Skip to content
2000
Volume 21, Issue 11
  • ISSN: 1567-2018
  • E-ISSN: 1875-5704

Abstract

Introduction/Objective

To prolong the ocular residence time of gatifloxacin and enhance its efficacy against bacterial keratitis, this study developed a velocity-controlled polyethylene glycol-dithiothreitol-boric acid (PDB) hydrogel loaded with gatifloxacin.

Methods

First, the basic properties of the synthesized PDB hydrogel and the gatifloxacin-loaded PDB hydrogel were assessed. Secondly, the degradation rate of the drug-loaded PDB was measured in a simulated body fluid environment with pH 7.4/5.5. The release behavior of the drug-loaded PDB was studied using a dialysis method with PBS solution of pH 7.4/5.5 as the release medium. Finally, a mouse model of bacterial keratitis was established, and tissue morphology was observed using hematoxylin-eosin staining. Additionally, mouse tear fluid was extracted to observe the antibacterial effect of the gatifloxacin-loaded PDB hydrogel.

Results

The results showed that the PDB hydrogel had a particle size of 124.9 nm and a zeta potential of -23.3 mV, with good porosity, thermosensitivity, viscosity distribution, rheological properties, and high cell compatibility. The encapsulation of gatifloxacin did not alter the physical properties of the PDB hydrogel and maintained appropriate swelling and stability, with a high drug release rate in acidic conditions. Furthermore, animal experiments demonstrated that the gatifloxacin-loaded PDB hydrogel exhibited superior therapeutic effects compared to gatifloxacin eye drops and displayed strong antibacterial capabilities against bacterial keratitis.

Conclusion

This study successfully synthesized PDB hydrogel and developed a gatifloxacin drug release system. The hydrogel exhibited good thermosensitivity, pH responsiveness, stability, and excellent biocompatibility, which can enhance drug retention, utilization, and therapeutic effects on the ocular surface.

Loading

Article metrics loading...

/content/journals/cdd/10.2174/0115672018279105240226050253
2024-12-01
2024-11-22
Loading full text...

Full text loading...

