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Cited by 1Ocular Surface and Contact LensAdvanced Drug Delivery SystemsNanoparticle-Based Drug Delivery

N-acylethanolamine acid amidase inhibitor-loaded polymeric micelles in the treatment of dry eye disease

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College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, Zhejiang Province, China, Zhao, Yang, Zhou, Bang-Yan, Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China, Zeng, Wen-Xuan, Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China, Du, Qi-Yue, Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China +8 more·2025·International Journal of Ophthalmology
DOI 10.18240/ijo.2025.10.01PMC PMC12454007
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Abstract

AIM: To investigate F96, a N-acylethanolamine acid amidase (NAAA) inhibitor, as a novel drug for treating dry eye disease (DED) and to enhance its corneal retention time by utilizing nanometer micelles to improve therapeutic efficacy. METHODS: The study compared nanomicelles encapsulating doxorubicin with an aqueous solution of doxorubicin to assess the ability of the nanomicelles to prolong drug retention on the ocular surface. Dry eye was induced in mice through subcutaneous injections of scopolamine hydrobromide. The efficacy of F96 was evaluated using various clinical assessments, including the phenol red cotton test, Oregon green dextran staining, periodic acid-Schiff (PAS) staining, and Terminal dUTP Nick-End Labeling (TUNEL) assay. RESULTS: Doxorubicin micelles exhibited significantly prolonged retention compared to the aqueous solution. By 15min, the corneal fluorescence intensity of the micelle group was markedly higher than that of theaqueous solution group (P<0.05), and this enhanced effect persisted for at least 4h. Furthermore, mice treated with F96 demonstrated superior outcomes in tear production, corneal staining, and goblet cell density compared to the control groups. Specifically, F96-mPPP significantly increased tear secretion (3.35±0.45 vs 1.85±0.51 mm in the vehicle group, P<0.001), restored conjunctival goblet cell density (54.5±4.5 vs 31.3±3.0, P<0.01), and reduced corneal fluorescein staining scores (3.4±0.32 vs 6.5±0.72, P<0.001). Additionally, F96-mPPP treatment markedly decreased TUNEL-positive cells in the corneal epithelium, indicating suppression of apoptosis. CONCLUSION: F96 nanometer micelles have the potential to serve as a promising novel approach for effectively alleviating ocular surface damage in the treatment of dry eye disease.

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  • F96-MPPP micellar preparation significantly prolongs ocular surface retention time of the drug compared with the aqueous solution of the drug.

    “Studies have confirmed that compared with the aqueous solution of the drug, this micellar preparation can significantly prolong the ocular surface retention time of the drug.”

    From From design to Deployment: The innovative role of nanomicelles in targeted ophthalmic therapeutics (2025) · cites this paper as [127]

    In “m-PPP increased Drug Retention time and Permeability in Cornea,” DOX-mPPP micelles showed greater ocular-surface retention than aqueous DOX-PBS in mice, with higher corneal fluorescence at 15 minutes that persisted for at least 4 hours. The retention experiment used doxorubicin as a surrogate; it did not directly compare F96-mPPP with an aqueous F96 solution. (LLM, conf=0.88)

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  • In DED model mice, F96-mPPP treatment significantly increases tear secretion, restores conjunctival goblet cell density, reduces corneal fluorescein staining score, and inhibits corneal epithelial cell apoptosis.

    “In DED model mice, F96-mPPP treatment can significantly increase tear secretion, restore the density of conjunctival goblet cells, reduce corneal fluorescein staining score, and inhibit corneal epithelial cell apoptosis [127].”

