Generic placeholder image

Current Drug Delivery

Author(s): Chenglong Li*, Guanting lu, Yue Jiang, Huaiyu Su* and Chen Li*

DOI: 10.2174/1567201821666230810115230

DownloadDownload PDF Flyer Cite As
A Novel Etanercept-loaded Nano-emulsion for Targeted Treatment of Inflammatory Arthritis via Draining Lymph Node

Page: [1106 - 1113] Pages: 8

  • * (Excluding Mailing and Handling)

Abstract

Background: Rheumatoid arthritis (RA) is a systemic autoimmune disease (AD), and the global incidence rate is 0.5 ~ 1%. Existing medications might reduce symptoms, however, there is no known cure for this illness. Etanercept (EN) can competitively inhibit TNF-α binding to the TNF receptor on the cell surface to treat RA. However, subcutaneous injection of free EN predisposes to systemic distribution and induces immune system hypofunction. Draining lymph nodes (LNs) play a significant role in the onset, maintenance, and progression of RA as they are the primary sites of aberrant immune response and inflammatory cytokine production.

Aim: The purpose of this study was to successfully treat RA with etanercept by encapsulating it in nanoemulsions (NEs/EN) and then delivering it specifically to draining LNs. The EN-loaded NEs were prepared by high-pressure homogenization method and modified with DSPE-mPEG2000 and Ca(OH)2.

Methods: A novel nano-emulsion (NE) was constructed to deliver EN (NE/EN) to RA-draining LNs. To decrease aggregation and load EN, DSPE-mPEG2000 and Ca(OH)2 were successively decorated on the surface of the lipid injectable emulsions. The hydrodynamic diameter and morphology of NEs/EN were investigated by using a laser particle size analyzer and transmission electron microscopy, respectively. The in vivo fluorescence imaging system was used to study the in vivo LN targeting ability of the formulation. In the therapeutic experiment, NEs/EN was subcutaneously administrated to inhibit the development of the mouse arthritis model.

Results: Circular dichroism spectrum and L929 cell experiment confirmed that NEs encapsulation had no impact on the biological activity of EN. In vivo investigation on collagen-induced arthritis (CIA) mouse model showed that NEs/EN have good inguinal lymph node targeting capabilities, as well as, anti-inflammatory effect against RA. Compared with the free group, the paw thickness and arthritic score in NEs/EN group were significantly alleviated. Moreover, the concentration of pro-inflammatory cytokines TNF-α and IL-1β in NEs/EN-treated mice was lower than that in free EN.

Conclusion: NEs/EN effectively improve the effectiveness of EN in the treatment of RA. Our work provides an experimental foundation for expanding the clinical application of EN.

