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Current Drug Delivery

Author(s): Prangtip Uthaiwat, Jureerut Daduang*, Aroonsri Priprem, Chatri Settasatian, Sirinart Chio-Srichan, Yao-Chang Lee, Pramote Mahakunakorn and Patcharee Boonsiri

DOI: 10.2174/1567201817666200525151848

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Topical Melatonin Niosome Gel for the Treatment of 5-FU-Induced Oral Mucositis in Mice

Page: [199 - 211] Pages: 13

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Abstract

Background: Oral mucositis, one of the most common complications of 5-Fluorouracil (5-FU) treatment, leads to several problems, including pain, diarrhea and malnutrition, and reduces the quality of life and subsequent treatments. Melatonin, a neurohormone with anti-inflammatory and antioxidant activities, was encapsulated in niosomes and embedded in a mucoadhesive gel formulation as a Melatonin Niosome Gel (MNG) to perform oral mucositis treatment.

Objective: This study aimed to investigate the effectiveness of MNG for the treatment of 5-FU-induced oral mucositis in mice.

Methods: Oral mucositis was induced in ICR mice by 5-FU and randomly assigned to receive daily applications of the topical oral MNG, a fluocinolone acetonide gel, a blank niosome gel, or no treatment for 5 days in comparison with a normal group. Average body weights, food consumption, and behaviors of the mice as well as microscopic histopathology, Fourier-Transform Infrared Spectroscopy (FTIR) analysis, proinflammatory cytokine levels, and oxidative stress markers of the tongues were monitored and collected after sacrifice.

Results: In comparison to the normal group, the average body weights of the 5-FU-MNG mice did not deviate from that of the normal group, nor was there a significant difference in the time to sleep or licking (p>0.05 for both parameters). In addition, the mice treated with MNG and fluocinolone acetonide did not show significantly different histopathological, FTIR, interleukin-1β or malondialdehyde (MDA) results in the tongues used as the oral tissue samples.

Conclusion: Topical MNG potentially inhibits inflammation and lipid oxidative stress in 5-FU-induced oral mucositis.

Keywords: Niosomes, melatonin, 5-fluorouracil, mucositis, anti-inflammation, antioxidant, Malondialdehyde (MDA).

