SMART BIOSURFACTANT NANOCARRIERS: ROS-LABILE ORAL DELIVERY SYSTEM FOR ENHANCED CELECOXIB EFFICACY IN RHEUMATOID ARTHRITIS
DOI:
https://doi.org/10.22159/ijap.2026v18i2.57021Keywords:
Rheumatoid arthritis, Celecoxib, Nanostructured lipid carriers, Sophorolipid, ROS-responsive delivery, Anti-inflammatory therapyAbstract
Objective: The chronic autoimmune illness known as rheumatoid arthritis (RA) is typified by joint destruction, oxidative stress, and ongoing inflammation. The selective COX-2 inhibitor celecoxib is useful in the treatment of RA, although its lack of disease-specific targeting, low oral bioavailability, and poor solubility restrict its effectiveness. In order to increase absorption, offer inflammation-triggered release, and boost treatment effectiveness in RA, this study set out to create a sophorolipid-stabilized, ROS-labile nanostructured lipid carrier (NLC) system for oral celecoxib administration.
Methods: Using microfluidic ethanol injection, NLCs were created with thioketal (TK)-PEG-cholesterol integrated at the interface and sophorolipid acting as a biosurfactant. Mucus penetration, epithelial transport, hemocompatibility, ROS-triggered release, and in-vitro pharmacological activity in LPS-stimulated macrophages were all assessed, along with the formulation's physicochemical and interfacial characteristics.
Results: Optimized NLCs displayed a size of 138 ± 6 nm, PDI < 0.2, zeta potential −21 mV, and encapsulation efficiency >90%. Under ROS exposure, drug release reached ~83% at 12 h versus ~21% in controls. SL-NLCs showed 3-fold higher mucus diffusivity and significantly improved Caco-2 permeability (P_app 5.7 × 10⁻⁶ cm/s). In vitro studies demonstrated superior cytokine suppression (TNF-α ↓68%, IL-6 ↓62%) and COX-2 downregulation. Hemolysis was <3%, indicating excellent biocompatibility.
Conclusion: With improved absorption, inflammation-specific release, and strong anti-inflammatory action, ROS-labile, sophorolipid-stabilized NLCs offer a secure and efficient oral delivery system for celecoxib that may find therapeutic use in RA.
References
1. Kondo N, Kanai T, Okada M. Rheumatoid arthritis and reactive oxygen species: a review. Curr Issues Mol Biol. 2023;45(4):3000–3015. doi:10.3390/cimb45040197
2. Wang L, Wang C, Jia X, et al. Oxidative stress and antioxidants in rheumatoid arthritis. Antioxidants (Basel). 2022;11(6):1153. doi:10.3390/antiox11061153
3. Prasad P, Pai A, Singh A, et al. Pathobiology of oxidative stress in rheumatoid arthritis: therapeutic insights. Biomed Pharmacother.2022;151:113122. doi:10.1016/j.biopha.2022.113122
4. Arslan A, Yilmaz F, Onay-Ucar E. Celecoxib nanoformulations: solubility, dissolution, and oral bioavailability. Pharmaceutics. 2023;15(2):356. doi:10.3390/pharmaceutics15020356
5. Zhu Y, Xu H, Liang J, et al. Hyaluronic acid-modified celecoxib nanostructured lipid carriers for oral delivery. Nanoscale Res Lett.2024;19:89. doi:10.1186/s11671-024-04070-0
6. Liu Y, Feng L, Liu R, et al. Microfluidics for nanoparticle drug delivery. Small. 2022;18(19):e2106580. doi:10.1002/smll.202106580
7. Osouli-Bostanabad K, Fowler J, Liu Y, et al. Microfluidic manufacture of lipid-based nanomedicines. Pharmaceutics. 2022;14(9):1816. doi:10.3390/pharmaceutics14091816
8. Pal S, Chatterjee N, Das AK, McClements DJ, Dhar P. Sophorolipids: properties and applications. Adv Colloid Interface Sci.2023;313:102856. doi:10.1016/j.cis.2023.102856
