Skip to main content
SpringerLink
Log in

Oral Administration of Melatonin or Succinyl Melatonin Niosome Gel Benefits 5-FU-Induced Small Intestinal Mucositis Treatment in Mice

  • Research Article
  • Published:
AAPS PharmSciTech Aims and scope Submit manuscript

Abstract

Mucositis is one of the most adverse effects of 5-fluorouracil (5-FU) and had no standard drug for treatment. Melatonin is a neurohormone, and can ameliorate radiotherapy-induced small intestinal mucositis. Melatonin encapsulated in niosomes improved its poor bioavailability. Succinyl melatonin, a melatonin derivative, showed prolonged release compared with melatonin. This study investigated the efficacy of melatonin niosome gel (MNG) and succinyl melatonin niosome gel (SNG) in 5-FU-induced small intestinal mucositis treatment in mice. MNG and SNG with particle sizes of 293 and 270 nm were shown to have mucoadhesive potentials. The effect of a daily oral application of MNG, SNG, or fluocinolone acetonide gel (FAG, positive control) was compared to that of the normal group. The body weight, food consumption, histology, Fourier transform infrared (FTIR) spectroscopy, inflammatory cytokines (tumor necrosis factor (TNF)-α and interleukin (IL)-1β), and malondialdehyde (MDA) in the small intestine were monitored. The results showed decreased %body weight and food consumption in all 5-FU-injected groups compared with the normal group. The MNG and SNG treatments maintained the food consumption and the normal integrity of the small intestines, as evidenced by villus length and crypt depth, similar to the observations in the normal groups. The FTIR spectra showed no change in lipids of the MNG and SNG groups compared with the normal group. Moreover, SNG could reduce IL-1β content to a level that was not different from the level in the normal groups. Therefore, the oral application of MNG and SNG could protect against 5-FU-induced small intestinal mucositis in mice.

Graphical abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Longley DB, Harkin DP, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330–8.

    Article  CAS  PubMed  Google Scholar 

  2. Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, Hauer-Jensen M, et al. Perspectives on cancer therapy-induced mucosal injury. Cancer. 2004;100(S9):1995–2025.

    Article  PubMed  Google Scholar 

  3. Peterson DE, Bensadoun RJ, Roila F. Management of oral and gastrointestinal mucositis: ESMO clinical practice guidelines. Ann Oncol. 2011;22(SUPPL. 6):78–84.

    Article  Google Scholar 

  4. Soares PMG, Mota JMSC, Gomes AS, Oliveira RB, Assreuy AMS, Brito GAC, et al. Gastrointestinal dysmotility in 5-fluorouracil-induced intestinal mucositis outlasts inflammatory process resolution. Cancer Chemother Pharmacol. 2008;63(1):91–8.

    Article  CAS  PubMed  Google Scholar 

  5. Sonis ST. New thoughts on the initiation of mucositis. Oral Dis. 2010;16(7):597–600.

    Article  CAS  PubMed  Google Scholar 

  6. Al-Ansari S, Zecha JAEM, Barasch A, de Lange J, Rozema FR, Raber-Durlacher JE. Oral mucositis induced by anticancer therapies. Curr Oral Heal Reports. 2015;2(4):202–11.

    Article  Google Scholar 

  7. Claustrat B, Leston J. Melatonin: physiological effects in humans. Neurochirurgie. 2015;61(2–3):77–84.

    Article  CAS  PubMed  Google Scholar 

  8. Singh M, Jadhav HR. Melatonin: functions and ligands. Drug Discov Today. 2014;19(9):1410–8.

    Article  CAS  PubMed  Google Scholar 

  9. Tarocco A, Caroccia N, Morciano G, Wieckowski MR, Ancora G, Garani G, et al. 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.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Favero G, Franceschetti L, Bonomini F, Rodella LF, Rezzani R. Melatonin as an anti-inflammatory agent modulating inflammasome activation. Int J Endocrinol. 2017:2017.1–13.

