Polymeric nanoparticles containing 4-methoxychalcone attenuates hyperglycemia in diabetes-induced mice

Document Type : Research Paper

Authors

1 Faculty of Pharmaceutical Sciences, Federal University of Amazonas, Manaus, AM, Brazil

2 Institute of Health Sciences, Federal University of Pará, Belém, PA, Brazil

3 Laboratory of Medicine, Food and Cosmetic Technology, University of Brasilia, Brasilia, DF, Brazil

4 Faculty of Health Sciences, Federal University of Grande Dourados, Dourados, MS, Brazil

5 Department of Pharmaceutical Biotechnology, Chabahar University of Medical Science, Chabahar, Iran

Abstract

Objective(s): Diabetes mellitus is a chronic metabolic disorder characterized by persistent disturbances in glucose homeostasis. Novel therapeutic strategies are needed to improve glycemic control while minimizing toxicity. This study investigated the hypoglycemic potential of 4‑methoxychalcone (MPP), synthesized via the Claisen–Schmidt reaction, and evaluated the efficacy of its nanoencapsulation in diabetic mice.
Methods: MPP was synthesized and subsequently nanoencapsulated (NCs) using ethanol, isopropyl palmitate, and organic phase surfactants. Nanocarriers were characterized by particle size, polydispersity index (PDI), zeta potential, and morphology through transmission electron microscopy (TEM). Diabetes was induced in CL57/6BL mice using streptozotocin/nicotinamide. Animals were treated for 28 days with free MPP (200 mg/kg), metformin (200 mg/kg), or NCs (10 mg/kg). Biochemical assays were performed on blood samples, and histological analyses were conducted on liver tissues.
Results: NCs exhibited a mean particle size of 187 nm, zeta potential of −19.9 mV, and PDI of 0.21, demonstrating stability across varying temperatures and pH conditions. TEM confirmed spherical morphology and uniform distribution. Both metformin (176.33 ± 44.68 mg/dL, p < 0.0001) and NCs (163.2 ± 76.3 mg/dL, p < 0.0001) significantly reduced blood glucose levels. NCs further normalized glycated hemoglobin (HbA1c) without evidence of hepatotoxicity, as indicated by low malondialdehyde levels and preserved liver histology.
Conclusion: Nanoencapsulation of MPP enhances its antidiabetic efficacy, enabling therapeutic effects at lower doses while reducing toxicity risks. This strategy represents a promising approach for the development of safer and more effective antidiabetic interventions.

