Green Synthesis of Smart Hydrogels via Radiation Crosslinking of Sodium Alginate and Citric Acid for pH-Sensitive Doxycycline Hyclate Release

Öz

Doxycycline hyclate (DH) is a second-generation tetracycline antibiotic with lower toxicity than its predecessors, used for bacterial infections and topically for mucosal and diabetic ulcers. Healthy skin's pH is mildly acidic (4.0-6.0), regulating bacterial flora and preventing infections. Wounds disrupt this pH, revealing the tissue's neutral pH of 7.4, necessitating pH-sensitive controlled drug release for effective chronic wound treatment. This study explores polysaccharide-based hydrogels synthesized by crosslinking sodium alginate/citric acid (NaAlg/CA) solutions using gamma radiation with varying citric acid concentrations for pH-sensitive DH release. The citric acid-modified polysaccharide hydrogels were created using a green method, free of additional chemicals. Citric acid significantly influenced swelling, critical for drug loading and release, with the highest swelling capacity (3500% mass) observed at a 5:1 NaAlg/CA ratio. Hydrogels were tested for pH-dependent swelling and DH drug release profiles at pH 5.5, 7.4, and 9.0. The results indicate that at pH 7.4, which replicates the pH of chronic wounds, the release of DH showed a prolonged profile up to 40 hours, distinct from the results at pH 5.5 and 9.0. These results highlight the capabilities of NaAlg/CA hydrogels created through gamma radiation, combining the biocompatibility and low toxicity of sodium alginate/citric acid, for efficient and sustainable drug delivery, especially valuable in acute wound care where pH-specific therapeutic effectiveness is essential.

Anahtar Kelimeler

• Hydrogel
• Sodium alginate/citric acid
• Ph sensitive drug release
• Polysaccharide
• Gamma radiation

Kaynakça

1. Ahmed, M. S., Islam, M., Hasan, M. K., & Nam, K. W. (2024). A Comprehensive Review of Radiation-Induced Hydrogels: Synthesis, Properties, and Multidimensional Applications. Gels, 10(6), 381.
2. Al-Arjan, W. S., Khan, M. U. A., Almutairi, H. H., Alharbi, S. M., & Razak, S. I. A. (2022). pH-Responsive PVA/BC-f-GO Dressing Materials for Burn and Chronic Wound Healing with Curcumin Release Kinetics. Polymers, 14(10), 1949.
3. Ali, F., Khan, I., Chen, J., Akhtar, K., Bakhsh, E. M., & Khan, S. B. (2022). Emerging Fabrication Strategies of Hydrogels and Its Applications. Gels, 8(4), 205.
4. Ardika, K.A.R., Marzaman, A.N.F., Kaharuddin, K.M., Parenden, M.D.K., Karimah, A., Musfirah, C.A., Pakki, E. and Permana, A.D. (2023). Development of chitosan-hyaluronic acid based hydrogel for local delivery of doxycycline hyclate in an ex vivo skin infection model. Journal of Biomaterials Science, Polymer Edition, 34(16), 2274-2290.
5. Anumolu, S. S., Menjoge, A. R., Deshmukh, M., Gerecke, D., Stein, S., Laskin, J., & Sinko, P. J. (2011). Doxycycline hydrogels with reversible disulfide crosslinks for dermal wound healing of mustard injuries. Biomaterials, 32(4), 1204–1217.
6. Augst, A. D., Kong, H. J., & Mooney, D. J. (2006). Alginate Hydrogels as Biomaterials. Macromolecular Bioscience, 6(8), 623–633.
7. Bashir, S., Hina, M., Iqbal, J., Rajpar, A. H., Mujtaba, M. A., Alghamdi, N. A., Wageh, S., Ramesh, K., & Ramesh, S. (2020). Fundamental Concepts of Hydrogels: Synthesis, Properties, and Their Applications. Polymers, 12(11), 2702.
8. Bidarra, S. J., Barrias, C. C., & Granja, P. L. (2014). Injectable alginate hydrogels for cell delivery in tissue engineering. Acta Biomaterialia, 10(4), 1646–1662.

