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Chitosan hydrogels chemically crosslinked with L-glutamic acid and their potential use in drug delivery

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Abstract

Controlled drug release systems have the characteristics of eliminating or reducing side effects and producing a therapeutic concentration of the drug that is stable in the body. The synthesis of hydrogels from natural polymers allows innovation in new materials that promote more effective, selective and safe therapies, in comparison with hydrogel systems based on synthetic polymers where their main limitation may be their biocompatibility and degradation. For this reason, in this work the synthesis of hydrogels of chitosan crosslinked with glutamic acid is proposed as the basis of new trends in smart materials for their potential use in the controlled release of drugs, the hydrogels were prepared from an amidation reaction between the amino groups of chitosan and the carboxyl groups of L-glutamic acid, using N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) as activator of the carboxyl groups. The hydrogels obtained were characterized by SEM, FTIR, TGA techniques, swelling kinetics and antimicrobial activity. They exhibited excellent swelling capacity and good performance when exposed to different pH and temperature conditions. The bacterial inhibition percentages demonstrated the antimicrobial activity of chitosan hydrogels and the results obtained potentially favored their use as reservoirs for controlled drug release.

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References

  1. Chiesa E, Genta I, Dorati R, Modena T, Conti B (2019) Poly(gamma-glutamic acid) based thermosetting hydrogels for injection: rheology and functional parameters evaluation. React Funct Polym 140:93–102. https://doi.org/10.1016/j.reactfunctpolym.2019.03.021

    Article  CAS  Google Scholar 

  2. Ahmed EM (2015) Hydrogel: preparation, characterization, and applications: a review. J Adv Res 6(2):105–121. https://doi.org/10.1016/j.jare.2013.07.006

    Article  CAS  PubMed  Google Scholar 

  3. Ullah F, Othman MBH, Javed F, Ahmad Z, Akil HM (2015) Classification, processing and application of hydrogels: a review. Mater Sci Eng C 57:414–433

    Article  CAS  Google Scholar 

  4. Hamedi H, Moradi S, Hudson SM, Tonelli AE (2018) Chitosan based hydrogels and their applications for drug delivery in wound dressings: a review. Carbohydr Polym 199(March):445–460. https://doi.org/10.1016/j.carbpol.2018.06.114

    Article  CAS  PubMed  Google Scholar 

  5. Peppas NA, Bures P, Leobandung W, Ichikawa H (2000) Hydrogels in pharmaceutical formulations. Eur J of Pharm Biopharm 50(1):27–46. https://doi.org/10.1016/S0939-6411(00)00090-4

    Article  CAS  Google Scholar 

  6. Timur M, Paşa A (2018) Synthesis, characterization, swelling, and metal uptake studies of aryl cross-linked Chitosan hydrogels. ACS Omega 3(12):17416–17424. https://doi.org/10.1021/acsomega.8b01872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Peniche C, Argüelles-Monal W, Peniche H, Acosta N (2003) Chitosan: an attractive biocompatible polymer for microencapsulation. Macromol Biosci 3(10):511–520. https://doi.org/10.1002/mabi.200300019

    Article  CAS  Google Scholar 

  8. Rinaudo M (2006) Chitin and chitosan: properties and applications. Prog Polym Sci (Oxford) 31(7):603–632. https://doi.org/10.1016/j.progpolymsci.2006.06.001

    Article  CAS  Google Scholar 

  9. Dergunov SA, Mun GA (2009) \(\gamma\)-irradiated chitosan-polyvinyl pyrrolidone hydrogels as pH-sensitive protein delivery system. Radiat Phys Chem 78(1):65–68. https://doi.org/10.1016/j.radphyschem.2008.07.003

    Article  CAS  Google Scholar 

  10. Moussout H, Ahlafi H, Aazza M, Bourakhouadar M (2016) Kinetics and mechanism of the thermal degradation of biopolymers chitin and chitosan using thermogravimetric analysis. Polym Degrad Stab 130:1–9. https://doi.org/10.1016/j.polymdegradstab.2016.05.016

    Article  CAS  Google Scholar 

  11. Vunain E, Mishra AK, Mamba BB (2017) Fundamentals of chitosan for biomedical applications, vol 1. Elsevier. https://doi.org/10.1016/B978-0-08-100230-8.00001-7