References

  1. GalvisV. TelloA. LaitonA.N. SalcedoS.L.L. Indications and techniques of corneal transplantation in a referral center in Colombia, South America (2012–2016).Int. Ophthalmol.20193981723173310.1007/s10792‑018‑0994‑z30047076
    [Google Scholar]
  2. TingD.S.J. HoC.S. DeshmukhR. SaidD.G. DuaH.S. Infectious keratitis: An update on epidemiology, causative microorganisms, risk factors, and antimicrobial resistance.Eye20213541084110110.1038/s41433‑020‑01339‑333414529
    [Google Scholar]
  3. TingD.S.J. HoC.S. DeshmukhR. SaidD.G. DuaH.S. Correction to: Infectious keratitis: An update on epidemiology, causative microorganisms, risk factors, and antimicrobial resistance.Eye20213510290810.1038/s41433‑021‑01568‑033976404
    [Google Scholar]
  4. ShahA. SachdevA. CoggonD. HossainP. Geographic variations in microbial keratitis: an analysis of the peer-reviewed literature.Br. J. Ophthalmol.201195676276710.1136/bjo.2009.16960721478201
    [Google Scholar]
  5. KeayL. EdwardsK. NaduvilathT. TaylorH.R. SnibsonG.R. FordeK. StapletonF. Microbial keratitis.Ophthalmology2006113110911610.1016/j.ophtha.2005.08.01316360210
    [Google Scholar]
  6. UngL. ChodoshJ. Foundational concepts in the biology of bacterial keratitisExp Eye Res202110.1016/j.exer.2021.108647
    [Google Scholar]
  7. GalvisV. TelloA. GuerraA. AcunaM.F. VillarrealD. Antibiotic susceptibility patterns of bacteria isolated from keratitis and intraocular infections at Fundacion Oftalmologica de Santander (FOSCAL), Floridablanca, Colombia.Biomedica201434123133
    [Google Scholar]
  8. HanH. GaoY. ChaiM. ZhangX. LiuS. HuangY. JinQ. GrzybowskiA. JiJ. YaoK. Biofilm microenvironment activated supramolecular nanoparticles for enhanced photodynamic therapy of bacterial keratitis.J. Control. Release202032767668710.1016/j.jconrel.2020.09.01432920078
    [Google Scholar]
  9. LakhundiS. SiddiquiR. KhanN.A. Pathogenesis of microbial keratitis.Microb. Pathog.20171049710910.1016/j.micpath.2016.12.01327998732
    [Google Scholar]
  10. Cabrera-AguasM. KhooP. WatsonS.L. Infectious keratitis: A review.Clin. Exp. Ophthalmol.202250554356210.1111/ceo.1411335610943
    [Google Scholar]
  11. Alvarez-LorenzoC. HirataniH. Gómez-AmozaJ.L. Martínez-PachecoR. SoutoC. ConcheiroA. Soft contact lenses capable of sustained delivery of timolol.J. Pharm. Sci.200291102182219210.1002/jps.1020912226845
    [Google Scholar]
  12. KapoorY. ThomasJ.C. TanG. JohnV.T. ChauhanA. Surfactant-laden soft contact lenses for extended delivery of ophthalmic drugs.Biomaterials200930586787810.1016/j.biomaterials.2008.10.03219010533
    [Google Scholar]
  13. IbrahimH.K. El-LeithyI.S. MakkyA.A. Mucoadhesive nanoparticles as carrier systems for prolonged ocular delivery of gatifloxacin/prednisolone bitherapy.Mol. Pharm.20107257658510.1021/mp900279c20163167
    [Google Scholar]
  14. SanfilippoC.M. AllaireC.M. DeCoryH.H. Besifloxacin ophthalmic suspension 0.6% compared with gatifloxacin ophthalmic solution 0.3% for the treatment of bacterial conjunctivitis in neonates.Drugs R D.201717116717510.1007/s40268‑016‑0164‑628078599
    [Google Scholar]
  15. DaniellM. Overview: Initial antimicrobial therapy for microbial keratitis.Br. J. Ophthalmol.20038791172117410.1136/bjo.87.9.117212928292
    [Google Scholar]
  16. LinA. RheeM.K. AkpekE.K. AmescuaG. FaridM. Garcia-FerrerF.J. VaruD.M. MuschD.C. DunnS.P. MahF.S. American Academy of Ophthalmology Preferred Practice Pattern Cornea and External Disease Panel Bacterial keratitis preferred practice pattern®.Ophthalmology20191261P1P5510.1016/j.ophtha.2018.10.01830366799