Graphical Abstract

[1]
Longley, D.B.; Harkin, D.P.; Johnston, P.G. 5-Fluorouracil: Mechanisms of action and clinical strategies. Nat. Rev. Cancer, 2003, 3(5), 330-338.
[http://dx.doi.org/10.1038/nrc1074] [PMID: 12724731]
[2]
Peterson, D.E.; Bensadoun, R-J.; Roila, F. ESMO Guidelines Working Group. Management of oral and gastrointestinal mucositis: ESMO clinical recommendations. Ann. Oncol., 2009, 20(Suppl. 4), 174-177.
[http://dx.doi.org/10.1093/annonc/mdp165] [PMID: 19454447]
[3]
Lalla, R.V.; Sonis, S.T.; Peterson, D.E. Management of oral mucositis in patients who have cancer. Dent. Clin. North Am., 2008, 52(1), 61-77.
[http://dx.doi.org/10.1016/j.cden.2007.10.002] [PMID: 18154865]
[4]
Sonis, S.T.; Elting, L.S.; Keefe, D.; Peterson, D.E.; Schubert, M.; Hauer-Jensen, M.; Bekele, B.N.; Raber-Durlacher, J.; Donnelly, J.P.; Rubenstein, E.B. Mucositis Study Section of the Multinational Association for Supportive Care in Cancer; International Society for Oral Oncology. Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer, 2004, 100(Suppl.9), 1995-2025.
[http://dx.doi.org/10.1002/cncr.20162] [PMID: 15108222]
[5]
Oliver Metzig, M.; Fuchs, D.; Tagscherer, K.E.; Gröne, H.J.; Schirmacher, P.; Roth, W. Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB. Oncogene, 2016, 35(26), 3399-3409.
[http://dx.doi.org/10.1038/onc.2015.398] [PMID: 26522725]
[6]
Sonis, S.T. New thoughts on the initiation of mucositis. Oral Dis., 2010, 16(7), 597-600.
[http://dx.doi.org/10.1111/j.1601-0825.2010.01681.x] [PMID: 20846150]
[7]
Im, K.I.; Nam, Y.S.; Kim, N.; Song, Y.; Lee, E.S.; Lim, J.Y.; Jeon, Y.W.; Cho, S.G. Regulation of HMGB1 release protects chemoradiotherapy-associated mucositis. Mucosal Immunol., 2019, 12(5), 1070-1081.
[http://dx.doi.org/10.1038/s41385-019-0132-x] [PMID: 30647411]
[8]
Ortiz, F.; Acuña-Castroviejo, D.; Doerrier, C.; Dayoub, J.C.; López, L.C.; Venegas, C.; García, J.A.; López, A.; Volt, H.; Luna-Sánchez, M.; Escames, G. Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation-induced oral mucositis. J. Pineal Res., 2015, 58(1), 34-49.
[http://dx.doi.org/10.1111/jpi.12191] [PMID: 25388914]
[9]
Lauritano, D.; Petruzzi, M.; Di Stasio, D.; Lucchese, A. Clinical effectiveness of palifermin in prevention and treatment of oral mucositis in children with acute lymphoblastic leukaemia: A case-control study. Int. J. Oral Sci., 2014, 6(1), 27-30.
[http://dx.doi.org/10.1038/ijos.2013.93] [PMID: 24357856]
[10]
Spielberger, R.; Stiff, P.; Bensinger, W.; Gentile, T.; Weisdorf, D.; Kewalramani, T.; Shea, T.; Yanovich, S.; Hansen, K.; Noga, S.; McCarty, J.; LeMaistre, C.F.; Sung, E.C.; Blazar, B.R.; Elhardt, D.; Chen, M.G.; Emmanouilides, C. Palifermin for oral mucositis after intensive therapy for hematologic cancers. N. Engl. J. Med., 2004, 351(25), 2590-2598.
[http://dx.doi.org/10.1056/NEJMoa040125] [PMID: 15602019]
[11]
Epstein, J.B.; Silverman, S., Jr; Paggiarino, D.A.; Crockett, S.; Schubert, M.M.; Senzer, N.N.; Lockhart, P.B.; Gallagher, M.J.; Peterson, D.E.; Leveque, F.G. Benzydamine HCl for prophylaxis of radiation-induced oral mucositis: Results from a multicenter, randomized, double-blind, placebo-controlled clinical trial. Cancer, 2001, 92(4), 875-885.
[http://dx.doi.org/10.1002/1097-0142(20010815)92:4<875::AID-CNCR1396>3.0.CO;2-1] [PMID: 11550161]
[12]