    From From design to Deployment: The innovative role of nanomicelles in targeted ophthalmic therapeutics (2025) · cites this paper as [127]

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Research works printed but not linked: 31

  1. Zhang Y, Yang M, Zhao SX, et al. Hyperosmolarity disrupts tight junction via TNF-α/MMP pathway in primary human corneal epithelial cells. Int J Ophthalmol 2022;15(5):683-689.
  2. Stapleton F, Alves M, Bunya VY, et al. TFOS DEWS II epidemiology report. Ocul Surf 2017;15(3):334-365.
  3. Zhang XM, Yang LT, Zhang Q, et al. Reliability of Chinese web- based ocular surface disease index questionnaire in dry eye patients: a randomized, crossover study. Int J Ophthalmol 2021;14(6):834-843.
  4. Lee BS, Kabat AG, Bacharach J, et al. Managing dry eye disease and facilitating realistic patient expectations: a review and appraisal of current therapies. Clin Ophthalmol 2020;14:119-126.
  5. Di Zazzo A, Roberti G, Mashaghi A, et al. Use of topical cannabinomimetic palmitoylethanolamide in ocular surface disease associated with antiglaucoma medications. J Ocul Pharmacol Ther 2017;33(9):670-677.
  6. Ye SH, Chen Q, Jiang N, et al. PPARα-dependent effects of palmitoylethanolamide against retinal neovascularization and fibrosis. Invest Ophthalmol Vis Sci 2020;61(4):15.
  7. Paterniti I, di Paola R, Campolo M, et al. Palmitoylethanolamide treatment reduces retinal inflammation in streptozotocin-induced diabetic rats. Eur J Pharmacol 2015;769:313-323.
  8. Chen Q, Ji CY, Zheng RH, et al. N-palmitoylethanolamine maintains local lipid homeostasis to relieve sleep deprivation-induced dry eye syndrome. Front Pharmacol 2019;10:1622.
  9. Fotio Y, Mabou Tagne A, Squire E, et al. NAAA-regulated lipid signaling in monocytes controls the induction of hyperalgesic priming in mice. Nat Commun 2024;15:1705.
  10. Piomelli D, Scalvini L, Fotio Y, et al. N-acylethanolamine acid amidase (NAAA): structure, function, and inhibition. J Med Chem 2020;63(14):7475-7490.
  11. Li YH, Li YT, Xu SN, et al. N-Acylethanolamine acid amidase (NAAA) exacerbates psoriasis inflammation by enhancing dendritic cell (DCs) maturation. Pharmacol Res 2022;185:106491.
  12. Palese F, Pontis S, Realini N, et al. Targeting NAAA counters dopamine neuron loss and symptom progression in mouse models of Parkinsonism. Pharmacol Res 2022;182:106338.
  13. Mascarenhas M, Chaudhari P, Lewis SA. Natamycin ocular delivery: challenges and advancements in ocular therapeutics. Adv Ther 2023;40(8):3332-3359.
  14. Han HJ, Li S, Xu MY, et al. Polymer-and lipid-based nanocarriers for ocular drug delivery: Current status and future perspectives. Adv Drug Deliv Rev 2023;196:114770.
  15. Binkhathlan Z, Ali R, Alomrani AH, et al. Role of polymeric micelles in ocular drug delivery: an overview of decades of research. Mol Pharm 2023;20(11):5359-5382.
  16. Grimaudo MA, Pescina S, Padula C, et al. Poloxamer 407/TPGS mixed micelles as promising carriers for cyclosporine ocular delivery. Mol Pharmaceutics 2018;15(2):571-584.
  17. Yang LH, Li L, Chen L, et al. Potential analgesic effects of a novel N-acylethanolamine acid amidase inhibitor F96 through PPAR-α. Sci Rep 2015;5:13565.
  18. Han Y, Guo SJ, Li YP, et al. Berberine ameliorate inflammation and apoptosis via modulating PI3K/AKT/NFκB and MAPK pathway on dry eye. Phytomedicine 2023;121:155081.
  19. Messmer EM. The pathophysiology, diagnosis, and treatment of dry eye disease. Dtsch Arztebl Int 2015;112(5):71-81.
  20. Ames P, Galor A. Cyclosporine ophthalmic emulsions for the treatment of dry eye: a review of the clinical evidence. Clin Investig (Lond) 2015;5(3):267-285.
  21. Hammerschmidt P, Ostkotte D, Nolte H, et al. CerS6-derived sphingolipids interact with mff and promote mitochondrial fragmentation in obesity. Cell 2019;177(6):1536-1552.e23.
  22. Raichur S, Brunner B, Bielohuby M, et al. The role of C16: 0 ceramide in the development of obesity and type 2 diabetes: CerS6 inhibition as a novel therapeutic approach. Mol Metab 2019;21:36-50.
  23. Bari A, Dasgupta A, Agarwal T, et al. Clinical efficacy and safety of preservative free cyclosporine in dry eye disease. Clin Ophthalmol 2025;19:1149-1154.
  24. Chaudhari P, Birangal S, Mavlankar N, et al. Oil-free eye drops containing Cyclosporine A/cyclodextrin/PVA supramolecular complex as a treatment modality for dry eye disease. Carbohydr Polym 2022;297:120007.
  25. Kaercher T, Sheppard JD, Hamm A, et al. Pooled results from two pivotal randomized controlled clinical trials: ESSENCE-1 and ESSENCE-2 to assess efficacy and safety of a water-free ciclosporin 0.1% formulation for the treatment of dry eye disease. Graefes Arch Clin Exp Ophthalmol 2025;263(4):1051-1060.
  26. Brière R, Bouchard F, Ismail S, et al. A pilot study on oral cyclosporine A in association with fulguration for the treatment of interstitial cystitis with Hunner's lesions. Neurourol Urodyn 2022;41(6):1498-1504.
  27. Jaffry M, Choudhry H, Aftab OM, et al. Antibody-drug conjugates and ocular toxicity. J Ocul Pharmacol Ther 2023;39(10):675-691.
  28. Tao Z, Li CC, Zhang AQ, et al. Study of transport, tissue distribution, depletion, and hepatotoxicity of Cyadox, a quinoxaline-1, 4-dioxide derivative. Front Pharmacol 2024;15:1401275.
  29. Wang JJ, Liu XX, Zhu CC, et al. Improving ocular bioavailability of hydrophilic drugs through dynamic covalent complexation. J Control Release 2023;355:395-405.
  30. Ju XY, Wu LP, Gao N, et al. Overcoming the stromal barrier of the cornea with a peptide conjugate nano-assembly to combat fungal keratitis. Adv Healthc Mater 2023;12(10):e2202409.
  31. Suzuki M, Ishii S, Ota M, et al. Enhancing marine biodegradability of poly(butylene succinate) by blending with 16-hydroxyhexadecanoic acid and poly(ε-caprolactone). Polym Degrad Stab 2024;228:110912.

