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基于壳聚糖的智能微针用于两性霉素B负载油质体的递送：通过TLR4/NLRP3途径利用兔模型靶向抗真菌眼贴有效对抗真菌性角膜炎。

Chitosan-Based Intelligent Microneedles for Delivery of Amphotericin B Loaded Oleosomes: Antifungal Ocular Patch Targeting for Effective Against Fungal Keratitis Using Rabbit Model via TLR4/NLRP3 Pathway.

作者信息

Elhabal Sammar Fathy, Al-Zuhairy Saeed Abdul-Kareem Saeed, Elrefai Mohamed Fathi Mohamed, El-Nabarawi Mohamed A, Hababeh Sandra, Zarif Attalla Kristina, Shoela Mai S, Nelson Jakline, Fady Marwa, Elzohairy Nahla A, Amin Mariam E, Ahmed Heba Sabry, Ewedah Tassneim M, Mousa Ibrahim, Hamdan Ahmed Mohsen Elsaid

机构信息

Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Modern University for Tech-Nology and Information (MTI) Mokattam, Cairo, Egypt.

Department of Pharmacy, Kut University College Kut, Wasit, 52001, Iraq.

出版信息

Int J Nanomedicine. 2025 May 8;20:5949-5981. doi: 10.2147/IJN.S514798. eCollection 2025.

DOI:
10.2147/IJN.S514798
PMID:40356856
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12068411/
Abstract

BACKGROUND

Fungal keratitis (FK), a major cause of blindness, remains challenging to treat due to poor drug penetration and antifungal resistance. Amphotericin-B (AmB), a water-insoluble and low-permeability, necessitates innovative delivery systems to improve its therapeutic efficacy.

METHODS

AmB was encapsulated within oleosomes (Ole) prepared using the ethanol injection method, using phosphatidylcholine (Lipoid S100) and sodium oleate, resulting in nanosized spherical globules. The optimized Ole were characterized, then the selected Ole were incorporated into sodium polyacrylate/PEG/chitosan-based microneedles (AmB-Ole/MNs) to improve ocular delivery by creating transient microchannels on the eye surface.

RESULTS

The optimized Ole showed a droplet size of (175 ± 0.78 nm), polydispersity index of (0.33 ± 0.04), zeta potential of (31 ± 0.43 mV), high entrapment efficiency (91±0.63%), and improved stability, bioavailability, and controlled drug release. The AmB-Ole/MNs system increases corneal penetration and contact time via transient microchannels in the eye surface, achieving sustained drug delivery over 72 hours with 70% ex vivo permeation over 80 hours compared to AmB. In vitro antifungal activity and histopathological examination showed that the AmB-Ole/MNs system has potent biofilm disruption (>90%) and 27 mm and 32 mm zones of inhibition against and Aspergillus niger, respectively. The Cytotoxicity test showed reduced AmB toxicity with biocompatibility and in vivo , ocular tolerance by targeting TLR4/NLRP3 pathways and histopathological studies.

CONCLUSION

The AmB-Ole/MNs system as an innovative ocular delivery platform for fungal keratitis offers sustained drug release, enhanced permeation, potent antifungal activity, and reduced toxicity. AmB-Ole/MNs showed promise for ocular AmB delivery for FK.

摘要

背景

真菌性角膜炎（FK）是导致失明的主要原因之一，由于药物渗透性差和抗真菌耐药性，其治疗仍然具有挑战性。两性霉素B（AmB）是一种水不溶性且低渗透性的药物，需要创新的给药系统来提高其治疗效果。

方法

采用乙醇注入法，使用磷脂酰胆碱（Lipoid S100）和油酸钠制备油质体（Ole），将AmB包裹在其中，形成纳米级球形颗粒。对优化后的油质体进行表征，然后将选定的油质体纳入基于聚丙烯酸钠/聚乙二醇/壳聚糖的微针（AmB-Ole/MNs）中，通过在眼表创建瞬态微通道来改善眼部给药。

结果

优化后的油质体显示液滴尺寸为（175±0.78nm），多分散指数为（0.33±0.04），zeta电位为（31±0.43mV），包封率高（91±0.63%），稳定性、生物利用度和药物控释性得到改善。AmB-Ole/MNs系统通过眼表的瞬态微通道增加角膜渗透性和接触时间，与AmB相比，在72小时内实现持续药物递送，80小时内体外渗透率达70%。体外抗真菌活性和组织病理学检查表明，AmB-Ole/MNs系统具有强大的生物膜破坏能力（>90%），对白色念珠菌和黑曲霉的抑菌圈分别为27mm和32mm。细胞毒性试验表明，通过靶向TLR4/NLRP3途径和组织病理学研究，AmB的毒性降低，具有生物相容性和体内眼部耐受性。

结论

AmB-Ole/MNs系统作为一种创新的真菌性角膜炎眼部给药平台，具有持续药物释放、增强渗透、强大的抗真菌活性和降低毒性的特点。AmB-Ole/MNs在眼部递送AmB治疗FK方面显示出前景。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12068411/33a29593248e/IJN-20-5949-g0012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12068411/33a29593248e/IJN-20-5949-g0012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12068411/8edbcfb29067/IJN-20-5949-g0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12068411/2d27fe90c6b7/IJN-20-5949-g0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12068411/53f55bcbde3c/IJN-20-5949-g0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12068411/c45f290c3b5b/IJN-20-5949-g0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12068411/8b3e19b12860/IJN-20-5949-g0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12068411/d189cebe990f/IJN-20-5949-g0006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12068411/1b6f6356a3b7/IJN-20-5949-g0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12068411/a8e9d9d2bb30/IJN-20-5949-g0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12068411/26212c1b31be/IJN-20-5949-g0010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e8a7/12068411/33a29593248e/IJN-20-5949-g0012.jpg

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