9. Bodugöz, H., Pekel, N., & Güven, O. (1999). Preparation of poly(vinyl alcohol) hydrogels with radiation grafted citric and succinic acid groups. Radiation Physics and Chemistry, 55(5–6), 667–671.
10. Bray, J. C., & Merrill, E. W. (1973). Poly(vinyl alcohol) hydrogels. Formation by electron beam irradiation of aqueous solutions and subsequent crystallization. Journal of Applied Polymer Science, 17(12), 3779–3794.
11. Caykara, T., Oren, S., Kantoglu, M., & Guven, O. (2000). The effect of gel composition on the uranyl ions adsorption capacity of poly(N-vinyl 2-pyrrolidone-g-citric acid) hydrogels prepared by gamma rays. Journal of Applied Polymer Science, 77(5), 1037–1043.
12. Chang, K. A., Chew, L. Y., Law, K. P., Ng, J. F., Wong, C. S., Wong, C. L., & Hussein, S. (2022). Effect of gamma irradiation on the physicochemical properties of sodium alginate solution and internally crosslinked film made thereof. Radiation Physics and Chemistry, 193, 109963.
13. Chen, X., Li, P., Kang, Y., Zeng, X., Xie, Y., Zhang, Y., Wang, Y., & Xie, T. (2019). Preparation of temperature-sensitive Xanthan/NIPA hydrogel using citric acid as crosslinking agent for bisphenol A adsorption. Carbohydrate Polymers, 206, 94–101.
14. Craciun, G., Calina, I. C., Demeter, M., Scarisoreanu, A., Dumitru, M., & Manaila, E. (2023). Poly(Acrylic Acid)-Sodium Alginate Superabsorbent Hydrogels Synthesized by Electron Beam Irradiation Part I: Impact of Initiator Concentration and Irradiation Dose on Structure, Network Parameters and Swelling Properties. Materials, 16(13), 4552.
15. De Cicco, F., Russo, P., Reverchon, E., García-González, C. A., Aquino, R. P., & Del Gaudio, P. (2016). Prilling and supercritical drying: A successful duo to produce core-shell polysaccharide aerogel beads for wound healing. Carbohydrate Polymers, 147, 482–489.
16. Demeter, M., Scărișoreanu, A., & Călina, I. (2023). State of the Art of Hydrogel Wound Dressings Developed by Ionizing Radiation. Gels, 9(1), 55.
17. Drury, J. L., & Mooney, D. J. (2003). Hydrogels for tissue engineering: scaffold design variables and applications. Biomaterials, 24(24), 4337–4351.
18. El-Arnaouty, M. B., Eid, M., & Ghaffar, A. M. A. (2015). Radiation Synthesis of Stimuli Responsive Micro-porous Hydrogels for Controlled Drug Release of Aspirin. Polymer-plastics Technology and Engineering, 54(12), 1215–1222.
19. El-Naggar, A. W., Senna, M., Mostafa, T., & Helal, R. (2016). Characterization and drug delivery properties of gamma irradiated poly (vinyl alcohol)/methylcellulose (PVA/MC) blends. The International Conference on Chemical and Environmental Engineering, 8(13), 2–22.
20. Farkas, N. I., Marincaș, L., Barabás, R., Bizo, L., Ilea, A., Turdean, G. L., Toșa, M., Cadar, O., & Barbu-Tudoran, L. (2022). Preparation and Characterization of Doxycycline-Loaded Electrospun PLA/HAP Nanofibers as a Drug Delivery System. Materials, 15(6), 2105.
21. Franklin, D., & Guhanathan, S. (2015). Investigation of citric acid–glycerol based pH-sensitive biopolymeric hydrogels for dye removal applications: A green approach. Ecotoxicology and Environmental Safety, 121, 80–86.
22. Gabriele, S., Buchanan, B., Kundu, A., Dwyer, H. C., Gabriele, J. P., Mayer, P., & Baranowski, D. C. (2019). Stability, Activity, and Application of Topical Doxycycline Formulations in a Diabetic Wound Case Study. PubMed, 31(2), 49–54.
