Nano-Based DDS for Anterior Segment Diseases: Comparison
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The eye is a delicate and complex organ protected by anatomical barriers that limit the bioavailability and residence time of topically administered drugs. Polymeric nano-based drug delivery systems (DDS) have been developed to address this challenge and improve therapeutic outcomes. Biodegradable polymers are often used in these DDS to minimize adverse effects and control the release of different loaded drugs.

The eye is a delicate and complex organ protected by anatomical barriers that limit the bioavailability and residence time of topically administered drugs. Polymeric nano-based drug delivery systems (DDS) have been developed to address this challenge and improve therapeutic outcomes. Biodegradable polymers are often used in these DDS to minimize adverse effects and control the release of different loaded drugs.

This review provides a comprehensive overview of the therapeutic potential of polymeric nano-based DDS for ocular diseases. We summarize key findings from preclinical and clinical studies conducted between 2017 and 2022 and discuss recent advances in polymer science that have contributed to the evolution of ocular DDS. Specifically, we focus on the potential of these systems to manage anterior segment diseases and glaucoma. Additionally, we compare and contrast polymeric and non-polymeric nano-based DDS for ocular diseases.

Overall, this article offers insights into the current state of the art and future directions for research in this area.

  • polymeric nanocarriers
  • biodegradable polymers
  • polymeric biomaterials
  • anteriorsegment diseases
  • glaucoma
  • ocular diseases
  • ocular drug-delivery

1. DDS for Ocular Surface Disease

Biodegradable Nano-Based DDS for Anterior Segment Diseases

DDS for Ocular Surface Disease

Ocular surface disease refers to damage of the surface layers of the eye, namely the cornea and conjunctiva. Dry eye disease (DED), or keratoconjunctivitis sicca, is the most common type of ocular surface disease. It is a complex condition characterized by insufficient or poor-quality tears, leading to discomfort, visual disturbances, and ocular surface damage. Various factors contribute to its development, including aging, medical conditions, medications, environmental factors, lifestyle habits, and hormonal changes. The severity of DED determines the pharmacologic therapy needed, ranging from mild cases, such as artificial tears, to severe cases requiring topical corticosteroids, immunosuppressants, or autologous tear therapies. However, these treatments have their limitations and side effects. For instance, artificial tears need frequent application and compliance, topical steroids can cause adverse effects, and autologous tear therapy is expensive and time-consuming. Moreover, DED affects ocular drug delivery, reducing topical medication efficacy and increasing systemic absorption risk. Thus, other therapeutic strategies have been developed to manage DED and enhance drug delivery.

Nanoemulsions encapsulating cyclosporine A such as CyclokatTM and RestasisTM have been approved for treating dry eye disease due to their highly solubilized state and improved stability. However, the high molecular weight of cyclosporine A and its higher affinity with the oil phase of the nanoemulsion have hampered drug delivery to ocular tissue. CequaTM, a nanomicelle solution containing cyclosporine A, has been shown to improve ocular surface integrity and increase tear production after 84 days of treatment. KPI-121, a mucin-penetrating particle (MPP) for the delivery of loteprednol etabonate, has also been approved by the FDA for the treatment of dry eye disease. The nanosuspension, developed by a milling procedure containing loteprednol etabonate and Pluronic F127 polymer, has a low molecular weight, evades entrapment by mucin, and has a reduced clearance rate compared to conventional eye drops. In clinical trials, KPI-121 has shown minimal toxicity and has successfully reduced signs and symptoms of dry eye disease. The F127 polymers used in KPI-121 form nanomicelle structures that can form hexagonal morphologies at higher temperatures, improving the stability of the system.

Recent clinical trials have investigated several novel biodegradable nano-sized DDS that aim to improve drug delivery for dry eye disease by reducing the need for frequent administration and increasing bioavailability. Mun et al. (2019) synthesized cholesterol-hyaluronate nanomicelles crosslinked with ethylene glycol dimethacrylate and hydroxyethyl methacrylate, resulting in contact lenses that demonstrated a prolonged therapeutic effect in a dry eye disease rabbit model. Other formulations of cyclosporine A based on mPEG-PLA copolymers have also been developed, demonstrating increased stability and prolonged shelf life through lyophilization.

