17]
Vaswani, K.; Koh, Y.Q.; Almughlliq, F.B.; Peiris, H.N.; Mitchell, M.D. A method for the isolation and enrichment of purified bovine milk exosomes. Reprod. Biol., 2017, 17(4), 341-348.
[http://dx.doi.org/10.1016/j.repbio.2017.09.007] [PMID: 29030127]
[18]
Yassin, A.M.; Abdel Hamid, M.I.; Farid, O.A.; Amer, H.; Warda, M. Dromedary milk exosomes as mammary transcriptome nano-vehicle: Their isolation, vesicular and phospholipidomic characterizations. J. Adv. Res., 2016, 7(5), 749-756.
[http://dx.doi.org/10.1016/j.jare.2015.10.003]
[19]
Han, Y.; Gao, Z.; Chen, L.; Kang, L.; Huang, W.; Jin, M.; Wang, Q.; Bae, Y.H. Multifunctional oral delivery systems for enhanced bioavailability of therapeutic peptides/proteins. Acta Pharm. Sin. B, 2019, 9(5), 902-922.
[http://dx.doi.org/10.1016/j.apsb.2019.01.004] [PMID: 31649842]
[20]
Gray, W.D.; Mitchell, A.J.; Searles, C.D. An accurate, precise method for general labeling of extracellular vesicles. MethodsX, 2015, 2, 360-367.
[http://dx.doi.org/10.1016/j.mex.2015.08.002] [PMID: 26543819]
[21]
Mehryab, F.; Rabbani, S.; Shahhosseini, S.; Shekari, F.; Fatahi, Y.; Baharvand, H.; Haeri, A. Exosomes as a next-generation drug delivery system: An update on drug loading approaches, characterization, and clinical application challenges. Acta Biomater., 2020, 113, 42-62.
[http://dx.doi.org/10.1016/j.actbio.2020.06.036] [PMID: 32622055]
[22]
Agrawal, A.K.; Aqil, F.; Jeyabalan, J.; Spencer, W.A.; Beck, J.; Gachuki, B.W.; Alhakeem, S.S.; Oben, K.; Munagala, R.; Bondada, S.; Gupta, R.C. Milk-derived exosomes for oral delivery of paclitaxel. Nanomedicine (Lond.), 2017, 13(5), 1627-1636.
[http://dx.doi.org/10.1016/j.nano.2017.03.001] [PMID: 28300659]
[23]
Yim, N.; Ryu, S.W.; Choi, K.; Lee, K.R.; Lee, S.; Choi, H.; Kim, J.; Shaker, M.R.; Sun, W.; Park, J.H.; Kim, D.; Heo, W.D.; Choi, C. Exosome engineering for efficient intracellular delivery of soluble proteins using optically reversible protein-protein interaction module. Nat. Commun., 2016, 7, 12277.
[http://dx.doi.org/10.1038/ncomms12277] [PMID: 27447450]
[24]
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]
[25]
Zheng, Z.; Li, Z.; Xu, C.; Guo, B.; Guo, P. Folate-displaying exosome mediated cytosolic delivery of siRNA avoiding endosome trapping. J. Control. Release, 2019, 311-312, 43-49.
[http://dx.doi.org/10.1016/j.jconrel.2019.08.021] [PMID: 31446085]
[26]
Wolf, T.; Baier, S.R.; Zempleni, J. The intestinal transport of bovine milk exosomes is mediated by endocytosis in human colon carcinoma caco-2 cells and rat small intestinal iec-6 cells. J. Nutr., 2015, 145(10), 2201-2206.
[http://dx.doi.org/10.3945/jn.115.218586] [PMID: 26269243]
[27]
Liao, Y.; Du, X.; Li, J.; Lönnerdal, B. Human milk exosomes and their microRNAs survive digestion in vitro and are taken up by human intestinal cells. Mol. Nutr. Food Res., 2017, 61(11)
[http://dx.doi.org/10.1002/mnfr.201700082] [PMID: 28688106]
[28]
Nuffer, W.A.; Trujillo, J.M. Liraglutide: A new option for the treatment of obesity. Pharmacotherapy, 2015, 35(10), 926-934.
[http://dx.doi.org/10.1002/phar.1639] [PMID: 26497479]
[29]
Jacobsen, L.V.; Flint, A.; Olsen, A.K.; Ingwersen, S.H. Liraglutide in type 2 diabetes mellitus: Clinical pharmacokinetics and pharmacodynamics. Clin. Pharmacokinet., 2016, 55(6), 657-672.
[http://dx.doi.org/10.1007/s40262-015-0343-6] [PMID: 26597252]
[30]
Fuhrmann, G.; Serio, A.; Mazo, M.; Nair, R.; Stevens, M.M. Active loading into extracellular vesicles significantly improves the cellular uptake and photodynamic effect of porphyrins. J. Control. Release, 2015, 205, 35-44.
[http://dx.doi.org/10.1016/j.jconrel.2014.11.029] [PMID: 25483424]
[31]
Pedaprolu, J.N.; Bonthu, M.; Vatchavai, B.; Kamatham, S.; Kolli, S.; Kapuganti, A.N. A new stability-indicating and validated rp-hplc method for the estimation of liraglutide in bulk and pharmaceutical dosage forms. Eur. Jou. of Anal. Chem., 2016, 12(2), 31-44.
[http://dx.doi.org/10.12973/ejac.2017.00152a]
[32]
Fuhrmann, G.; Herrmann, I.K.; Stevens, M.M. Cell-derived vesicles for drug therapy and diagnostics: Opportunities and challenges. Nano Today, 2015, 10(3), 397-409.
[http://dx.doi.org/10.1016/j.nantod.2015.04.004] [PMID: 28458718]
[33]
Gao, H.N.; Guo, H.Y.; Zhang, H.; Xie, X.L.; Wen, P.C.; Ren, F.Z. Yak-milk-derived exosomes promote proliferation of intestinal epithelial cells in an hypoxic environment. J. Dairy Sci., 2019, 102(2), 985-996.
[http://dx.doi.org/10.3168/jds.2018-14946] [PMID: 30580945]
[34]
Koh, Y.Q.; Peiris, H.N.; Vaswani, K.; Meier, S.; Burke, C.R.; Macdonald, K.A.; Roche, J.R.; Almughlliq, F.; Arachchige, B.J.; Reed, S.; Mitchell, M.D. Characterization of exosomes from body fluids of dairy cows. J. Anim. Sci., 2017, 95(9), 3893-3904.
[http://dx.doi.org/10.2527/jas2017.1727] [PMID: 28992005]

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