Kadakia, K.C.; Rozell, S.A.; Butala, A.A.; Loprinzi, C.L. Supportive cryotherapy: A review from head to toe. J. Pain Symptom Manage., 2014, 47(6), 1100-1115.
[http://dx.doi.org/10.1016/j.jpainsymman.2013.07.014] [PMID: 24210702]
[13]
Claustrat, B.; Leston, J. Melatonin: Physiological effects in humans. Neurochirurgie, 2015, 61(2-3), 77-84.
[http://dx.doi.org/10.1016/j.neuchi.2015.03.002] [PMID: 25908646]
[14]
Reiter, R.J.; Calvo, J.R.; Karbownik, M.; Qi, W.; Tan, D.X. Melatonin and its relation to the immune system and inflammation. Ann. N. Y. Acad. Sci., 2000, 917, 376-386.
[http://dx.doi.org/10.1111/j.1749-6632.2000.tb05402.x] [PMID: 11268363]
[15]
Radogna, F.; Diederich, M.; Ghibelli, L. Melatonin: A pleiotropic molecule regulating inflammation. Biochem. Pharmacol., 2010, 80(12), 1844-1852.
[http://dx.doi.org/10.1016/j.bcp.2010.07.041] [PMID: 20696138]
[16]
Bilici, D.; Akpinar, E.; Kiziltunç, A. Protective effect of melatonin in carrageenan-induced acute local inflammation. Pharmacol. Res., 2002, 46(2), 133-139.
[http://dx.doi.org/10.1016/S1043-6618(02)00089-0] [PMID: 12220952]
[17]
Abdel Moneim, A.E.; Ortiz, F.; Leonardo-Mendonça, R.C.; Vergano-Villodres, R.; Guerrero-Martínez, J.A.; López, L.C.; Acuña-Castroviejo, D.; Escames, G. Protective effects of melatonin against oxidative damage induced by Egyptian cobra (Naja haje) crude venom in rats. Acta Trop., 2015, 143, 58-65.
[http://dx.doi.org/10.1016/j.actatropica.2014.12.007] [PMID: 25542296]
[18]
Fernández-Gil, B.; Moneim, A.E.; Ortiz, F.; Shen, Y.Q.; Soto-Mercado, V.; Mendivil-Perez, M.; Guerra-Librero, A.; Acuña-Castroviejo, D.; Molina-Navarro, M.M.; García-Verdugo, J.M.; Sayed, R.K.; Florido, J.; Luna, J.D.; López, L.C.; Escames, G. Melatonin protects rats from radiotherapy-induced small intestine toxicity. PLoS One, 2017, 12(4), e0174474.
[http://dx.doi.org/10.1371/journal.pone.0174474] [PMID: 28403142]
[19]
Tarocco, A.; Caroccia, N.; Morciano, G.; Wieckowski, M.R.; Ancora, G.; Garani, G.; Pinton, P. Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care. Cell Death Dis., 2019, 10(4), 317.
[http://dx.doi.org/10.1038/s41419-019-1556-7] [PMID: 30962427]
[20]
Najafi, M.; Shirazi, A.; Motevaseli, E.; Rezaeyan, A.H.; Salajegheh, A.; Rezapoor, S. Melatonin as an anti-inflammatory agent in radiotherapy. Inflammopharmacology, 2017, 25(4), 403-413.
[http://dx.doi.org/10.1007/s10787-017-0332-5] [PMID: 28255737]
[21]
Najafi, M.; Shirazi, A.; Motevaseli, E.; Geraily, G.; Norouzi, F.; Heidari, M.; Rezapoor, S. The melatonin immunomodulatory actions in radiotherapy. Biophys. Rev., 2017, 9(2), 139-148.
[http://dx.doi.org/10.1007/s12551-017-0256-8] [PMID: 28510090]
[22]
Farhood, B.; Goradel, N.H.; Mortezaee, K.; Khanlarkhani, N.; Salehi, E.; Nashtaei, M.S.; Mirtavoos-Mahyari, H.; Motevaseli, E.; Shabeeb, D.; Musa, A.E.; Najafi, M. Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization. Clin. Transl. Oncol., 2019, 21(3), 268-279.
[http://dx.doi.org/10.1007/s12094-018-1934-0] [PMID: 30136132]
[23]
Harpsøe, N.G.; Andersen, L.P.; Gögenur, I.; Rosenberg, J. Clinical pharmacokinetics of melatonin: A systematic review. Eur. J. Clin. Pharmacol., 2015, 71(8), 901-909.
[http://dx.doi.org/10.1007/s00228-015-1873-4] [PMID: 26008214]
[24]