    [Google Scholar]
  17. BinkhathlanZ. AliR. AlomraniA.H. Abul KalamM. AlshamsanA. LavasanifarA. Role of polymeric micelles in ocular drug delivery: An overview of decades of research.Mol. Pharm.202320115359538210.1021/acs.molpharmaceut.3c0059837769017
    [Google Scholar]
  18. NasrM. SaberS. BazeedA.Y. RamadanH.A. EbadaA. CiorbaA.L. CavaluS. ElagamyH.I. Advantages of cubosomal formulation for gatifloxacin delivery in the treatment of bacterial keratitis: In vitro and in vivo approach using clinical isolate of methicillin-resistant staphylococcus aureus. Materials2022159337410.3390/ma1509337435591708
    [Google Scholar]
  19. ParmarP. SalmanA. KalavathyC.M. KaliamurthyJ. PrasanthD.A. ThomasP.A. JesudasanC.A.N. Comparison of topical gatifloxacin 0.3% and ciprofloxacin 0.3% for the treatment of bacterial keratitis.Am. J. Ophthalmol.20061412282286.e110.1016/j.ajo.2005.08.08116458681
    [Google Scholar]
  20. LeeS. LeeJ. H. ParkJ. H. YoonY. ChungW. K. TchahH. KimM. J. KimK. H. In vivo 3D measurement of moxifloxacin and gatifloxacin distributions in the mouse cornea using multiphoton microscopy.Sci Rep201662533910.1038/srep25339
    [Google Scholar]
  21. ShiY. LvH. FuY. LuQ. ZhongJ. MaD. HuangY. XueW. Preparation and characterization of a hydrogel carrier to deliver gatifloxacin and its application as a therapeutic contact lens for bacterial keratitis therapy.Biomed. Mater.20138505500710.1088/1748‑6041/8/5/05500724057809
    [Google Scholar]
  22. SinghR. B. DasS. ChodoshJ. SharmaN. ZegansM. E. KowalskiR. P. JhanjiV. Paradox of complex diversity: Challenges in the diagnosis and management of bacterial keratitis.Prog Retin Eye Res20228810102810.1016/j.preteyeres.2021.101028
    [Google Scholar]
  23. SchultzC. Gatifloxacin ophthalmic solution for treatment of bacterial conjunctivitis: Safety, efficacy and patient perspective.Ophthalmol. Eye Dis.20124OED.S738310.4137/OED.S738323650458
    [Google Scholar]
  24. KassL.E. NguyenJ. Nanocarrier‐hydrogel composite delivery systems for precision drug release.Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol.2022142e175610.1002/wnan.175634532989
    [Google Scholar]
  25. HoT.C. ChangC.C. ChanH.P. ChungT.W. ShuC.W. ChuangK.P. DuhT.H. YangM.H. TyanY.C. Hydrogels: Properties and applications in biomedicine.Molecules2022279290210.3390/molecules2709290235566251
    [Google Scholar]
  26. LuoY. LiZ. WangX. WangJ. DuanX. LiR. PengY. YeQ. HeY. Characteristics of culture-condition stimulated exosomes or their loaded hydrogels in comparison with other extracellular vesicles or MSC lysates.Front Bioeng Biotechnol202210101683310.3389/fbioe.2022.1016833
    [Google Scholar]
  27. JindalS. AwasthiR. GoyalK. KulkarniG.T. Hydrogels for localized drug delivery: A special emphasis on dermatologic applications.Dermatol. Ther.20223511e1583010.1111/dth.1583036106409
    [Google Scholar]
  28. QianY. LuS. MengJ. ChenW. LiJ. Thermo‐responsive hydrogels coupled with photothermal agents for biomedical applications.Macromol. Biosci.20232312230021410.1002/mabi.20230021437526220
    [Google Scholar]
  29. ChangD. ParkK. FamiliA. Hydrogels for sustained delivery of biologics to the back of the eye.Drug Discov. Today20192481470148210.1016/j.drudis.2019.05.03731202673
    [Google Scholar]
  30. WuY. WangY. LongL. HuC. KongQ. WangY. A spatiotemporal release platform based on pH/ROS stimuli-responsive hydrogel in wound repairing.J. Control. Release202234114716510.1016/j.jconrel.2021.11.02734813880
    [Google Scholar]