  12. Dimassi S, Tabary N, Chai F, Blanchemain N, Martel B (2018) Sulfonated and sulfated chitosan derivatives for biomedical applications: a review. Carbohydr Polym 202:382–396. https://doi.org/10.1016/j.carbpol.2018.09.011

    Article  CAS  PubMed  Google Scholar 

  13. Ahmed S, Ikram S (2016) Chitosan based scaffolds and their applications in wound healing. Achiev Life Sci 10(1):27–37. https://doi.org/10.1016/j.als.2016.04.001

    Article  Google Scholar 

  14. Muxika A, Etxabide A, Uranga J, Guerrero P, de la Caba K (2017) Chitosan as a bioactive polymer: processing, properties and applications. Int J Biol Macromol 105:1358–1368. https://doi.org/10.1016/j.ijbiomac.2017.07.087

    Article  CAS  PubMed  Google Scholar 

  15. Mohammadzadeh Pakdel P, Peighambardoust SJ (2018) Review on recent progress in chitosan-based hydrogels for wastewater treatment application. Carbohydr Polym 201:264–279. https://doi.org/10.1016/j.carbpol.2018.08.070

    Article  CAS  PubMed  Google Scholar 

  16. Song Z, Li G, Guan F, Liu W (2018) Application of chitin/chitosan and their derivatives in the papermaking industry. Polymers. https://doi.org/10.3390/polym10040389

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wei H, Gao B, Ren J, Li A, Yang H (2018) Coagulation/flocculation in dewatering of sludge: a review. Water Res 143(2015):608–631. https://doi.org/10.1016/j.watres.2018.07.029

    Article  CAS  PubMed  Google Scholar 

  18. Ahmed S, Annu AA, Sheikh JA (2018) review on chitosan centred scaffolds and their applications in tissue engineering. Int J Biol Macromol 116(2017):849–862. https://doi.org/10.1016/j.ijbiomac.2018.04.176

    Article  CAS  PubMed  Google Scholar 

  19. Morin-Crini N, Lichtfouse E, Torri G, Crini G (2019) Fundamentals and applications of Chitosan, pp 49–123. https://doi.org/10.1007/978-3-030-16538-3_2

  20. Habibie S, Hamzah M, Anggaravidya M, Kalembang E (2016) The effect of chitosan on physical and mechanical properties of paper. J Chem Eng Mater Sci 7(1):1–10. https://doi.org/10.5897/jcems2015.0235

    Article  CAS  Google Scholar 

  21. Dash M, Chiellini F, Ottenbrite RM, Chiellini E (2011) Chitosan: a versatile semi-synthetic polymer in biomedical applications. Prog Polym Sci(Oxford) 36(8):981–1014. https://doi.org/10.1016/j.progpolymsci.2011.02.001

    Article  CAS  Google Scholar 

  22. Bernkop-Schnürch A, Dünnhaupt S (2012) Chitosan-based drug delivery systems. Eur J Pharm Biopharm 81(3):463–469. https://doi.org/10.1016/j.ejpb.2012.04.007

    Article  CAS  PubMed  Google Scholar 

  23. Wei Z, Yang JH, Liu ZQ, Xu F, Zhou JX, Zrínyi M, Osada Y, Chen YM (2015) Novel biocompatible polysaccharide-based self-healing hydrogel. Adv Funct Mater 25(9):1352–1359. https://doi.org/10.1002/adfm.201401502

    Article  CAS  Google Scholar 

  24. Ferreira MOG, Leite LLR, de Lima IS, Barreto HM, Nunes LCC, Ribeiro AB, Osajima JA, da Silva Filho EC (2016) Chitosan Hydrogel in combination with Nerolidol for healing wounds. Carbohydr Polym 152:409–418. https://doi.org/10.1016/j.carbpol.2016.07.037

    Article  CAS  PubMed  Google Scholar 

  25. Tsao CT, Chang CH, Lin YY, Wu MF, Wang JL, Han JL, Hsieh, KH (2010) Antibacterial activity and biocompatibility of a chitosan-\(\gamma\)- poly(glutamic acid) polyelectrolyte complex hydrogel. https://doi.org/10.1016/j.carres.2010.06.002

  26. Lee YH, Chang JJ, Yang MC, Chien CT, Lai WF (2012) Acceleration of wound healing in diabetic rats by layered hydrogel dressing. Carbohydr Polym 88(3):809–819. https://doi.org/10.1016/j.carbpol.2011.12.045