Keywords

Main Subjects

References

  1. Champe PC, Harvey RA, Ferrier DR. Bioquímica Ilustrada. 3a Porto Alegre (PA): Artmed; 2006.
  2. Baynes JW, Dominiczak MH. Bioquímica Medica. 5a Rio de Janeiro (RJ): Elsevier; 2019.
  3. Teng B, Duong M, Tossidou I, Yu X, Schiffer M. Role of protein kinase C in podocytes and development of glomerular damage in diabetic nephropathy. Front Endocrinol (Lausanne). 2014;5:5-179.
  4. Yingnan F, Lau ESH, Wu H, Yang A, Chow E, So Asa-Yee, et al. Incidence of long-term diabetes complications and mortality in youth-onset type 2 diabetes: A systematic review. Diabetes Res Clin Pract. 2022;191:e110030.
  5. Hamed AE, Elsahar M, Elwan NM, El-Nakeep S, Naguib M, Soliman HH, et al. Managing diabetes and liver disease association. Arab J Gastroenterol. 2018;19:166-179.
  6. Hamed AE, Elwan N, Naguib M, Elwakil R, Esmat G, El Kassas M, et al. Diabetes Association with Liver Diseases: An Overview for Clinicians. Endocr Metab Immune Disord Drug Targets. 2019;19:274-280.
  7. Meza LCE, San Martín OCA, Provoste JJr, Zaror CJF. [Pathophysiology of diabetic nephropathy: a literature review]. 2017;17:e6839.
  8. Shah MS, Brownlee M. Molecular and Cellular Mechanisms of Cardiovascular Disorders in Diabetes. Circ Res. 2016;118:1808-1829.
  9. Lehrke M, Marx N. Diabetes Mellitus and Heart Failure. Am J Med. 2017;130: S40-S50.
  10. Ochoa-González FL, González-Curiel IE, Cervantes-Villagrana AR, Fernández-Ruiz JC, Castañeda-Delgado JE. Innate Immunity Alterations in Type 2 Diabetes Mellitus: Understanding Infection Susceptibility. Curr Mol Med. 2021;21:318-331.
  11. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107:1058-1070.
  12. Pavlou DI, Paschou SA, Anagnostis P, Spartalis M, Spartalis E, Vryonidou A, Tentolouris N, Siasos G. Hypertension in patients with type 2 diabetes mellitus: Targets and management. Maturitas. 2018;112:71-77.
  13. Smulyan H, Lieber A, Safar ME. Hypertension, Diabetes Type II, and Their Association: Role of Arterial Stiffness. Am J Hypertens. 2016;29:5-13.
  14. Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;5:41.
  15. Brazilian Diabetes Society Guideline. Brazil: Brazilian Diabetes Society (SBD), 2019-2020. Available: https://www.saude.ba.gov.br/wp content/uploads/2020/02/Brazilian-Diabetes-Society-Guidelines -2019-2020.pdf
  16. Chantelau E, Lange G, Sonnenberg GE, Berger M. Acute cutaneous complications and catheter needle colonization during insulin pump therapy. Diabetes Care. 1987;10:478-482.
  17. Aloke C, Egwu CO, Aja PM, Obasi NA, Chukwu J, Akumadu BO, et al. Current Advances in the Management of Diabetes Mellitus. Biomedicines. 2022;10:2436.
  18. Apolinário AC, Salata GC, Bianco AFR, Fukumoria C, Lopes LB. Opening the pandora’s box of nanomedicine: there is indeed plenty of room at the bottom. Quim Nova. 2020;43:212-225.
  19. Hsieh CT, Hsieh TJ, El-Shazly M, Chuang DW, Tsai YH, Yen CT, et al. Synthesis of chalcone derivatives as potential anti-diabetic agents. Bioorg Med Chem Lett. 2012;22: 3912-3915.
  20. Federação Internacional de Diabetes. Diabetes Atlas, (10ª ed. Bruxelas). 2024. Available: https://www.diabetesatlas.org. https://diabetesatlas.org/atlas/tenth-edition/
  21. Shih TL, Ming-Hwa LMH, Li CW, Kuo CF. Halo-Substituted Chalcones and Azachalcones-Inhibited, Lipopolysaccharited-Stimulated, Pro-Inflammatory Responses through the TLR4-Mediated Pathway. Molecules. 2018;23:597.
  22. Neto RAM, Santos CBR, Henriques SVC, Machado LO, Cruz JN, Silva CHTP, et al. Novel chalcones derivatives with potential antineoplastic activity investigated by docking and molecular dynamics simulations. J Biomol Struct Dyn. 2022;40:2204-2216.
  23. Lee YS, Lim SS, Shin KH, Kim YS, Ohuchi K, Jung SH. Anti-angiogenic and anti-tumor activities of 2'-hydroxy-4'-methoxychalcone. Biol Pharm Bull. 2006;29:1028-103.
  24. Zhuang C, Zhang W, Sheng C, Zhang W, Xing C, Miao Z. Chalcone: A Privileged Structure in Medicinal Chemistry. Chem Rev. 2017;117:7762-7810.
  25. Welday KS, Hailu GS, Taye DK. Design, Synthesis, Characterization and in vivo Antidiabetic Activity Evaluation of Some Chalcone Derivatives. Drug Des Devel Ther. 2021;15:3119-3129.
  26. Prelog V. Untersuchungen über assimétrica Synthesen I. Über den sterischen Verlauf der Reaktion von α-Ketosäure-esttern optisch activer Alkohole mit Grignard 'schen Verbindungen. Helvetica Chimica Acta. 1953;36:308-319.
  27. Kaewin S, Poolsri W, Korkut GG, Patrakka J, Aiebchun T, Rungrotmongkol T, et al. A sulfonamide chalcone AMPK activator ameliorates hyperglycemia and diabetic nephropathy in db/db mice. Biomed Pharmacother. 2023;165:115158.