Graphical Abstract

[1]
McInnes, I.B.; Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med., 2011, 365(23), 2205-2219.
[http://dx.doi.org/10.1056/NEJMra1004965] [PMID: 22150039]
[2]
Smolen, J.S.; Aletaha, D.; McInnes, I.B. Rheumatoid arthritis. Lancet, 2016, 388(10055), 2023-2038.
[http://dx.doi.org/10.1016/S0140-6736(16)30173-8] [PMID: 27156434]
[3]
Smolen, J.S.; Aletaha, D.; Barton, A.; Burmester, G.R.; Emery, P.; Firestein, G.S.; Kavanaugh, A.; McInnes, I.B.; Solomon, D.H.; Strand, V.; Yamamoto, K. Rheumatoid arthritis. Nat. Rev. Dis. Primers, 2018, 4(1), 18001.
[http://dx.doi.org/10.1038/nrdp.2018.1] [PMID: 29417936]
[4]
Arima, H.; Koirala, S.; Nema, K.; Nakano, M.; Ito, H.; Poudel, K.M.; Pandey, K.; Pandey, B.D.; Yamamoto, T. High prevalence of rheumatoid arthritis and its risk factors among Tibetan highlanders living in Tsarang, Mustang district of Nepal. J. Physiol. Anthropol., 2022, 41(1), 12.
[http://dx.doi.org/10.1186/s40101-022-00283-3] [PMID: 35366946]
[5]
Roodenrijs, N.M.T.; Welsing, P.M.J.; van der Goes, M.C.; Tekstra, J.; Lafeber, F.P.J.G.; Jacobs, J.W.G.; van Laar, J.M. Healthcare utilization and economic burden of difficult-to-treat rheumatoid arthritis: A cost-of-illness study. Rheumatology, 2021, 60(10), 4681-4690.
[http://dx.doi.org/10.1093/rheumatology/keab078] [PMID: 33502493]
[6]
Kerschbaumer, A.; Sepriano, A.; Smolen, J.S.; van der Heijde, D.; Dougados, M.; van Vollenhoven, R.; McInnes, I.B.; Bijlsma, J.W.J.; Burmester, G.R.; de Wit, M.; Falzon, L.; Landewé, R. Efficacy of pharmacological treatment in rheumatoid arthritis: A systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis. Ann. Rheum. Dis., 2020, 79(6), 744-759.
[http://dx.doi.org/10.1136/annrheumdis-2019-216656] [PMID: 32033937]
[7]
Zhao, S.; Mysler, E.; Moots, R.J. Etanercept for the treatment of rheumatoid arthritis. Immunotherapy, 2018, 10(6), 433-445.
[http://dx.doi.org/10.2217/imt-2017-0155] [PMID: 29482402]
[8]
Feyen, O.; Lueking, A.; Kowald, A.; Stephan, C.; Meyer, H.E.; Göbel, U.; Niehues, T. Off-target activity of TNF-α inhibitors characterized by protein biochips. Anal. Bioanal. Chem., 2008, 391(5), 1713-1720.
[http://dx.doi.org/10.1007/s00216-008-1938-7] [PMID: 18344017]
[9]
Kerensky, T.A.; Gottlieb, A.B.; Yaniv, S.; Au, S. Etanercept: efficacy and safety for approved indications. Expert Opin. Drug Saf., 2012, 11(1), 121-139.
[http://dx.doi.org/10.1517/14740338.2012.633509] [PMID: 22074366]
[10]
Gholami, A.; Azizpoor, J.; Aflaki, E.; Rezaee, M.; Keshavarz, K. Cost-effectiveness analysis of biopharmaceuticals for treating rheumatoid arthritis: Infliximab, adalimumab, and etanercept. BioMed Res. Int., 2021, 2021, 1-12.
[http://dx.doi.org/10.1155/2021/4450162] [PMID: 34877355]
[11]
Moots, R.J.; Mays, R.; Stephens, J.; Tarallo, M. Burden of dose escalation with tumour necrosis factor inhibitors in rheumatoid arthritis: A systematic review of frequency and costs. Clin. Exp. Rheumatol., 2015, 33(5), 737-745.
[PMID: 26053198]
[12]
Benaglio, F.; Vitolo, B.; Scarabelli, M.; Binda, E.; Bugatti, S.; Caporali, R.; Montecucco, C.; Manzo, A. The draining lymph node in rheumatoid arthritis: Current concepts and research perspectives. BioMed Res. Int., 2015, 2015, 1-10.