23. Ghobashy, M. M., Elbarbary, A. M., & Hegazy, D. E. (2021). Gamma radiation synthesis of a novel amphiphilic terpolymer hydrogel pH-responsive based chitosan for colon cancer drug delivery. Carbohydrate Polymers, 263, 117975.
24. Giovagnoli, S., Tsai, T., & DeLuca, P. P. (2010). Formulation and Release Behavior of Doxycycline–Alginate Hydrogel Microparticles Embedded into Pluronic F127 Thermogels as a Potential New Vehicle for Doxycycline Intradermal Sustained Delivery. AAPS PharmSciTech, 11(1), 212–220.
25. Gugleva, V., Titeva, S., Rangelov, S., & Momekova, D. (2019). Design and in vitro evaluation of doxycycline hyclate niosomes as a potential ocular delivery system. International journal of pharmaceutics, 567, 118431.
26. Haque, S. N., Bhuyan, M. M., & Jeong, J. H. (2024). Radiation-Induced Hydrogel for Water Treatment. Gels, 10(6), 375.
27. Hedayatyanfard, K., Khoulenjani, S. B., Abdollahifar, M. A., Amani, D., Habibi, B., Zare, F., Asadirad, A., Pouriran, R., & Ziai, S. A. (2020). Chitosan/PVA/Doxycycline Film and Nanofiber Accelerate Diabetic Wound Healing in a Rat Model. Iran. J. Pharmaceut. Res., 19(4), 225–239.
28. Hennink, W., & Van Nostrum, C. (2002). Novel crosslinking methods to design hydrogels. Advanced Drug Delivery Reviews, 54(1), 13–36.
29. Hoffman, A. S. (2002). Hydrogels for biomedical applications. Advanced Drug Delivery Reviews, 54(1), 3–12.
30. Huq, T., Khan, A., Dussault, D., Salmieri, S., Khan, R. A., & Lacroix, M. (2012). Effect of gamma radiation on the physico-chemical properties of alginate-based films and beads. Radiation Physics and Chemistry, 81(8), 945–948.
31. Javali, M. A., & Vandana, K. (2012). A comparative evaluation of atrigel delivery system (10% doxycycline hyclate) Atridox with scaling and root planing and combination therapy in treatment of periodontitis: A clinical study. Journal of Indian Society of Periodontology, 16(1), 43.
32. Karadag, E., Saraydin, D., Sahiner, N., & Güven, O. (2001). Radiation induced acrylamide/citric acid hydrogels and their swelling behaviors. Journal of Macromolecular Science. Pure and Applied Chemistry/Journal of Macromolecular Science. Part a. Pure & Applied Chemistry, 38(11), 1105–1121.
33. Kazmi, S. A. R., Qureshi, M. Z., Ali, S., & Masson, J. F. (2019). In vitro drug release and biocatalysis from pH-responsive gold nanoparticles synthesized using doxycycline. Langmuir, 35(49), 16266-16274.
34. Kim, M. H., Kim, B. S., Lee, J., Cho, D., Kwon, O. H., & Park, W. H. (2017). Silk fibroin/hydroxyapatite composite hydrogel induced by gamma-ray irradiation for bone tissue engineering. Biomaterials Research/Biomaterials Research, 21(1).
35. Klouda, L., & Mikos, A. G. (2008). Thermoresponsive hydrogels in biomedical applications. European Journal of Pharmaceutics and Biopharmaceutics, 68(1), 34–45.
36. Koetting, M. C., Peters, J. T., Steichen, S. D., & Peppas, N. A. (2015). Stimulus-responsive hydrogels: Theory, modern advances, and applications. Materials Science & Engineering. R, Reports, 93, 1–49.
37. Kogawa, A. C., & Salgado, H. R. N. (2012). Quantification of Doxycycline Hyclate in Tablets by HPLC–UV Method. Journal of Chromatographic Science, 51(10), 919–925.
38. Kruse, C. R., Singh, M., Targosinski, S., Sinha, I., Sørensen, J. A., Eriksson, E., & Nuutila, K. (2017). The effect of pH on cell viability, cell migration, cell proliferation, wound closure, and wound reepithelialization: In vitro and in vivo study. Wound Repair and Regeneration, 25(2), 260–269.