    Article  CAS  Google Scholar 

  27. Pereira CL, Antunes JC, Gonçalves RM, Ferreira-Da-Silva F, Barbosa MA (2012) Biosynthesis of highly pure poly-gamma-glutamic acid for biomedical applications. J Mater Sci Mater Med 23(7):1583–1591. https://doi.org/10.1007/s10856-012-4639-x

    Article  CAS  PubMed  Google Scholar 

  28. Puppi D, Migone C, Morelli A, Bartoli C, Gazzarri M, Pasini D, Chiellini F (2016) Microstructured chitosan/poly(\(\gamma\)-glutamic acid) polyelectrolyte complex hydrogels by computer-aided wet-spinning for biomedical three-dimensional scaffolds. J Bioact Comp Polym 31(5):531–549. https://doi.org/10.1177/0883911516631355

    Article  CAS  Google Scholar 

  29. Yan X, Tong Z, Chen Y, Mo Y, Feng H, Li P, Qu X, Jin S (2017) Bioresponsive materials for drug delivery based on carboxymethyl chitosan/poly(gamma-glutamic acid) composite microparticles. Mar Drugs. https://doi.org/10.3390/md15050127

    Article  PubMed  PubMed Central  Google Scholar 

  30. Torres J, Kremer C, Pardo H, Suescun L, Mombrú A, Castiglioni J, Domínguez S, Mederos A, Kremer E (2003) Preparation and crystal structure of new samarium complexes with glutamic acid. J Mol Struct 660(1–3):99–106. https://doi.org/10.1016/j.molstruc.2003.08.003

    Article  CAS  Google Scholar 

  31. Fouad EA, El-Badry M, Alanazi FK, Arafah MM, Alsarra IA (2009) Preparation and investigation of acetyl salicylic acid-glutamic acid complex: a novel oral delivery system. Digest J Nanomater Biostruct 4(2):299–308

    Google Scholar 

  32. Singh J, Dutta PK, Dutta J, Hunt AJ, Macquarrie DJ, Clark JH (2009) Preparation and properties of highly soluble chitosan-l-glutamic acid aerogel derivative. Carbohydr Polym 76(2):188–195. https://doi.org/10.1016/j.carbpol.2008.10.011

    Article  CAS  Google Scholar 

  33. Bregier-Jarzebowska R (2015) Mixed-ligand complexes of copper(II) ions with L-glutamic acid in the systems with triamines and non-covalent interaction between bioligands in aqueous solution. Open Chem 13(1):113–124. https://doi.org/10.1515/chem-2015-0038

    Article  Google Scholar 

  34. Hemmati M, Kazemi B, Najafi F, Zarebkohan A, Shirkoohi R (2016) Synthesis and evaluation of a glutamic acid-modified hPAMAM complex as a promising versatile gene carrier. J Drug Target 24(5):408–421. https://doi.org/10.3109/1061186X.2015.1078338

    Article  CAS  PubMed  Google Scholar 

  35. Abdelwahab HE, Hassan SY, Mostafa MA, El Sadek MM (2016) Synthesis and characterization of glutamic-chitosan hydrogel for copper and nickel removal from wastewater. Molecules. https://doi.org/10.3390/molecules21060684

    Article  PubMed  PubMed Central  Google Scholar 

  36. Thangavel P, Ramachandran B, Chakraborty S, Kannan R, Lonchin S, Muthuvijayan V (2017) Accelerated healing of diabetic wounds treated with l-glutamic acid loaded hydrogels through enhanced collagen deposition and angiogenesis: an in vivo study. Sci Rep 7(1):1–15. https://doi.org/10.1038/s41598-017-10882-1

    Article  CAS  Google Scholar 

  37. Tsao CT, Chang CH, Li YD, Wu MF, Lin CP, Han JL, Chen SH, Hsieh KH (2011) Development of chitosan/ dicarboxylic acid hydrogels as wound dressing materials. J Bioact Comp Polym 26(5):519–536. https://doi.org/10.1177/0883911511422627

    Article  CAS  Google Scholar 

  38. Shariatinia Z, Jalali AM (2018) Chitosan-based hydrogels: preparation, properties and applications. Int J Biol Macromol 115:194–220. https://doi.org/10.1016/j.ijbiomac.2018.04.034

    Article  CAS  PubMed  Google Scholar 

  39. Aycan D, Alemdar N (2018) Development of pH-responsive chitosan-based hydrogel modified with bone ash for controlled release of amoxicillin. Carbohydr Polym 184:401–407. https://doi.org/10.1016/j.carbpol.2017.12.023