Bénès, L.; Claustrat, B.; Horrière, F.; Geoffriau, M.; Konsil, J.; Parrott, K.A.; DeGrande, G.; McQuinn, R.L.; Ayres, J.W. Transmucosal, oral controlled-release, and transdermal drug administration in human subjects: A crossover study with melatonin. J. Pharm. Sci., 1997, 86(10), 1115-1119.
[http://dx.doi.org/10.1021/js970011z] [PMID: 9344167]
[25]
Priprem, A.; Nukulkit, C.; Johns, N.P.; Laohasiriwong, S.; Yimtae, K.; Soontornpas, C. Transmucosal delivery of melatonin-encapsulated niosomes in a mucoadhesive gel. Ther. Deliv., 2018, 9(5), 343-357.
[http://dx.doi.org/10.4155/tde-2018-0001] [PMID: 29681235]
[26]
Zetner, D.; Andersen, L.P.; Rosenberg, J. Pharmacokinetics of alternative administration routes of melatonin: A systematic review. Drug Res. (Stuttg.), 2016, 66(4), 169-173.
[PMID: 26514093]
[27]
Priprem, A.; Johns, J.R.; Limsitthichaikoon, S.; Limphirat, W.; Mahakunakorn, P.; Johns, N.P. Intranasal melatonin nanoniosomes: pharmacokinetic, pharmacodynamics and toxicity studies. Ther. Deliv., 2017, 8(6), 373-390.
[http://dx.doi.org/10.4155/tde-2017-0005] [PMID: 28530143]
[28]
Onseng, K.; Johns, N.P.; Khuayjarernpanishk, T.; Subongkot, S.; Priprem, A.; Hurst, C.; Johns, J. Beneficial effects of adjuvant melatonin in minimizing oral mucositis complications in head and neck cancer patients receiving concurrent chemoradiation. J. Altern. Complement. Med., 2017, 23(12), 957-963.
[http://dx.doi.org/10.1089/acm.2017.0081] [PMID: 28657801]
[29]
Yeung, C.Y.; Chan, W.T.; Jiang, C.B.; Cheng, M.L.; Liu, C.Y.; Chang, S.W.; Chiang Chiau, J.S.; Lee, H.C. Amelioration of chemotherapy-induced intestinal mucositis by orally administered probiotics in a mouse model. PLoS One, 2015, 10(9), e0138746.
[http://dx.doi.org/10.1371/journal.pone.0138746] [PMID: 26406888]
[30]
Kim, H.J.; Kim, J.H.; Moon, W.; Park, J.; Park, S.J.; Song, G.A.; Han, S.H.; Lee, J.H. Rebamipide attenuates 5-Fluorouracil-induced small intestinal mucositis in a mouse model. Biol. Pharm. Bull., 2015, 38(2), 179-183.
[http://dx.doi.org/10.1248/bpb.b14-00400] [PMID: 25747976]
[31]
Kato, S.; Hayashi, S.; Kitahara, Y.; Nagasawa, K.; Aono, H.; Shibata, J.; Utsumi, D.; Amagase, K.; Kadowaki, M. Saireito (TJ-114), a Japanese traditional herbal medicine, reduces 5-fluorouracil-induced intestinal mucositis in mice by inhibiting cytokine-mediated apoptosis in intestinal crypt cells. PLoS One, 2015, 10(1), e0116213.
[http://dx.doi.org/10.1371/journal.pone.0116213] [PMID: 25565296]
[32]
Chang, C.T.; Hsiang, C.Y.; Ho, T.Y.; Wu, C.Z.; Hong, H.H.; Huang, Y.F. Comprehensive assessment of host responses to 5-fluorouracil-induced oral mucositis through transcriptomic analysis. PLoS One, 2015, 10(8), e0135102.
[http://dx.doi.org/10.1371/journal.pone.0135102] [PMID: 26266941]
[33]
Bertolini, M.; Sobue, T.; Thompson, A.; Dongari-Bagtzoglou, A. Chemotherapy induces oral mucositis in mice without additional noxious stimuli. Transl. Oncol., 2017, 10(4), 612-620.
[http://dx.doi.org/10.1016/j.tranon.2017.05.001] [PMID: 28666190]
[34]
Fucci, D.; Petrosino, L. The human tongue: Normal structure and function and associated pathologies. Speech and language., 1981, 305-374.
[http://dx.doi.org/10.1016/B978-0-12-608606-5.50013-2]
[35]
du Toit, D.F. The tongue: structure and function relevant to disease and oral health. SADJ, 2003, 58(9), 375-376, 380-383.
[PMID: 14964052]
[36]
Duncan, M.; Grant, G. Oral and intestinal mucositis - causes and possible treatments. Aliment. Pharmacol. Ther., 2003, 18(9), 853-874.