39. Kuo, S. H., Shen, C. J., Shen, C. F., & Cheng, C. M. (2020). Role of pH Value in Clinically Relevant Diagnosis. Diagnostics, 10(2), 107.
40. Li, L., He, Y., Zheng, X., Yi, L., & Nian, W. (2021a). Progress on Preparation of pH/Temperature-Sensitive Intelligent Hydrogels and Applications in Target Transport and Controlled Release of Drugs. International Journal of Polymer Science, 2021, 1–14.
41. Li, Y., Wang, Z., Wang, X., Yan, B., Peng, Y., & Ran, R. (2021b). Fe3+-citric acid/sodium alginate hydrogel: A photo-responsive platform for rapid water purification. Carbohydrate Polymers, 269, 118269.
42. Lugao, A. B., & Malmonge, S. M. (2001). Use of radiation in the production of hydrogels. Nuclear Instruments and Methods in Physics Research. Section B, Beam Interactions With Materials and Atoms/Nuclear Instruments & Methods in Physics Research. Section B, Beam Interactions With Materials and Atoms, 185(1–4), 37–42.
43. Maiti, S., Maji, B., & Yadav, H. (2024). Progress on green crosslinking of polysaccharide hydrogels for drug delivery and tissue engineering applications. Carbohydrate Polymers, 326, 121584.
44. Makuuchi, K. (2010). Critical review of radiation processing of hydrogel and polysaccharide. Radiation Physics and Chemistry, 79(3), 267–271.
45. Mashabela, L. T., Maboa, M. M., Miya, N. F., Ajayi, T. O., Chasara, R. S., Milne, M., Mokhele, S., Demana, P. H., Witika, B. A., Siwe-Noundou, X., & Poka, M. S. (2022). A Comprehensive Review of Cross-Linked Gels as Vehicles for Drug Delivery to Treat Central Nervous System Disorders. Gels, 8(9), 563.
46. Moghaddam, R. H., Dadfarnia, S., Shabani, A. M. H., Amraei, R., & Moghaddam, Z. H. (2020). Doxycycline drug delivery using hydrogels of O-carboxymethyl chitosan conjugated with caffeic acid and its composite with polyacrylamide synthesized by electron beam irradiation. International Journal of Biological Macromolecules, 154, 962–973.
47. Möller, S., Weisser, J., Bischoff, S., & Schnabelrauch, M. (2007). Dextran and hyaluronan methacrylate based hydrogels as matrices for soft tissue reconstruction. Biomolecular Engineering, 24(5), 496–504.
48. Patlolla, V. G. R., Peter Holbrook, W., Gizurarson, S., & Kristmundsdottir, T. (2019). Doxycycline and monocaprin in situ hydrogel: Effect on stability, mucoadhesion and texture analysis and in vitro release. Gels, 5(4), 47.
49. Phaechamud, T., & Charoenteeraboon, J. (2008). Antibacterial activity and drug release of chitosan sponge containing doxycycline hyclate. Aaps PharmSciTech, 9, 829-835.
50. Phaechamud, T., Senarat, S., Puyathorn, N., & Praphanwittaya, P. (2019). Solvent exchange and drug release characteristics of doxycycline hyclate-loaded bleached shellac in situ-forming gel and-microparticle. International journal of biological macromolecules, 135, 1261-1272.
51. Pooresmaeil, M., Javanbakht, S., Namazi, H., & Shaabani, A. (2021). Application or function of citric acid in drug delivery platforms. Medicinal Research Reviews, 42(2), 800–849.
52. Ranch, K. M., Maulvi, F. A., Koli, A. R., Desai, D. T., Parikh, R. K., & Shah, D. O. (2021). Tailored doxycycline hyclate loaded in situ gel for the treatment of periodontitis: Optimization, in vitro characterization, and antimicrobial studies. AAPS PharmSciTech, 22, 1-11.
53. Rosiak, J., & Ulański, P. (1999). Synthesis of hydrogels by irradiation of polymers in aqueous solution. Radiation Physics and Chemistry, 55(2), 139–151.