    Article  CAS  PubMed  Google Scholar 

  40. Figueroa-Pizano MD, Vélaz I, Peñas FJ, Zavala-Rivera P, Rosas-Durazo AJ, Maldonado-Arce AD, Martínez-Barbosa ME (2018) Effect of freeze-thawing conditions for preparation of chitosan-poly (vinyl alcohol) hydrogels and drug release studies. Carbohydr Polym 195:476–485. https://doi.org/10.1016/j.carbpol.2018.05.004

    Article  CAS  PubMed  Google Scholar 

  41. Pinho E, Machado S, Soares G (2019) Smart hydrogel for the ph-selective drug delivery of antimicrobial compounds. Macromol Symp 385(1):1–7. https://doi.org/10.1002/masy.201800182

    Article  CAS  Google Scholar 

  42. Lou C, Tian X, Deng H, Wang Y (2020) Jiang X (2020) Dialdehyde-\(\beta\)-cyclodextrin-crosslinked carboxymethyl chitosan hydrogel for drug release. Carbohydr Polym 231:115678. https://doi.org/10.1016/j.carbpol.2019.115678

    Article  CAS  PubMed  Google Scholar 

  43. Spann CT, Tutrone WD, Weinberg JM, Scheinfeld N, Ross B (2003) Topical antibacterial agents for wound care: a primer. Dermatol Surg 29(6):620–626. https://doi.org/10.1046/j.1524-4725.2003.29143.x

    Article  PubMed  Google Scholar 

  44. Nitanan T, Akkaramongkolporn P, Rojanarata T, Ngawhirunpat T, Opanasopit P (2013) Neomycin-loaded poly(styrene sulfonic acid-co-maleic acid) (PSSA-MA)/polyvinyl alcohol (PVA) ion exchange nanofibers for wound dressing materials. Int J Pharm 448(1):71–78. https://doi.org/10.1016/j.ijpharm.2013.03.011

    Article  CAS  PubMed  Google Scholar 

  45. Karadag E, Saraydin D (2002) Swelling of superabsorbent acrylamide/sodium acrylate hydrogels prepared using multifunctional crosslinkers. Turk J Chem 26(6):863–875

    CAS  Google Scholar 

  46. Korsmeyer RW, Gurny R, Doelker E, Buri P, Peppas NA (1983) Mechanisms of solute release from porous hydrophilic polymers. Int J Pharm 15(1):25–35. https://doi.org/10.1016/0378-5173(83)90064-9

    Article  CAS  Google Scholar 

  47. Higuchi T (1961) Rate of release of medicaments from ointment bases containing drugs in suspension. Chem Pharm Bull. https://doi.org/10.1248/cpb.23.3288

    Article  Google Scholar 

  48. Machín R, Isasi JR, Vélaz I (2013) Hydrogel matrices containing single and mixed natural cyclodextrins, Mechanisms of drug release. Eur Polym J 49(12):3912–3920. https://doi.org/10.1016/j.eurpolymj.2013.08.020

    Article  CAS  Google Scholar 

  49. Costa P, Lobo JM (2001) Modeling and comparison of dissolution profiles. Pharm Sci 16(2):41–46. https://doi.org/10.14227/DT160209P41

    Article  Google Scholar 

  50. Brugnerotto J, Lizardi J, Goycoolea FM, Argüelles-Monal W, Desbrières J, Rinaudo M (2001) An infrared investigation in relation with chitin and chitosan characterization. Polymer 42(8):3569–3580. https://doi.org/10.1016/S0032-3861(00)00713-8

    Article  CAS  Google Scholar 

  51. Paulino AT, Simionato JI, Garcia JC, Nozaki J (2006) Characterization of chitosan and chitin produced from silkworm crysalides. Carbohydr Polym 64(1):98–103. https://doi.org/10.1016/j.carbpol.2005.10.032

    Article  CAS  Google Scholar 

  52. Duarte ML, Ferreira MC, Marvão MR, Rocha J (2002) An optimised method to determine the degree of acetylation of chitin and chitosan by FTIR spectroscopy. Int J Biol Macromol 31(1–3):1–8. https://doi.org/10.1016/S0141-8130(02)00039-9