  31. WangJ. ZhuM. HuY. ChenR. HaoZ. WangY. LiJ. Exosome‐hydrogel system in bone tissue engineering: A promising therapeutic strategy.Macromol. Biosci.2023234220049610.1002/mabi.20220049636573715
    [Google Scholar]
  32. HoqueJ. SangajN. VargheseS. Stimuli‐responsive supramolecular hydrogels and their applications in regenerative medicine.Macromol. Biosci.2019191180025910.1002/mabi.20180025930295012
    [Google Scholar]
  33. LiZ. FanZ. XuY. LoW. WangX. NiuH. LiX. XieX. KhanM. GuanJ. pH-sensitive and thermosensitive hydrogels as stem-cell carriers for cardiac therapy.ACS Appl. Mater. Interfaces2016817107521076010.1021/acsami.6b0137427064934
    [Google Scholar]
  34. YangY. FengG. WangJ. ZhangR. ZhongS. WangJ. CuiX. Injectable chitosan-based self-healing supramolecular hydrogels with temperature and pH dual-responsivenesses.Int. J. Biol. Macromol.20232271038104710.1016/j.ijbiomac.2022.11.27936460241
    [Google Scholar]
  35. HendiA. Umair HassanM. ElsherifM. AlqattanB. ParkS. YetisenA.K. ButtH. Healthcare applications of ph-sensitive hydrogel-based devices: A review.Int. J. Nanomedicine2020153887390110.2147/IJN.S24574332581536
    [Google Scholar]
  36. van DamE.P. YuanH. KouwerP.H.J. BakkerH.J. Structure and dynamics of a temperature-sensitive hydrogel.J. Phys. Chem. B2021125298219822410.1021/acs.jpcb.1c0312134279949
    [Google Scholar]
  37. NorouziM. NazariB. MillerD.W. Injectable hydrogel-based drug delivery systems for local cancer therapy.Drug Discov. Today201621111835184910.1016/j.drudis.2016.07.00627423369
    [Google Scholar]
  38. YangK. WanS. ChenB. GaoW. ChenJ. LiuM. HeB. WuH. Dual pH and temperature responsive hydrogels based on β-cyclodextrin derivatives for atorvastatin delivery.Carbohydr. Polym.201613630030610.1016/j.carbpol.2015.08.09626572359
    [Google Scholar]
  39. PanG. ZhangJ. LiangY. GuoB. Latest findings on stimuli-responsive hydrogel wound dressings applied in diabetic chronic wound repair.SI Department and ax u ex UE BAOy IX UE ban202354472673010.12182/2023076020637545064
    [Google Scholar]
  40. LinD. LeiL. ShiS. LiX. Stimulus‐responsive hydrogel for ophthalmic drug delivery.Macromol. Biosci.2019196190000110.1002/mabi.20190000131026123
    [Google Scholar]
  41. WangD. YangX. LiuQ. YuL. DingJ. Enzymatically cross-linked hydrogels based on a linear poly(ethylene glycol) analogue for controlled protein release and 3D cell culture.J. Mater. Chem. B Mater. Biol. Med.20186386067607910.1039/C8TB01949E32254817
    [Google Scholar]
  42. AiY. SheW. WuS. ShaoQ. JiangZ. ChenP. MeiL. ZouC. PengY. HeY. AM1241-loaded poly(ethylene glycol)-dithiothreitol hydrogel repairs cranial bone defects by promoting vascular endothelial growth factor and COL-1 expression.Front Cell Dev Biol20221088859810.3389/fcell.2022.888598
    [Google Scholar]
  43. D’souzaA.A. ShegokarR. Polyethylene glycol (PEG): A versatile polymer for pharmaceutical applications.Expert Opin. Drug Deliv.20161391257127510.1080/17425247.2016.118248527116988
    [Google Scholar]
  44. YinL. PangY. ShanL. GuJ. The in vivo pharmacokinetics of block copolymers containing polyethylene glycol used in nanocarrier drug delivery systems.Drug Metab. Dispos.202250682783610.1124/dmd.121.00056835066464
    [Google Scholar]
  45. ShahN. HussainM. RehanT. KhanA. KhanZ.U. Overview of polyethylene glycol-based materials with a special focus on core-shell particles for drug delivery application.Curr. Pharm. Des.202228535236710.2174/138161282766621091010433334514984
    [Google Scholar]