  11. Tahan G, Gramignoli R, Marongiu F, Aktolga S, Cetinkaya A, Tahan V, et al. Melatonin expresses powerful anti-inflammatory and antioxidant activities resulting in complete improvement of acetic-acid-induced colitis in rats. Dig Dis Sci. 2011;56(3):715–20.

    Article  CAS  PubMed  Google Scholar 

  12. Poeggeler B, Thuermann S, Dose A, Schoenke M, Burkhardt S, Hardeland R. Melatonin’s unique radical scavenging properties - roles of its functional substituents as revealed by a comparison with its structural analogs. J Pineal Res. 2002;33(1):20–30.

    Article  CAS  PubMed  Google Scholar 

  13. Sánchez A, Calpena AC, Clares B. Evaluating the oxidative stress in inflammation: role of melatonin. Int J Mol Sci. 2015;16(8):16981–7004.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Ortiz F, Acuña-Castroviejo D, Doerrier C, Dayoub JC, Lõpez LC, Venegas C, et al. Melatonin blunts the mitochondrial/NLRP3 connection and protects against radiation-induced oral mucositis. J Pineal Res. 2015;58(1):34–49.

    Article  CAS  PubMed  Google Scholar 

  15. Fernandez-Gil B, Abdel Moneim AE, Ortiz F, Shen YQ, Soto-Mercado V, Mendivil-Perez M, et al. Melatonin protects rats from radiotherapy-induced small intestine toxicity. PLoS One. 2017;12(4):1–21.

    Article  Google Scholar 

  16. Onseng K, Johns NP, Khuayjarernpanishk T, Subongkot S, Priprem A, Hurst C, et al. 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):957–63.

    Article  PubMed  Google Scholar 

  17. Harpsøe NG, Andersen LPH, Gögenur I, Rosenberg J. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. 2015;71(8):901–9.

    Article  PubMed  CAS  Google Scholar 

  18. Priprem A, Nukulkit C, Johns NP, Laohasiriwong S, Yimtae K, Soontornpas C. Transmucosal delivery of melatonin-encapsulated niosomes in a mucoadhesive gel. Ther Deliv. 2018;9(5):343–57.

    Article  CAS  PubMed  Google Scholar 

  19. Priprem A, Netweera V, Mahakunakorn P, Johns NP, Johns JR. Prolonged anti-inflammatory activity of topical melatonin by niosomal encapsulation. Adv Mater Res. 2014;902:70–5.

    Article  CAS  Google Scholar 

  20. Moghassemi S, Hadjizadeh A. Nano-niosomes as nanoscale drug delivery systems: an illustrated review. J Control Release. 2014;185(1):22–36.

    Article  CAS  PubMed  Google Scholar 

  21. Ag Seleci D, Seleci M, Walter JG, Stahl F, Scheper T. Niosomes as nanoparticular drug carriers: fundamentals and recent applications. J Nanomater. 2016;2016:1–14.

    Article  Google Scholar 

  22. Sosnik A, Das Neves J, Sarmento B. Mucoadhesive polymers in the design of nano-drug delivery systems for administration by non-parenteral routes: a review. Prog Polym Sci. 2014;39(12):2030–75.

    Article  CAS  Google Scholar 

  23. Huang YL, Kou JP, Liu JH, Liu N, Yu BY. Comparison of anti-inflammatory activities of ruscogenin, a major steroidal sapogenin from Radix Ophiopogon japonicus, and its succinylated derivative, RUS-2HS. Drug Dev Res. 2008;69(4):196–202.

    Article  CAS  Google Scholar 

  24. Skorik YA, Kritchenkov AS, Moskalenko YE, Golyshev AA, Raik SV, Whaley AK, et al. Synthesis of N-succinyl- and N-glutaryl-chitosan derivatives and their antioxidant, antiplatelet, and anticoagulant activity. Carbohydr Polym. 2017;166:166–72.

    Article  CAS  PubMed  Google Scholar 

  25. Vǎn Thoi P, Nam NH. Design and synthesis of sustain-acting melatonin prodrugs. J Chemother. 2013;2013:1–7.

    Google Scholar 

  26. Nukulkit C, Priprem A, Damrongrungruang T, Benjavongkulchai E, Pratheepawanit JN. Effect of polycaprolactone on in vitro release of melatonin encapsulated niosomes in artificial and whole saliva. J Drug Deliv Sci Technol. 2014;24(2):153–8.