9. Ceresa C, Fracchia L, Sansotera AC, De Rienzo MAD, Banat IM. Biosurfactants in biomedical and pharmaceutical applications. Pharmaceutics. 2023;15(8):2156. doi:10.3390/pharmaceutics15082156
10. Adu SA, Twumasi P, Ibrahim M, et al. Bioprocess optimization for sophorolipids. Fermentation. 2023;9(11):985. doi:10.3390/fermentation9110985
11. Rinaldi A, Diederich M. Reactive oxygen species-responsive thioketal linkers in drug delivery. Biomedicines. 2022;10(9):2152. doi:10.3390/biomedicines10092152
12. Dai Z, Tian L, Sun Q, et al. Reactive oxygen species-responsive liposomes for inflammation-targeted therapy. Nanoscale. 2021;13(34):14373–14392. doi:10.1039/D1NR04278E
13. Xue M, Ma P, Zhang L, et al. Reactive oxygen species-cleavable prodrugs in nanomedicine. Acta Pharm Sin B. 2023;13(5):2134–2154. doi:10.1016/j.apsb.2022.12.025
14. Zhou Y, Wang D, Gao J, et al. Celecoxib delivery systems for inflammatory diseases. J Drug Deliv Sci Technol.2024;85:105698. doi:10.1016/j.jddst.2023.105698
15. Xu S, Zhao X, Chen Y, et al. Celecoxib nanomedicines in oncology and inflammation. Adv Drug Deliv Rev.2024;206:115389. doi:10.1016/j.addr.2023.115389
16. Ammar HO, Ghorab MM, Zaki NM, et al. Nanostructured lipid carriers for improved oral celecoxib delivery. Pharm Dev Technol. 2020;25(2):220–230. doi:10.1080/10837450.2019.1704463
17. Shi X, Li Y, Wang X, et al. Integration of reactive oxygen species generation and prodrug activation. Biointegration. 2021;2(2):73–86. doi:10.15212/bioi-2021-0011
18. Pan X, Li Z, Wang D, et al. Dynamic pendant-drop pitfalls in interfacial science. Langmuir. 2022;38(49):15068–15083. doi:10.1021/acs.langmuir.2c01193
19. Wang Y, Chen H, Xu Q, et al. Hypochlorous acid-responsive probes and delivery systems. ACS Appl Mater Interfaces. 2025;17(2):1711–1723. doi:10.1021/acsami.4c18731
20. Palos-Pinto A, Cordero ML, Dominguez A, et al. Sophorolipids in drug and vaccine delivery. Colloids Surf B Biointerfaces.2023;223:113093. doi:10.1016/j.colsurfb.2022.113093
21. Xue Y, Wang Q, Zhang G, et al. Biosurfactant-stabilized lipid nanoparticles. Nanomedicine (Lond). 2022;17(14):867–884. doi:10.2217/nnm-2022-0044
22. Sharma R, Patel M, Banat IM. Biosurfactants in medical sciences. Molecules. 2024;29(11):2606. doi:10.3390/molecules29112606
23. El Omari Y, Rharbi Y, Blein T. Advances in interfacial rheology. Polymers (Basel). 2022;14(12):2513. doi:10.3390/polym14122513
24. Maeki M, Saito T, Sato Y, et al. Ethanol effects in microfluidic lipid nanoparticle preparation. Micromachines (Basel). 2024;15(3):292. doi:10.3390/mi15030292
25. Liu C, Zhang W, Li J, et al. Engineering nanoparticles to overcome the mucus barrier. Mater Today Adv.2021;11:100138. doi:10.1016/j.mtadv.2021.100138
26. Ramirez A, Weigandt KM, Hanes J, et al. Multiple particle tracking to probe mucus rheology. Biophys J. 2022;121(9):1713–1726. doi:10.1016/j.bpj.2022.03.011
27. Shepherd SJ, Issadore D, Mitchell MJ. Microfluidic formulation of nanoparticles for drug delivery. J Control Release.2021;332:12–27. doi:10.1016/j.jconrel.2021.02.022
28. Cheng Y, Wang H, Zhang J, et al. Microfluidic lipid vesicle generation: advances and challenges. Lab Chip. 2024;24(20):4058–4080. doi:10.1039/D4LC00380B
29. Javid-Naderi MJ, et al. Advanced microfluidic techniques for lipid nanoparticles. Biopr Rep. 2025;4(3):031304. doi:10.1063/5.0202217
30. Hassan H, Tahir NA, Khalid A, et al. Central composite design applied to solid lipid nanoparticles for acyclovir. Pharmaceuticals (Basel). 2021;14(9):871. doi:10.3390/ph14090871