  46. SukJ. S. XuQ. KimN. HanesJ. EnsignL. M. PEGylation as a strategy for improving nanoparticle-based drug and gene delivery.Adv Drug Deliv Rev201699285110.1016/j.addr.2015.09.012
    [Google Scholar]
  47. FjelstrupS. AndersenM. ThomsenJ. WangJ. StougaardM. PedersenF. HoY.P. HedeM. KnudsenB. The effects of dithiothreitol on DNA.Sensors2017176120110.3390/s1706120128538659
    [Google Scholar]
  48. AbdussalamA. ChenY. YuanF. MaX. LouB. XuG. Dithiothreitol–lucigenin chemiluminescent system for ultrasensitive dithiothreitol and superoxide dismutase detection.Anal. Chem.20229431110231102910.1021/acs.analchem.2c0169035878317
    [Google Scholar]
  49. WhitelyM. CereceresS. DhavalikarP. SalhadarK. WilemsT. SmithB. MikosA. Cosgriff-HernandezE. Improved in situ seeding of 3D printed scaffolds using cell-releasing hydrogels.Biomaterials201818519420410.1016/j.biomaterials.2018.09.02730245387
    [Google Scholar]
  50. TanpichaiS. PhoothongF. BoonmahitthisudA. Superabsorbent cellulose-based hydrogels cross-liked with borax.Sci. Rep.2022121892010.1038/s41598‑022‑12688‑235618796
    [Google Scholar]
  51. HeL. SzopinskiD. WuY. LuinstraG.A. TheatoP. Toward self-healing hydrogels using one-pot thiol–ene click and borax-diol chemistry.ACS Macro Lett.20154767367810.1021/acsmacrolett.5b0033635596485
    [Google Scholar]
  52. LiuC. LeiF. LiP. WangK. JiangJ. A review on preparations, properties, and applications of cis-ortho-hydroxyl polysaccharides hydrogels crosslinked with borax.Int. J. Biol. Macromol.20211821179119110.1016/j.ijbiomac.2021.04.09033895176
    [Google Scholar]
  53. LiuY. MaoJ. GuoZ. HuY. WangS. Polyvinyl alcohol/carboxymethyl chitosan hydrogel loaded with silver nanoparticles exhibited antibacterial and self-healing properties.Int. J. Biol. Macromol.202222021122210.1016/j.ijbiomac.2022.08.06135970368
    [Google Scholar]
  54. ChengH. FanZ. WangZ. GuoZ. JiangJ. XieY. Highly stretchable, fast self-healing nanocellulose hydrogel combining borate ester bonds and acylhydrazone bonds.Int J Biol Macromol202324512547110.1016/j.ijbiomac.2023.125471
    [Google Scholar]
  55. HanJ. LeiT. WuQ. High-water-content mouldable polyvinyl alcohol-borax hydrogels reinforced by well-dispersed cellulose nanoparticles: Dynamic rheological properties and hydrogel formation mechanism.Carbohydr. Polym.201410230631610.1016/j.carbpol.2013.11.04524507286
    [Google Scholar]
  56. WhitcherJ.P. SrinivasanM. UpadhyayM.P. Corneal blindness: A global perspective.Bull. World Health Organ.2001793214221[J].11285665
    [Google Scholar]
  57. ThomasP.A. GeraldineP. Infectious keratitis.Curr. Opin. Infect. Dis.200720212914110.1097/QCO.0b013e328017f87817496570
    [Google Scholar]
  58. EgrilmezS. Yildirim-ThevenyŞ. Treatment-resistant bacterial keratitis: Challenges and solutions.Clin. Ophthalmol.20201428729710.2147/OPTH.S18199732099313
    [Google Scholar]
  59. MahF. Cervantes Clinical use of gatifloxacin ophthalmic solution for treatment of bacterial conjunctivitis.Clin. Ophthalmol.2011549550210.2147/OPTH.S1377821573098
    [Google Scholar]
  60. HoffmanL.R. D’ArgenioD.A. MacCossM.J. ZhangZ. JonesR.A. MillerS.I. Aminoglycoside antibiotics induce bacterial biofilm formation.Nature200543670541171117510.1038/nature0391216121184
    [Google Scholar]
  61. YuanX. MarcanoD.C. ShinC.S. HuaX. IsenhartL.C. PflugfelderS.C. AcharyaG. Ocular drug delivery nanowafer with enhanced therapeutic efficacy.ACS Nano2015921749175810.1021/nn506599f25585134
    [Google Scholar]
  62. HuangQ. ZouY. ArnoM.C. ChenS. WangT. GaoJ. DoveA.P. DuJ. Hydrogel scaffolds for differentiation of adipose-derived stem cells.Chem. Soc. Rev.201746206255627510.1039/C6CS00052E28816316