[http://dx.doi.org/10.1046/j.1365-2036.2003.01784.x] [PMID: 14616150]
[37]
Nukulkit, C.; Priprem, A.; Damrongrungruang, T.; Benjavongkulchai, E.; Pratheepawanit Johns, N. Effect of polycaprolactone on in vitro release of melatonin encapsulated niosomes in artificial and whole saliva. J. Drug Deliv. Sci. Technol., 2014, 24, 153-158.
[http://dx.doi.org/10.1016/S1773-2247(14)50025-1]
[38]
Hamouda, N.; Sano, T.; Oikawa, Y.; Ozaki, T.; Shimakawa, M.; Matsumoto, K.; Amagase, K.; Higuchi, K.; Kato, S. Apoptosis, dysbiosis and expression of inflammatory cytokines are sequential events in the development of 5-fluorouracil-induced intestinal mucositis in mice. Basic Clin. Pharmacol. Toxicol., 2017, 121(3), 159-168.
[http://dx.doi.org/10.1111/bcpt.12793] [PMID: 28374966]
[39]
Priprem, A.; Netweera, V.; Mahakunakorn, P.; Johns, N.P.; Johns, J.R. Prolonged anti-Inflammatory activity of topical melatonin by niosomal encapsulation. Adv. Mat. Res., 2014, 902, 70-75.
[http://dx.doi.org/10.4028/www.scientific.net/AMR.902.70]
[40]
Laboratory Animals (US); National Research Council of the National Academies (US). Guide for the Care and Use of Laboratory Animals. 8th ed Washington, DC National Academies Press; , 2011.
[41]
Lovergne, L.; Bouzy, P.; Untereiner, V.; Garnotel, R.; Baker, M.J.; Thiéfin, G.; Sockalingum, G.D. Biofluid infrared spectro-diagnostics: pre-analytical considerations for clinical applications. Faraday Discuss., 2016, 187, 521-537.
[http://dx.doi.org/10.1039/C5FD00184F] [PMID: 27048927]
[42]
Baker, M.J.; Trevisan, J.; Bassan, P.; Bhargava, R.; Butler, H.J.; Dorling, K.M.; Fielden, P.R.; Fogarty, S.W.; Fullwood, N.J.; Heys, K.A.; Hughes, C.; Lasch, P.; Martin-Hirsch, P.L.; Obinaju, B.; Sockalingum, G.D.; Sulé-Suso, J.; Strong, R.J.; Walsh, M.J.; Wood, B.R.; Gardner, P.; Martin, F.L. Using Fourier transform IR spectroscopy to analyze biological materials. Nat. Protoc., 2014, 9(8), 1771-1791.
[http://dx.doi.org/10.1038/nprot.2014.110] [PMID: 24992094]
[43]
Chevreau, N.; Wang, Y.; Funk-Archuleta, M. Effect of diets on 5-fluorouracil and cyclophosphamide toxicity. Nutr. Cancer, 1995, 23(2), 205-220.
[http://dx.doi.org/10.1080/01635589509514375] [PMID: 7644388]
[44]
World Health Organization. WHO handbook for reporting results of cancer treatment. Geneva World Health Organization; , 1979.
[45]
AL-Rhman, S.A.; AL-Fartwsy, A.R.; AL-Shuaily, E.H. Morphologyhistological study of the tongue in local mice species by using special stain. Am. J. Sci., 2016, 12, 13-20.
[46]
Okubo, T.; Clark, C.; Hogan, B.L. Cell lineage mapping of taste bud cells and keratinocytes in the mouse tongue and soft palate. Stem Cells, 2009, 27(2), 442-450.
[http://dx.doi.org/10.1634/stemcells.2008-0611] [PMID: 19038788]
[47]
Dörr, W.; Kummermehr, J. Proliferation kinetics of mouse tongue epithelium under normal conditions and following single dose irradiation. Virchows Arch. B Cell Pathol. Incl. Mol. Pathol., 1991, 60(5), 287-294.
[http://dx.doi.org/10.1007/BF02899559] [PMID: 1685035]
[48]
Kiselev, M.A.; Ermakova, E.V.; Gruzinov, A.Y.; Zabelin, A.V. Formation of the long-periodicity phase in model membranes of the outermost layer of skin (stratum corneum). Crystallogr. Rep., 2014, 59, 112-116.
[http://dx.doi.org/10.1134/S106377451306014X]
[49]
