Recent development of polymer nanomicelles in the treatment of eye diseases

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TL;DR

This review summarizes the use of polymer nanomicelles for ocular drug delivery from 2014 to 2023, highlighting their ability to enhance drug solubility, corneal penetration, and sustained release. These nanocarriers show promise in treating conditions such as fungal/bacterial infections, dry eye, glaucoma, and macular degeneration, but only a few formulations have reached clinical use. Key challenges include stability, drug loading, toxicity, and regulatory hurdles that must be addressed for clinical translation.

Full summary

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**Background:** Eye diseases are a major health burden, and topical administration (e.g., eye drops) is used for ~90% of cases. However, anatomical barriers (cornea, conjunctiva, blood-aqueous barrier, blood-retinal barrier) and clearance mechanisms (tear dilution, nasolacrimal drainage) severely limit drug bioavailability, often requiring frequent high-dose dosing that causes side effects and poor compliance. Polymer nanomicelles—core-shell structures formed by self-assembly of amphiphilic polymers—offer a solution by encapsulating hydrophobic drugs, enhancing corneal penetration, prolonging ocular surface retention, and enabling controlled release. This review consolidates advances in polymer nanomicelle-based ocular drug delivery from 2014 to 2023.

**Methods:** The authors conducted a narrative review of literature on polymer nanomicelles for ocular drug delivery, covering natural and synthetic carrier materials, types of micelles (amphiphilic block copolymers, graft polymers, random copolymers, polyelectrolyte micelles, and intelligent stimulus-responsive systems), and their applications in various eye diseases. The review includes data from in vitro, ex vivo, and in vivo studies (animal models) and mentions a few clinically approved products.

**Key Results:** - **Fungal infections:** Voriconazole-loaded phenylboronic acid-chitosan-vitamin E copolymer micelles showed drug loading of 7.90% ± 0.02% and 75% release within 0.5 h in vitro. Mixed micelles of voriconazole with Pluronic P123/F68 and Labrasol achieved effective mucoadhesion and slow release in rabbits. Itraconazole-loaded Pluronic F127/F68 in situ gel had minimum size 79.99 nm, encapsulation efficiency 91.32% ± 1.73%, and 8-h permeability 90.28% ± 0.31%. Terbinafine-loaded Solutol HS-15 micelles had near 100% encapsulation and pH-dependent release (93.2% ± 3.4% at pH 5.0 over 6 h). - **Bacterial infections:** Erythromycin-loaded Soluplus/Kolliphor HS-15/Carbopol 934P micelles had size 87.14 nm and encapsulation efficiency 86.94%. Chitosan-PLGA/poloxamer mixed micelles with moxifloxacin (1:10 ratio) showed enhanced mucoadhesion and corneal permeation. Levofloxacin/chondroitin sulfate-loaded sugar copolymer micelles achieved 83% cumulative release over 48 h under bacterial induction. - **Dry eye:** Cyclosporine A (CsA) micelles using TPGS and Solutol HS-15 improved corneal penetration and retention. Cequa® (0.09% CsA) is FDA-approved. Myricetin-loaded PVCL-PVA-PEG micelles were non-irritating in rabbits. Melatonin-loaded PVCL-PVA-PEG micelles reduced oxidative stress in dry eye mouse models. - **Glaucoma:** Dorzolamide/indomethacin-loaded PCL-g-P(NVCL-co-NVP) micelles reduced intraocular pressure in rabbits. Methazolamide-loaded mPEG-PCL micelles showed high encapsulation and anti-glaucoma effect. Nimodipine-loaded Rebaudioside A/TPGS mixed micelles enhanced ocular delivery. - **Neovascularization:** Diclofenac/anti-VEGF antibody-loaded PDLLA-PEG-PDLLA thermosensitive hydrogel reduced corneal neovascularization in rabbits. Aflibercept-loaded EPC (PEG-PPG-PCL) micelles reached therapeutic concentrations in mouse posterior segment. Simvastatin-loaded TPGS micelles delivered drug through sclera in pig models; ~80% drug remained after 1 month at 4°C, but only 30% at 25°C. - **Uveitis:** Dexamethasone-loaded PCL-PEG-PCL micelles improved corneal penetration. Triamcinolone acetonide-loaded PEG-b-PLA micelles in chitosan hydrogel released only 42.8% ± 1.6% over one week. - **Retinoblastoma:** Celastrol nanomicelles inhibited retinoblastoma growth in xenograft mouse models via HIF-1α/VEGF pathway. - **Contact lenses:** Cyclosporin-loaded C-HA micelle-embedded pHEMA lenses released drug for >10 days in vitro.

**Clinical Implications:** Polymer nanomicelles represent a promising platform to overcome ocular barriers and improve drug bioavailability for a wide range of eye diseases. However, only a few products (e.g., Cequa®) have reached clinical use. Major challenges include: (1) potential toxicity of polymers (e.g., PEG-b-PLA may cause neuroendocrine disruption); (2) interspecies differences in corneal permeability (rabbit > pig/cow); (3) stability issues (e.g., simvastatin micelles lost 70% drug at 25°C in 1 month); (4) regulatory hurdles and GMP compliance for nanomedicines; (5) need for more clinical trials to confirm safety, efficacy, and pharmacokinetics in humans. Future research should focus on biocompatible and safer polymers, improved drug loading and stability, and scalable manufacturing processes.