    [Google Scholar]
  63. GutierrezA.M. FrazarE.M. X KlausM.V. PaulP. HiltJ.Z. Hydrogels and hydrogel nanocomposites: Enhancing healthcare through human and environmental treatment.Adv. Healthc. Mater.2022117e210182010.1002/adhm.20210182034811960
    [Google Scholar]
  64. GaoW. ZhangY. ZhangQ. ZhangL. Nanoparticle-hydrogel: A hybrid biomaterial system for localized drug delivery.Ann. Biomed. Eng.20164462049206110.1007/s10439‑016‑1583‑926951462
    [Google Scholar]
  65. MakhathiniS.S. MdandaS. KondiahP.J. KharodiaM.E. RumboldK. AlagidedeI. PathakY. BulbuliaZ. Rants’oT.A. KondiahP.P.D. Biomedicine innovations and its nanohydrogel classifications.Pharmaceutics20221412283910.3390/pharmaceutics1412283936559335
    [Google Scholar]
  66. GranataG. PetraliaS. ForteG. ConociS. ConsoliG. M. L. Injectable supramolecular nanohydrogel from a micellar self-assembling calix[4]arene derivative and curcumin for a sustained drug release.Mater Sci Eng C Mater Biol Appl202011111084210.1016/j.msec.2020.110842
    [Google Scholar]
  67. XiaoY. GuY. QinL. ChenL. ChenX. CuiW. LiF. XiangN. HeX. Injectable thermosensitive hydrogel-based drug delivery system for local cancer therapy.Colloids Surf B Biointerfaces.202120011158110.1016/j.colsurfb.2021.111581
    [Google Scholar]
  68. LvH. WuB. SongJ. WuW. CaiW. XuJ. Hydrogel, a novel therapeutic and delivery strategy, in the treatment of intrauterine adhesions.J. Mater. Chem. B Mater. Biol. Med.20219336536655210.1039/D1TB01005K34324619
    [Google Scholar]
  69. WuY. LiY. HanR. LongZ. SiP. ZhangD. Dual-cross-linked PEI/PVA hydrogel for pH-responsive drug delivery.Biomacromolecules202324115364537010.1021/acs.biomac.3c0082437906107
    [Google Scholar]
  70. ZhouJ. WangH. ChenH. LingY. XiZ. LvM. ChenJ. pH-responsive nanocomposite hydrogel for simultaneous prevention of postoperative adhesion and tumor recurrence.Acta Biomater.202315822823810.1016/j.actbio.2022.12.02536563777
    [Google Scholar]
  71. XueC. XuX. ZhangL. LiuY. LiuS. LiuZ. WuM. ShuaiQ. Self-healing/pH-responsive/inherently antibacterial polysaccharide-based hydrogel for a photothermal strengthened wound dressingColloids Surf B Biointerfaces202221811273810.1016/j.colsurfb.2022.112738
    [Google Scholar]
  72. RazaF. ZhuY. ChenL. YouX. ZhangJ. KhanA. KhanM.W. HasnatM. ZafarH. WuJ. GeL. Paclitaxel-loaded pH responsive hydrogel based on self-assembled peptides for tumor targeting.Biomater. Sci.2019752023203610.1039/C9BM00139E30839983
    [Google Scholar]
  73. LiY. BuiQ.N. DuyL.T.M. YangH.Y. LeeD.S. One-step preparation of ph-responsive polymeric nanogels as intelligent drug delivery systems for tumor therapy.Biomacromolecules20181962062207010.1021/acs.biomac.8b0019529625005
    [Google Scholar]
  74. HuangY. ChenY. LuZ. YuB. ZouL. SongX. HanH. JinQ. JiJ. Facile synthesis of self-targeted Zn(2+) -gallic acid nanoflowers for specific adhesion and elimination of gram-positive bacteriaSmall2023e230257810.1002/smll.202302578
    [Google Scholar]
  75. Sautrot-BaP. RazzaN. BreloyL. AndaloussiS.A. ChiapponeA. SangermanoM. HélaryC. BelbekhoucheS. CoradinT. VersaceD.L. Photoinduced chitosan–PEG hydrogels with long-term antibacterial properties.J. Mater. Chem. B Mater. Biol. Med.20197426526653810.1039/C9TB01170F31578530
    [Google Scholar]
/content/journals/cdd/10.2174/0115672018279105240226050253
Loading
/content/journals/cdd/10.2174/0115672018279105240226050253
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test