31. Talarico L, Carbone C, Lopedota A, et al. Central composite design optimization of steroid-loaded solid lipid nanoparticles. Molecules. 2023;28(15):5747. doi:10.3390/molecules28155747
32. Sruthi S, Gopinath S, Athisayaraj MS, Kumar SS. Central composite design for pharmaceutical formulations. J Young Pharm. 2024;16(3):400–409. doi:10.5530/jyp.2024.16.52
33. Pan Z, Chen X, Zhang J, et al. Interfacial property determination by pendant-drop method. Curr Opin Colloid Interface Sci.2024;69:101843. doi:10.1016/j.cocis.2024.101843
34. Xu L, Xu Z, Wang L, et al. Interfacial rheology of modified silica nanoparticles. Nanomaterials (Basel). 2024;14(10):2054. doi:10.3390/nano14102054
35. Risse K, Müller-Buschbaum P. Large-amplitude dilatational interfacial rheology. Adv Colloid Interface Sci.2025;322:103356. doi:10.1016/j.cis.2025.103356
36. Zhang H, Yang Y, Chai Y, et al. Interfacial wetting-induced nanorheology. Phys Rev Res.2025;7:023226. doi:10.1103/PhysRevResearch.7.023226
37. Esfandiarian A, Arabloo M, Hemmati-Sarapardeh A. Pendant-drop best practices for interfacial tension measurement. Colloids Surf APhysicochem Eng Asp.2022;650:129605. doi:10.1016/j.colsurfa.2022.129605
38. Liu Y, Wang Z, Zhang P, et al. Reactive oxygen species-triggered release nanocarriers. Nano Today.2020;35:100987. doi:10.1016/j.nantod.2020.100987
39. Boyles M, et al. Standard operating procedure for DCFH₂-DA cell-free ROS detection. Nanotoxicology. 2022;16(10):1222–1241. doi:10.1080/15376516.2022.2029656
40. Sedaghat MH, et al. Nanoparticle diffusion in respiratory mucus: biophysical insights. J Aerosol Med Pulm Drug Deliv. 2023;36(2):60–81. doi:10.1089/jamp.2022.0049
41. ACS Nano. Mucus-penetration of surface-engineered nanoparticles. ACS Nano. 2023;17(8):7439–7453. doi:10.1021/acsnano.2c11147
42. Tjakra M, et al. Optimized artificial colonic mucus model. Mol Pharm. 2024;21(7):1724–1735. doi:10.1021/acs.molpharmaceut.5c00298
43. Kus M, Ibragimow I, Piotrowska-Kempisty H. Caco-2 cell monolayer standardization. Pharmaceutics. 2023;15(11):2523. doi:10.3390/pharmaceutics15112523
44. Pires CL, Praça C, et al. Caco-2 monolayers: TEER and LY permeability validation. Pharmaceutics. 2021;13(10):1563. doi:10.3390/pharmaceutics13101563
45. Sciurti E, et al. TEER and ion sensor integration on Transwell systems. Micromachines (Basel). 2023;14(3):496. doi:10.3390/mi14030496
46. Hiebl V, et al. Caco-2 cholesterol transport assay protocol. BiolProced Online.2020;22:16. doi:10.1186/s12575-020-00120-w
47. Gruber S, et al. ISO 10993-5: realities in cytotoxicity evaluation. Front BioengBiotechnol.2023;11:1204948. doi:10.3389/fbioe.2023.1204948
48. Gatto C, et al. ISO 10993-5 direct versus extract cytotoxicity tests. ACS Omega. 2022;7(43):38450–38458. doi:10.1021/acsomega.2c04697
49. Burkhardt F, et al. Threshold <70% viability in ISO 10993-5 cytotoxicity testing. Sci Rep.2022;12:8121. doi:10.1038/s41598-022-11426-y
50. Sharma P, Singh R, Patel D, et al. Hemocompatibility and cytotoxicity assessment of lipid-based nanocarriers for oral drug delivery. Int J Pharm Pharm Sci. 2023;15(8):56–62. doi:10.22159/ijpps.2023v15i8.47852
51. Kumar A, Devi S, Rajan R, et al. Evaluation of anti-inflammatory potential of phytoconstituent-loaded nanoparticles using RAW 264.7 macrophage model. Asian J Pharm Clin Res. 2020;13(12):101–106. doi:10.22159/ajpcr.2020.v13i12.40125
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