    Article  CAS  Google Scholar 

  27. Priprem A, Damrongrungruang T, Limsitthichaikoon S, Khampaenjiraroch B, Nukulkit C, Thapphasaraphong S, et al. Topical niosome gel containing an anthocyanin complex: a potential oral wound healing in rats. AAPS PharmSciTech. 2018;19(4):1681–92.

    Article  CAS  PubMed  Google Scholar 

  28. Kanjanabat S, Pongjanyakul T. Preparation and characterization of nicotine-magnesium aluminum silicate complex-loaded sodium alginate matrix tablets for buccal delivery. AAPS PharmSciTech. 2011;12(2):683–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 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.

  30. Hamouda N, Sano T, Oikawa Y, Ozaki T, Shimakawa M, Matsumoto K, et al. 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):159–68.

    Article  CAS  PubMed  Google Scholar 

  31. Kato S, Hayashi S, Kitahara Y, Nagasawa K, Aono H, Shibata J, et al. 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):1–15.

    Article  Google Scholar 

  32. Dies H, Cheung B, Tang J, Rheinstädter MC. The organization of melatonin in lipid membranes. Biochim Biophys Acta. 2015;1848(4):1032–40.

    Article  CAS  PubMed  Google Scholar 

  33. Coviello T, Trotta AM, Marianecci C, Carafa M, Di Marzio L, Rinaldi F, et al. Gel-embedded niosomes: preparation, characterization and release studies of a new system for topical drug delivery. Colloids Surf B: Biointerfaces. 2015;125:291–9.

    Article  CAS  PubMed  Google Scholar 

  34. Esiringü F, Tuğcu-Demiröz F, Acartürk F, Coşkun Cevher Ş, Bircan F, Sarı Kılıçaslan SM. Investigation of the effect of intracolonic melatonin gel formulation on acetic acid-induced colitis. Drug Deliv. 2016;23(7):2318–26.

    Article  PubMed  CAS  Google Scholar 

  35. Koziolek M, Grimm M, Becker D, Iordanov V, Zou H, Shimizu J, et al. Investigation of pH and temperature profiles in the GI tract of fasted human subjects using the Intellicap® System. J Pharm Sci. 2015;104(9):2855–63.

    Article  CAS  PubMed  Google Scholar 

  36. Beasley DE, Koltz AM, Lambert JE, Fierer N, Dunn RR. The evolution of stomach acidity and its relevance to the human microbiome. PLoS One. 2015;10(7):e0134116.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. 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):322–9.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Bertolini M, Sobue T, Thompson A, Dongari-Bagtzoglou A. Chemotherapy induces oral mucositis in mice without additional noxious stimuli. Transl Oncol. 2017;10(4):612–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Uthaiwat P, Daduang J, Priprem A, Settasatian C, Chio-Srichan S, Lee Y-C, et al. Topical melatonin niosome gel for the treatment of 5-FU-induced oral mucositis in mice. Curr Drug Deliv. 2020;17. https://doi.org/10.2174/1567201817666200525151848.

  40. Ciriaco M, Ventrice P, Russo G, Scicchitano M, Mazzitello G, Scicchitano F, et al. Corticosteroid-related central nervous system side effects. J Pharmacol Pharmacother. 2013;4(Suppl 1):S94–8.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Markovic BD, Vladimirov SM, Cudina OA, Odovic JV, Karljikovic-Rajic KD. A PAMPA assay as fast predictive model of passive human skin permeability of new synthesized corticosteroid C-21 esters. Molecules. 2012;17(1):480–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Umar S. Intestinal stem cells. Curr Gastroenterol Rep. 2010;12(5):340–8.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Movasaghi Z, Rehman S, Rehman IU. Fourier transform infrared (FTIR) spectroscopy of biological tissues. Appl Spectrosc Rev. 2008;43(2):134–79.