Peachey, E.; Rogers, B.; Brien, J.F.; Maclean, A.; Rogers, D. Measurement of acute and chronic behavioural effects of methamphetamine in the mouse. Psychopharmacology (Berl.), 1976, 48(3), 271-275.
[http://dx.doi.org/10.1007/BF00496860] [PMID: 823582]
[50]
Mogil, J.S. Animal models of pain: progress and challenges. Nat. Rev. Neurosci., 2009, 10(4), 283-294.
[http://dx.doi.org/10.1038/nrn2606] [PMID: 19259101]
[51]
Viet, C.T.; Corby, P.M.; Akinwande, A.; Schmidt, B.L. Review of preclinical studies on treatment of mucositis and associated pain. J. Dent. Res., 2014, 93(9), 868-875.
[http://dx.doi.org/10.1177/0022034514540174] [PMID: 24943201]
[52]
Zhdanova, I.V.; Wurtman, R.J.; Lynch, H.J.; Ives, J.R.; Dollins, A.B.; Morabito, C.; Matheson, J.K.; Schomer, D.L. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin. Pharmacol. Ther., 1995, 57(5), 552-558.
[http://dx.doi.org/10.1016/0009-9236(95)90040-3] [PMID: 7768078]
[53]
Terazono, H.; Hamdan, A.; Matsunaga, N.; Hayasaka, N.; Kaji, H.; Egawa, T.; Makino, K.; Shigeyoshi, Y.; Koyanagi, S.; Ohdo, S. Modulatory effects of 5-fluorouracil on the rhythmic expression of circadian clock genes: A possible mechanism of chemotherapy-induced circadian rhythm disturbances. Biochem. Pharmacol., 2008, 75(8), 1616-1622.
[http://dx.doi.org/10.1016/j.bcp.2008.01.011] [PMID: 18329632]
[54]
Ha, J.H.; Hwang, D-Y.; Yu, J.; Park, D-H.; Ryu, S-H. Onset of manic episode during chemotherapy with 5-fluorouracil. Psychiatry Investig., 2011, 8(1), 71-73.
[http://dx.doi.org/10.4306/pi.2011.8.1.71] [PMID: 21519541]
[55]
Naidu, M.U.R.; Ramana, G.V.; Rani, P.U.; Mohan, I.K.; Suman, A.; Roy, P. Chemotherapy-induced and/or radiation therapy-induced oral mucositis-complicating the treatment of cancer. Neoplasia, 2004, 6(5), 423-431.
[http://dx.doi.org/10.1593/neo.04169] [PMID: 15548350]
[56]
Oronsky, B.; Goyal, S.; Kim, M.M.; Cabrales, P.; Lybeck, M.; Caroen, S.; Oronsky, N.; Burbano, E.; Carter, C.; Oronsky, A. A Review of clinical radioprotection and chemoprotection for oral mucositis. Transl. Oncol., 2018, 11(3), 771-778.
[http://dx.doi.org/10.1016/j.tranon.2018.03.014] [PMID: 29698934]
[57]
Gruber, S.; Bozsaky, E.; Roitinger, E.; Schwarz, K.; Schmidt, M.; Dörr, W. Early inflammatory changes in radiation-induced oral mucositis : Effect of pentoxifylline in a mouse model. Strahlenther. Onkol., 2017, 193(6), 499-507.
[http://dx.doi.org/10.1007/s00066-017-1119-8] [PMID: 28258409]
[58]
Song, M.K.; Park, M.Y.; Sung, M.K. 5-Fluorouracil-induced changes of intestinal integrity biomarkers in BALB/c mice. J. Cancer Prev., 2013, 18(4), 322-329.
[http://dx.doi.org/10.15430/JCP.2013.18.4.322] [PMID: 25337561]
[59]
Kim, H.; Bartley, G.E.; Young, S.A.; Davis, P.A.; Yokoyama, W. HPMC supplementation reduces abdominal fat content, intestinal permeability, inflammation, and insulin resistance in diet-induced obese mice. Mol. Nutr. Food Res., 2012, 56(9), 1464-1476.
[http://dx.doi.org/10.1002/mnfr.201200082] [PMID: 22782912]
[60]
Koizumi, R.; Azuma, K.; Izawa, H.; Morimoto, M.; Ochi, K.; Tsuka, T.; Imagawa, T.; Osaki, T.; Ito, N.; Okamoto, Y.; Saimoto, H.; Ifuku, S. Oral administration of surface-deacetylated chitin nanofibers and chitosan inhibit 5-fluorouracil-induced intestinal mucositis in mice. Int. J. Mol. Sci., 2017, 18(2), 1-11.
[http://dx.doi.org/10.3390/ijms18020279] [PMID: 28134832]