Eye diseases like age-related macular degeneration (AMD), diabetic retinopathy (DR), proliferative vitreoretinopathy (PVR), etc., are major contributors to severe visual impairment and blindness. Various physiological barriers hinder therapeutic drugs from effectively penetrating the retina, significantly impeding the treatment of these eye conditions.

Currently, common administration routes for ocular diseases include systemic, topical ocular, periocular, and intravitreal injection. However, drugs delivered via these routes face challenges navigating anatomical and physiological barriers, thereby diminishing their efficacy in fundus delivery. Nanotechnology-based drug delivery systems, characterized by their nanoscale size and high surface area-to-volume ratio, offer promising solutions. They can encapsulate therapeutic agents of diverse physicochemical properties and be tailored with surfactants to enhance solubility and permeability across physiological barriers. Additionally, they safeguard biologics from degradation, thus enhancing drug safety and bioavailability, while also enabling targeted delivery to specific ocular sites, unlocking vast therapeutic potential.

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Figure 1. Nanotechnology-based drug delivery systems for ocular application [1]

Nanotechnology-based ocular drug delivery systems

In recent years, the application of nanotechnologies has been undergoing significant progress in the treatment of various eye diseases. Liposomes, nanoparticles, dendrimers, nanoemulsions and nanomicelles are considered the most practical nanotechnology-based ophthalmic delivery systems offering numerous benefits over common therapeutics.

Liposomes

Liposomes are small vesicles formed by phospholipid bilayers, capable of encapsulating hydrophilic or lipophilic drugs. They are widely used in the treatment of retinal diseases, such as Visudyne, a liposomal formulation of verteporfin, which was the first FDA-approved drug for treating AMD. Liposomes offer the following unique advantages.

Phospholipid bilayer membranes easily fuse with biological membranes, facilitating drug penetration into the cornea for release. Additionally, liposomes have a certain adsorption capacity to the cornea, which can increase drug retention time in the cornea and promote ocular drug absorption. The membrane materials used in liposome preparation mainly consist of phospholipids and cholesterol, which exhibit excellent biocompatibility and biodegradability, allowing them to be metabolized normally. Therefore, liposomes, as drug carriers, hold significant potential for development.

Nanoparticles

Nanoparticles are spherical, polymeric particles composed of natural or artificial polymers, with diameters ranging from 10 to 1000 nm, including nanospheres and nanocapsules. While nanocapsules of vesicular structure generally have the drug immersed in a liquid core surrounded by a solidified polymeric shell, nanospheres are a solid/mass polymeric matrix in which drug is encapsulated inside or over the structure surface. Due to their small particle size, nanoparticles can improve drug solubility, exhibit good biocompatibility and biodegradability, and are widely used as carriers for ocular drug delivery systems. Currently, commonly used biocompatible adhesives for preparing mucoadhesive nanoparticles include polyethylene glycol (PEG), chitosan, hyaluronic acid, etc., which can significantly enhance the corneal retention time of drugs.

Dendrimers

Dendrimers are three-dimensional, immensely branched, well-organized nanoscopic macromolecules (typically 5000-500,000 g/mol), and possess a low polydispersity index.

Dendrimers offer the versatility to be tailored by coupling or attaching various molecules like amines, carboxylic acids, PEG, phosphates, sulfonates, and lysine, enabling sustained therapeutic effects. Furthermore, they exhibit favorable therapeutic efficacy and biocompatibility when administered via intravenous or intravitreal injection. Dendrimers serve as promising carriers for gene therapy in treating fundus diseases. Several clinical trials involving dendrimers have been initiated, with in vitro studies on diabetic retinopathy patients showing that intravitreal injection of dendrimers can traverse retinal and choroidal tissue layers and be internalized by choroidal cells.

Nanoemulsions

Nanoemulsions are transparent or translucent, thermodynamically stable oil-in-water (O/W) mixtures spontaneously formed by oil phase, aqueous phase, emulsifiers, and co-emulsifiers in appropriate proportions. The oil phase in nanoemulsions can enhance the solubility of lipophilic drugs, while emulsifiers and co-emulsifiers can prolong the contact time between drugs and corneal epithelial cells, thereby increasing drug corneal permeability and facilitating drug delivery to deeper ocular tissue structures.

Nanomicelles

Polymeric micelles are self-assembling nanostructures with a hydrophilic shell and a hydrophobic core with a moderate size range of 10–100 nm. They are renowned for enhancing solubility and sustaining drug release. Compared to solid nanoparticles, polymeric nanomicelles are typically easier to prepare and achieve sterilization, while also exhibiting high thermodynamic stability. The most commonly used hydrophilic block is polyethylene glycol-polyethylene oxide (PEG-PEO). PEG is non-toxic and minimizes ionic bonding, stabilizing the spatial structure of micelles. Additionally, PEG prevents protein binding in biological matrices, reducing immunogenicity, and protecting micelles from enzymatic degradation.

Approved nanotechnology-based delivery systems for ocular diseases

With the increasing number of products on the market, the development of nanotechnology for the treatment of ocular diseases seems promising. Table 1 lists some FDA-approved nanocarriers for ocular diseases.

Table 1. Some FDA-approved nanocarriers for the treatment of ocular diseases [1]

Conclusion

The annual rise in the incidence of ophthalmic conditions like glaucoma, cataracts, and retinal degenerative disorders prompts the exploration of advanced treatment approaches. Nanomedicines, including polymeric micelles, nano-suspensions, nanoparticles, liposomes, and nanoemulsions offer promising solutions. These formulations not only enhance drug solubility but also improve drug bioavailability in ocular tissues. They extend drug corneal retention time, reduce dosing frequency, improve patient adherence, and minimize adverse reactions, presenting significant opportunities in ocular drug delivery. Nonetheless, challenges like poor stability, low drug loading, and ocular irritation persist. While most of these formulations are still experimental, further research is essential to mitigate adverse reactions, increase drug loading, optimize drug delivery to the posterior eye segment, and ensure formulation safety and efficacy.

Polyethylene glycol (PEG) is widely utilized in drug delivery and nanotechnology due to its reported“stealth”properties and biocompatibility. Biopharma PEG has been focusing on the development of a full range of medical applications and technologies for nanocarrier systems (including various types of nanoparticles, liposomes, micelles, etc.), and has accumulated a large number of data models and rich research experience in the construction and optimization of nanocarriers for drugs. We can produce and provide Cholesterol (Plant-Derived), DSPE, and classic PEG lipids, such as mPEG-DMG, ALC-0159 and mPEG-DSPE for your LNPs R&D.

References:
[1] Li S, Chen L, Fu Y. Nanotechnology-based ocular drug delivery systems: recent advances and future prospects. J Nanobiotechnology. 2023 Jul 22;21(1):232. doi: 10.1186/s12951-023-01992-2. PMID: 37480102; PMCID: PMC10362606.

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