    Article  CAS  Google Scholar 

  44. Balan V, Mihai CT, Cojocaru FD, Uritu CM, Dodi G, Botezat D, et al. Vibrational spectroscopy fingerprinting in medicine: from molecular to clinical practice. Materials (Basel). 2019;12(18):1–40.

    Article  CAS  Google Scholar 

  45. Gao Y, Huo X, Dong L, Sun X, Sai H, Wei G, et al. Fourier transform infrared microspectroscopy monitoring of 5-fluorouracil-induced apoptosis in SW620 colon cancer cells. Mol Med Rep. 2015;11(4):2585–91.

    Article  CAS  PubMed  Google Scholar 

  46. Focaccetti C, Bruno A, Magnani E, Bartolini D, Principi E. Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ROS production in endothelial cells and cardiomyocytes. PLoS One. 2015;10(2):e0115686.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. National Center for Biotechnology Information. US National Library of Medicine, Rockville. 2020. https://pubchem.ncbi.nlm.nih.gov/compound/Fluocinolone-acetonide. Accessed 29 June 2020.

  48. Burry JN. Topical drug addiction: adverse effects of fluorinated corticosteroid creams and ointments. Med J Aust. 1973;1(8):393–6.

    Article  CAS  PubMed  Google Scholar 

  49. Oliver JC, Bland LA, Oettinger CW, Arduino MJ, McAllister SK, Aguero SM, et al. Cytokine kinetics in an in vitro whole blood model following an endotoxin challenge. Lymphokine Cytokine Res. 1993;12(2):115–20.

    CAS  PubMed  Google Scholar 

  50. Greischel A, Zahn G. Pharmacokinetics of recombinant human tumor necrosis factor alpha in rhesus monkeys after intravenous administration. J Pharmacol Exp Ther. 1989;251(1): :358-61.

  51. Kim H, Bartley GE, Young SA, Davis PA, Yokoyama W. HPMC supplementation reduces abdominal fat content, intestinal permeability, inflammation, and insulin resistance in diet-induced obese mice. Mol Nutr Food Res. 2012;56:1464–76.

    Article  CAS  PubMed  Google Scholar 

  52. Koizumi R, Azuma K, Izawa H, Morimoto M, Ochi K. Oral administration of surface-deacetylated chitin nanofibers and chitosan inhibit 5-fluorouracil-induced intestinal mucositis in mice. Int J Mol Sci. 2017;18(2):279.

    Article  PubMed Central  CAS  Google Scholar 

  53. Limsitthichaikoon S, Khampaenjiraroch B, Damrongrungruang T, Limphirat W, Thapphasaraphong S, Priprem A. Topical oral wound healing potential of anthocyanin complex: animal and clinical studies. Ther Deliv. 2018;9(5):359–74.

    Article  CAS  PubMed  Google Scholar 

  54. Arafa MG, Ghalwash D, El-Kersh DM, Elmazar MM. Propolis-based niosomes as oromuco-adhesive films: a randomized clinical trial of a therapeutic drug delivery platform for the treatment of oral recurrent aphthous ulcers. Sci Rep. 2018;8:18056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhang H, Zhang J, Streisand JB. Oral mucosal drug delivery: clinical pharmacokinetics and therapeutic applications. Clin Pharmacokinet. 2002;41(9):661–80.

    Article  CAS  PubMed  Google Scholar 

  56. Patel VF, Liu F, Brown MB. Advances in oral transmucosal drug delivery. J Control Release. 2011;153(2):106–16.

    Article  CAS  PubMed  Google Scholar 

  57. Hua S. Advances in nanoparticulate drug delivery approaches for sublingual and buccal administration. Front Pharmacol. 2019;10:1–9.

    Article  CAS  Google Scholar 

  58. Abhang P, Momin M, Inamdar M, Kar S. Transmucosal drug delivery- an overview. Drug Deliv Lett. 2013;4(1):26–37.

    Article  CAS  Google Scholar 

  59. Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvoa JR. Significance of melatonin in antioxidative defense system: reactions and products. NeuroSignals. 2000;9(3–4):137–59.