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Authors
College of Life Sciences and Medicine, Z. S.-T. U., Zhao, Y., Zhou, B.-Y., Eye Institute of Xiamen University, F. P. K. L. O. O. A. V. S., Zeng, W.-X., Eye Institute of Xiamen University, F. P. K. L. O. O. A. V. S., Du, Q.-Y., Eye Institute of Xiamen University, F. P. K. L. O. O. A. V. S., Chen, F.-Y., Eye Institute of Xiamen University, F. P. K. L. O. O. A. V. S., Ren, J., Eye Institute of Xiamen University, F. P. K. L. O. O. A. V. S., Fu, H.-W., College of Life Sciences and Medicine, Z. S.-T. U., Qiu, Y., & Eye Institute of Xiamen University, F. P. K. L. O. O. A. V. S.
Affiliations
  • Zhejiang Sci-Tech University (CN)
  • Shandong University (CN)
  • Xiamen University (CN)
ORCID
Venue
International Journal of Ophthalmology
Publisher
Press of International Journal of Ophthalmology (IJO Press)
Published
2025-10-18
Volume
18
Issue
10
Pages
1815-1822
ISSN
  • 2222-3959 (ISSN-L)
  • 2227-4898
DOI
10.18240/ijo.2025.10.01
PMC
PMC12454007
OpenAlex
W4414184961
Cited by
1
References
0
Citations by year
2025: 1
FWCI
0.91
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • International Journal of Ophthalmology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (82274162)
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Ocular Surface and Contact Lens
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
dry eye, polymeric micelles, ocular drug delivery, corneal retention, goblet cells, tear secretion, scopolamine-induced dry eye, ocular surface damage

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