[http://dx.doi.org/10.1155/2015/420251] [PMID: 25793195]
[13]
Robertson, M.D.; Hart, F.D.; White, W.F.; Nuki, G.; Boardman, P.L. Rheumatoid lymphadenopathy. Ann. Rheum. Dis., 1968, 27(3), 253-260.
[http://dx.doi.org/10.1136/ard.27.3.253] [PMID: 5655317]
[14]
van Baarsen, L.G.M.; de Hair, M.J.H.; Ramwadhdoebe, T.H.; Zijlstra, I.A.J.; Maas, M.; Gerlag, D.M.; Tak, P.P. The cellular composition of lymph nodes in the earliest phase of inflammatory arthritis. Ann. Rheum. Dis., 2013, 72(8), 1420-1424.
[http://dx.doi.org/10.1136/annrheumdis-2012-202990] [PMID: 23661491]
[15]
Feng, X.; Xu, W.; Li, Z.; Song, W.; Ding, J.; Chen, X. Immunomodulatory nanosystems. Adv. Sci., 2019, 6(17), 1900101.
[http://dx.doi.org/10.1002/advs.201900101] [PMID: 31508270]
[16]
Jiang, H.; Wang, Q.; Sun, X. Lymph node targeting strategies to improve vaccination efficacy. J. Control. Release, 2017, 267, 47-56.
[http://dx.doi.org/10.1016/j.jconrel.2017.08.009] [PMID: 28818619]
[17]
Cao, J.; Zhang, N.; Wang, Z.; Su, J.; Yang, J.; Han, J.; Zhao, Y. Microneedle-assisted transdermal delivery of etanercept for rheumatoid arthritis treatment. Pharmaceutics, 2019, 11(5), 235.
[http://dx.doi.org/10.3390/pharmaceutics11050235] [PMID: 31096705]
[18]
Popivanova, B.K.; Kitamura, K.; Wu, Y.; Kondo, T.; Kagaya, T.; Kaneko, S.; Oshima, M.; Fujii, C.; Mukaida, N. Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J. Clin. Invest., 2008, 118(2), 560-570.
[PMID: 18219394]
[19]
Ghosh, G.; Panicker, L. Protein–nanoparticle interactions and a new insight. Soft Matter, 2021, 17(14), 3855-3875.
[http://dx.doi.org/10.1039/D0SM02050H] [PMID: 33885450]
[20]
Kim, N.A.; Lim, D.G.; Lim, J.Y.; Kim, K.H.; Jeong, S.H. Comprehensive evaluation of etanercept stability in various concentrations with biophysical assessment. Int. J. Pharm., 2014, 460(1-2), 108-118.
[http://dx.doi.org/10.1016/j.ijpharm.2013.11.019] [PMID: 24269208]
[21]
Byun, H.S.; Park, K.A.; Won, M.; Yang, K.J.; Shin, S.; Piao, L.; Kwak, J.Y.; Lee, Z.W.; Park, J.; Seok, J.H.; Liu, Z.G.; Hur, G.M. Phorbol 12-myristate 13-acetate protects against tumor necrosis factor (TNF)-induced necrotic cell death by modulating the recruitment of TNF receptor 1-associated death domain and receptor-interacting protein into the TNF receptor 1 signaling complex: Implication for the regulatory role of protein kinase C. Mol. Pharmacol., 2006, 70(3), 1099-1108.
[http://dx.doi.org/10.1124/mol.106.025452] [PMID: 16798936]
[22]
O’Connell, M.A.; Kelleher, D.; Liskamp, R.M.J.; Hall, N.; O’Neill, L.A.J.; Long, A. TNF-mediated cytotoxicity of L929 cells: Role of staurosporine in enhancement of cytotoxicity and translocation of protein kinase C isozymes. Cytokine, 1997, 9(2), 83-92.
[http://dx.doi.org/10.1006/cyto.1996.0140] [PMID: 9071558]
[23]
Harrell, M.I.; Iritani, B.M.; Ruddell, A. Lymph node mapping in the mouse. J. Immunol. Methods, 2008, 332(1-2), 170-174.
[http://dx.doi.org/10.1016/j.jim.2007.11.012] [PMID: 18164026]
[24]
Brand, D.D.; Latham, K.A.; Rosloniec, E.F. Collagen-induced arthritis. Nat. Protoc., 2007, 2(5), 1269-1275.
[http://dx.doi.org/10.1038/nprot.2007.173] [PMID: 17546023]