54. Rosiak, J., Ulański, P., Pajewski, L., Yoshii, F., & Makuuchi, K. (1995). Radiation formation of hydrogels for biomedical purposes. Some remarks and comments. Radiation Physics and Chemistry, 46(2), 161–168.
55. Rowley, J. A., Madlambayan, G., & Mooney, D. J. (1999). Alginate hydrogels as synthetic extracellular matrix materials. Biomaterials, 20(1), 45–53.
56. Saliy, O., Popova, M., Tarasenko, H., & Getalo, O. (2024). Development strategy of novel drug formulations for the delivery of doxycycline in the treatment of wounds of various etiologies. European Journal of Pharmaceutical Sciences, 195, 106636.
57. Sanapalli, B. K. R., Gounder, K. C., Ambhore, N. S., Kuppuswamy, G., Krishnamurthy, P. T., & Karri, V. V. S. R. (2021). Doxycycline Loaded Collagen-Chitosan Composite Scaffold for the Accelerated Healing of Diabetic Wounds. Journal of Visualized Experiments, 174.
58. Schreml, S., Szeimies, R., Karrer, S., Heinlin, J., Landthaler, M., & Babilas, P. (2010). The impact of the pH value on skin integrity and cutaneous wound healing. JEADV. Journal of the European Academy of Dermatology and Venereology/Journal of the European Academy of Dermatology and Venereology, 24(4), 373–378.
59. Şen, M. (2011). Effects of molecular weight and ratio of guluronic acid to mannuronic acid on the antioxidant properties of sodium alginate fractions prepared by radiation-induced degradation. Applied Radiation and Isotopes, 69(1), 126–129.
60. Sezen, S., Thakur, V. K., & Ozmen, M. M. (2021). Highly Effective Covalently Crosslinked Composite Alginate Cryogels for Cationic Dye Removal. Gels, 7(4), 178.
61. Singh, R., Pal, D., & Chattopadhyay, S. (2020a). Target-Specific Superparamagnetic Hydrogel with Excellent pH Sensitivity and Reversibility: A Promising Platform for Biomedical Applications. ACS Omega, 5(34), 21768–21780.
62. Singh, P., Baisthakur, P., & Yemul, O. S. (2020b). Synthesis, characterization and application of crosslinked alginate as green packaging material. Heliyon, 6(1), e03026.
63. Sood, N., Bhardwaj, A., Mehta, S., & Mehta, A. (2014). Stimuli-responsive hydrogels in drug delivery and tissue engineering. Drug Delivery, 23(3), 748–770.
64. Tan, H., Chu, C. R., Payne, K. A., & Marra, K. G. (2009). Injectable in situ forming biodegradable chitosan–hyaluronic acid based hydrogels for cartilage tissue engineering. Biomaterials, 30(13), 2499–2506.
65. Tranquilan-Aranilla, C., Yoshii, F., Rosa, A. D., & Makuuchi, K. (1999). Kappa-carrageenan–polyethylene oxide hydrogel blends prepared by gamma irradiation. Radiation Physics and Chemistry, 55(2), 127–131.
66. Yang, J., Rao, L., Wang, Y., Zhao, Y., Liu, D., Wang, Z., Fu, L., Wang, Y., Yang, X., Li, Y., & Liu, Y. (2022). Recent Advances in Smart Hydrogels Prepared by Ionizing Radiation Technology for Biomedical Applications. Polymers, 14(20), 4377.
67. Zhang, J., Hurren, C., Lu, Z., & Wang, D. (2022). pH-sensitive alginate hydrogel for synergistic anti-infection. International Journal of Biological Macromolecules, 222, 1723–1733.
68. Zong, Y., Zong, B., Zha, R., Zhang, Y., Li, X., Wang, Y., Fang, H., Wong, W., & Li, C. (2023). An Antibacterial and Anti‐Oxidative Hydrogel Dressing for Promoting Diabetic Wound Healing and Real‐Time Monitoring Wound pH Conditions with a NIR Fluorescent Imaging System. Advanced Healthcare Materials/Advanced Healthcare Materials, 12(24).