    Article  CAS  Google Scholar 

  60. Tretter L, Patocs A, Chinopoulos C. Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis. Biochim Biophys Acta. 2016;1857(8):1086–101.

    Article  CAS  PubMed  Google Scholar 

  61. Zhang YY, Yang L. Interactions between human cytochrome P450 enzymes and steroids: physiological and pharmacological implications. Expert Opin Drug Metab Toxicol. 2009;5(6):621–9.

    Article  CAS  PubMed  Google Scholar 

  62. Boora K. Fluocinolone. xPharm: the comprehensive pharmacology reference. 2007. 1–5.

Download references

Acknowledgements

Faculty of Medicine, Khon Kaen University, is thanked for facilitating advanced instruments. Pimpichaya Sangchart, Pei-Yu Huang, Chin-Wei Kuo, and Kanokporn Sahunalu are appreciated for technical assistance.

Funding

This work was financially supported by Royal Golden Jubilee (RGJ) Ph.D. program (grant number PHD/0218/2557) joint with Synchrotron Light Research Institute (Public Organization), Thailand, Research and Academic Services from Khon Kaen University (grant number RP63002), Centre for Research and Development of Medical Diagnostic Laboratories, Khon Kaen University, Thailand.

Author information

Authors and Affiliations

  1. Biomedical Sciences Program, Graduate School, Khon Kaen University, Khon Kaen, 40002, Thailand

    Prangtip Uthaiwat

  2. Melatonin Research Group, Khon Kaen University, Khon Kaen, 40002, Thailand

    Aroonsri Priprem

  3. Synchrotron Light Research Institute (Public Organization), Nakhon Ratchasima, 30000, Thailand

    Sirinart Chio-Srichan

  4. Department of Pathology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Chatri Settasatian

  5. National Synchrotron Radiation Research Center, Hsinchu, 30076, Taiwan, Republic of China

    Yao-Chang Lee

  6. Division of Pharmaceutical Toxicology, Faculty of Pharmaceutical Sciences, Melatonin Research Group, Khon Kaen University, Khon Kaen, 40002, Thailand

    Pramote Mahakunakorn

  7. Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand

    Patcharee Boonsiri

  8. Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, 40002, Thailand

    Chanvit Leelayuwat, Patcharaporn Tippayawat & Jureerut Daduang

  9. Division of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Melatonin Research Group, Khon Kaen University, Khon Kaen, 40002, Thailand

    Ploenthip Puthongking

Authors
  1. Prangtip Uthaiwat
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aroonsri Priprem
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sirinart Chio-Srichan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chatri Settasatian
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yao-Chang Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Pramote Mahakunakorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Patcharee Boonsiri
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chanvit Leelayuwat
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Patcharaporn Tippayawat
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ploenthip Puthongking
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jureerut Daduang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jureerut Daduang.

Ethics declarations

Competing Interest

The authors declare no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

ESM 1

(DOCX 16 kb)

Supplementary Fig. 1

Cumulative release curves of melatonin from MG, MN, and MNG (a) in PBS pH 2 and (b) in PBS pH 7.8. Cumulative release curves of succinyl melatonin from SG, SN, and SNG, (c) in PBS pH 2, (d) in PBS pH 7.8, and (e) Higuchi release model in PBS pH 2 (mean ± SD, n = 3) (PNG 1728 kb)

High Resolution (TIF 2785 kb)

Supplementary Fig. 2.

FTIR spectra of succinyl melatonin in a solution at pH 11 with a gradual decline of C-N stretching in 8 min and an incline of N-H stretching (red line), indicating the conversion of succinyl melatonin into melatonin at this condition. (PNG 1007 kb)

High Resolution (TIF 1603 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Uthaiwat, P., Priprem, A., Chio-Srichan, S. et al. Oral Administration of Melatonin or Succinyl Melatonin Niosome Gel Benefits 5-FU-Induced Small Intestinal Mucositis Treatment in Mice. AAPS PharmSciTech 22, 200 (2021). https://doi.org/10.1208/s12249-021-01941-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1208/s12249-021-01941-y

KEY WORDS

Search

Navigation