  28. Acho LDR, Oliveira ESC, Carneiro SB, Melo FPA, Mendonça LS, Costa RA, et al. Antidiabetic Activities and GC-MS Analysis of 4-Methoxychalcone. Applied Chem. 2024;4:140-156.
  29. Cabrera M, Simoen M, Falchi G, Lavaggi ML, Piro OE, Castellano EE, et al. Synthetic chalcones, flavanones, and flavones as antitumoral agents: biological evaluation and structure-activity relationships. Bioorg Med Chem. 2007;15:3356-3367.
  30. Iftikhar S, Khan S, Bilal A, Manzoor S, Abdullah M, Emwas AH, et al. Synthesis and evaluation of modified chalcone based p53 stabilizing agents. Bioorg Med Chem Lett. 2017;27: 4101-4106.
  31. Melo CP, Pimenta M. Nanociência e Nanotecnologia. Brasília (DF). Revista Parcerias Estratégicas. 2004;18:9-21.
  32. Fessi H, Puisieux F, Devissaguet JPh, Ammoury N, Benita S. Nanocapsule formation by interfacial polymer deposition following solvent displacement. Int J Pharm. 1989;55:R1-R4.
  33. Dimer FA, Friedrich RB, Beck RCR, Guterres SS. Impacts of nanotechnology on health: production of medicines. Quim Nova. 2013;36:1520-1526.
  34. Acácio BR, Robles VB, Prada AL, Assis JM, de Souza TP, Keita H, et al. Kollicoat MAE® 100P as a film former polymer for nanoparticles preparation. Rev Colomb Cienc Quím Farm. 2022;51:1215-1231.
  35. Oliveira ESC, Acho LDR, Morales-Gamba RD, Rosário AS, Barcellos JFM, Lima ES, et al. Hypoglycemic effect of the dry leaf extract of Myrcia multiflora in streptozotocin-induced diabetic mice. J Ethnopharmacol. 2023;307:116241.
  36. Ahmed M, Ahmed S. Functional, Diagnostic and Therapeutic Aspects of Gastrointestinal Hormones. Gastroenterol Res. 2019;12:233-244.
  37. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Bioquímica Anal. 1979;95:351-358.
  38. Gomes MDB. Glitazones and metabolic syndrome: mechanisms of action, pathophysiology and therapeutic indications. Arquivos Brasileiros de Endocrinologia & Metabologia. 2006;50:271-280.
  39. Owens IDE, Peppas NA. Opsonization, biodistribution, and pharmacokinetics of polymeric nanoparticles. Int. Journal of Pharm. 2006;307:93-102.
  40. Kulkarni SA, Feng SS. Effects of Particle Size and Surface Modification on Cellular Uptake and Biodistribution of Polymeric Nanoparticles for Drug Delivery. Pharmaceutical Research. 2013;30:2512-2522.
  41. Zeta Meter, Inc. Potencial Zeta: Um Curso Completo em 5 Minutos. available in http://www.zeta-meter.com
  42. Han Y, Lee SH, Lee IS, Lee KY. Regulatory effects of 4-methoxychalcone on adipocyte differentiation through PPARγ activation and reverse effect on TNF-α in 3T3-L1 cells. Food Chem Toxicol. 2017;106:17-24.
  43. Legrand P, Barratt G, Mosqueira V, Fessi H. Devissaguet JP. Polymeric nanocapsules as drug delivery systems. S.T.P. Pharma sciences. 1999;9:411-418.
  44. Neto SF, Prada AL, Acho LDR, Torquato HFV, Lima CS, Paredes-Gamero EJ, et al. α-amyrin-loaded nanocapsules produce selective cytotoxic activity in leukemic cells. Biomed Pharmacother. 2021;139:111656.
  45. Valencia MS. Synthesis and characterization of nanoparticles containing polyphenols with potential application in the food industry [PhD Thesis]. Pernambuco: Federal University of Pernambuco: 2020.
  46. Patel P, Obrigado A, Kapoor DU, Prajapati BG. QbD decorated ellagic acid loaded polymeric nanoparticles: Factors influencing desolvation method and preliminary evaluations. Nano-Structures & Nano-Objects, 2024;40:101378.
  47. Shahsavani D, Kazerani HR, Kaveh S, Gholipour-Kanani H. Determination of some normal serum parameters in starry sturgeon (Acipenser stellatus Pallas, 1771) during spring season. Comp Clin Path. 2010;19:57-61.
  48. Young JF, Stagsted J, Jensen SK, Karlsson AH, Henckel P. Ascorbic acid, alpha-tocopherol, and oregano supplements reduce stress-induced deterioration of chicken meat quality. Poultry Science. 2003;82:1343-1351.
  49. Cotinguiba GG, Silva JRN, de Sá Azevedo RR, Rocha TJM, dos Santos AF. Método de avaliação da defesa antioxidante: uma revisão de literatura. Journal of Health Sciences. 2013;15:231-237.
  50. American Diabetes Association. 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes—2024. Diabetes Care. 2024;47(Supplement 1):S20-S42.
  51. Sociedade Brasileira de Diabetes. Diretrizes da Sociedade Brasileira de diabetes 2023-2024. São Paulo: Editora Clannad. 2023; 65.
  52. Marshall RH, Eissa M, Bluth EI, Gulotta PM, Davis NK. Hepatorenal index as an accurate, simple, and effective tool in screening for steatosis. AJR Am J Roentgenol. 2012;199:997-1002.

 

Nanomedicine Journal
Volume 13, Issue 1
January 2026
Pages 159-169

Files

Share

How to cite

Statistics