    Article  CAS  PubMed  Google Scholar 

  53. Valderruten NE, Valverde JD, Zuluaga F, Ruiz-Durántez E (2014) Synthesis and characterization of chitosan hydrogels cross-linked with dicarboxylic acids. React Funct Polym 84:21–28. https://doi.org/10.1016/j.reactfunctpolym.2014.08.006

    Article  CAS  Google Scholar 

  54. Zou X, Zhao X, Ye L, Wang Q, Li H (2015) Preparation and drug release behavior of pH-responsive bovine serum albumin-loaded chitosan microspheres. J Ind Eng Chem 21:1389–1397. https://doi.org/10.1016/j.jiec.2014.06.012

    Article  CAS  Google Scholar 

  55. Corazzari I, Nisticò R, Turci F, Faga MG, Franzoso F, Tabasso S, Magnacca G (2015) Advanced physico-chemical characterization of chitosan by means of TGA coupled on-line with FTIR and GCMS: thermal degradation and water adsorption capacity. Polym Degrad Stab 112:1–9. https://doi.org/10.1016/j.polymdegradstab.2014.12.006

    Article  CAS  Google Scholar 

  56. Martínez-Camacho AP, Cortez-Rocha MO, Ezquerra-Brauer JM, Graciano-Verdugo AZ, Rodriguez-Félix F, Castillo-Ortega MM, Yépiz-Gómez MS, Plascencia-Jatomea M (2010) Chitosan composite films: thermal, structural, mechanical and antifungal properties. Carbohydr Polym 82(2):305–315. https://doi.org/10.1016/j.carbpol.2010.04.069

    Article  CAS  Google Scholar 

  57. Prakash G, Boopathy M, Selvam R, Johnsanthosh Kumar S, Subramanian K (2018) The effect of anthracene-based chalcone derivatives in the resazurin dye reduction assay mechanisms for the investigation of Gram-positive and Gram-negative bacterial and fungal infection. New J Chem 42(2):1037–1045. https://doi.org/10.1039/C7NJ04125J

    Article  CAS  Google Scholar 

  58. Severino R, Vu KD, Donsì F, Salmieri S, Ferrari G, Lacroix M (2014) Antibacterial and physical effects of modified chitosan based-coating containing nanoemulsion of mandarin essential oil and three non-thermal treatments against Listeria innocua in green beans. Int J Food Microbiol 191:82–88. https://doi.org/10.1016/j.ijfoodmicro.2014.09.007

    Article  CAS  PubMed  Google Scholar 

  59. Goy RC, De Britto D, Assis OBG (2009) A review of the antimicrobial activity of chitosan. Polimeros 19(3):241–247. https://doi.org/10.1590/S0104-14282009000300013

    Article  CAS  Google Scholar 

  60. Goy RC, Morais STB, Assis OBG (2016) Evaluation of the antimicrobial activity of chitosan and its quaternized derivative on E. Coli and S. aureus growth. Braz J Pharmacogn 26(1):122–127. https://doi.org/10.1016/j.bjp.2015.09.010

    Article  CAS  Google Scholar 

  61. Zhang Y, Huo M, Zhou J, Zou A, Li W, Yao C, Xie S (2010) DDSolver: an add-in program for modeling and comparison of drug dissolution profiles. AAPS J 12(3):263–271. https://doi.org/10.1208/s12248-010-9185-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Danay Prez-Caballero also would like to acknowledge CONACyT (National Council of Science and Technology Mexico) for the financial support provided during the completion of this study.

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Authors and Affiliations

  1. Departamento de Investigación en Polímeros y Materiales, Universidad de Sonora, 83000, Hermosillo, Sonora, Mexico

    D. E. Rodríguez-Félix, D. Pérez-Caballero, T. del Castillo-Castro, M. M. Castillo-Ortega, Y. Garmendía-Diago, J. Alvarado-Ibarra & S. E. Burruel-Ibarra

  2. Departamento de Investigación y Posgrado en Alimentos, Universidad de Sonora, 83000, Hermosillo, Sonora, Mexico

    M. Plascencia-Jatomea

  3. Centro de Investigación en Química Aplicada, Saltillo, Coahuila, Mexico

    A. S. Ledezma-Pérez

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  1. D. E. Rodríguez-Félix
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Rodríguez-Félix, D.E., Pérez-Caballero, D., del Castillo-Castro, T. et al. Chitosan hydrogels chemically crosslinked with L-glutamic acid and their potential use in drug delivery. Polym. Bull. 80, 2617–2636 (2023). https://doi.org/10.1007/s00289-022-04152-y

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