Rebamipide is a promising drug for treating tear deficiency and corneal epithelial damage. It has been shown to increase mucin and lipid layers in the tear film while reducing ocular surface dryness. To improve drug delivery and increase compliance, researchers are developing novel drug delivery systems that can evade nasolacrimal clearance. Copolymeric nanoparticles made from 2-hydroxypropyl-β-cyclodextrin and methylcellulose have demonstrated sustained release and improved delivery to the goblet cells and meibomian glands. Additionally, hydrogenated soybean phospholipids and high-purity cholesterol multilamellar nanoliposomes have shown equivalent therapeutic effects to the commercially available formulation, while reducing the frequency of administration and adverse effects by improving drug retention and concentration at the cornea and aqueous humor.

Wang et al. recently synthesized rapamycin nanospheres based on 3-hydroxybutyrate-co-3-hydroxyvalerate copolymers that can effectively penetrate the tear film barrier. These nanospheres have shown potential advantages for Sjögren-associated dry eye disease, such as increasing tear meniscal height, decreasing tear break-up time, and improving Schirmer’s test scores. However, further research is needed to determine their long-term safety and efficacy [153].

Luo et al. have developed a thermo-responsive in situ gel for the treatment of dry eye disease. This gel is synthesized by functionalizing poly(N-isopropylacrylamide) with mucoadhesive gelatin and helix pomatia. In a rabbit model, a single application of the gel increased the bioavailability of the drug epigallocatechin gallate beyond the therapeutic level for 14 days [154].

Mucolytic agents are drugs that reduce mucus viscosity and inhibit inflammation. These agents typically have a thiol group, which breaks disulfide bonds in mucoprotein complexes, or are enzymes like papain or bromelain that cleave cross-links of mucus glycoproteins. Modification of nanocarriers with mucolytic agents can enable controlled drug release, enhanced permeation, and improved mucoadhesion. However, while mucolytic enzyme-loaded nanoparticles have been developed for penetrating intestinal mucous layers, research on ocular delivery is currently limited [155].

N-acetylcysteine (NAC) is a mucolytic agent that has been used to treat various anterior segment diseases, including cataracts, DED, and filamentous keratitis. However, intracorneal injection of NAC is associated with rapid mucolytic activity and adverse side effects, such as edema, sloughing, and corneal haze. To address this issue, thiolated polymers can be used to achieve a controlled, sustained release of NAC. Chitosan is an attractive option for forming highly mucoadhesive copolymers for ocular drug delivery systems. By optimizing the concentration of NAC on the surface of chitosan, the thiol groups of NAC can form covalent bonds with mucosal glycoproteins. Nepp et al. found sustained improvement in patients with dry eye disease with chitosan-NAC eye drops (LacrimeraTM). Thiolated polymers have the advantage of significantly improving adhesion to the ocular mucus layer, and therefore improving contact time with the drug, by binding with positively charged glucosamine as well as negatively charged carboxylic acids in mucosal proteins. This approach was used by Sheng et al. to synthesize nanomicelles for the delivery of flurbiprofen to reduce inflammation in DED. The nanomicelles successfully increased the bioavailability of flurbiprofen in an in vivo rabbit eye model. However, a practical barrier with mucoadhesive nanocarriers is that in vivo studies in rabbit models may not bring clinically translatable results given that rabbit eyes have superior bioadhesion and higher mucus production compared to human eyes [159].

Several novel drug-delivery systems have been developed to treat dry eye disease. The most widely used topical medications in North America are nanoemulsions encapsulating cyclosporine A (RestasisTM) and its nanomicelle form (CequaTM). These DDS offer promising results by increasing drug bioavailability, reducing the need for frequent administration, and translating clinically into improved symptom management, greater compliance, and fewer side effects.

In addition to DED, Meibomian gland dysfunction (MGD) is another common ocular surface disease that impairs meibomian gland function, leading to decreased meibum secretion and blockages. This can cause changes in the tear film composition, specifically the lipid layer, resulting in increased tear evaporation, hyperosmolarity, inflammation, and ocular surface damage. Treatment for MGD currently involves heat therapy, massage, and lid margin hygiene, but artificial tears and topical steroids may have limited effectiveness due to low patient compliance.

Chronic inflammation and oxidative stress are critical factors in the development and progression of MGD [160]. While preservative-free fluorometholone eyedrops can be used for drug administration, multiple installations are required, and they can cause adverse effects if used without DDS [161]. To address this issue, Choi et al. developed polyhydroxyethyl methacrylate-based contact lenses embedded with cerium oxide nanoparticles for scavenging reactive oxygen species. These contact lenses improved the viability of human conjunctival and meibomian gland epithelial cells, even in media with high H2O2 concentrations, and showed protective effects in a mouse model when 3% H2O2 eyedrops were administered [162].

In Phase 3 clinical trials, nanoemulsions encapsulating cyclosporine A (nano-cyclosporine; Cyporin NTM, Taejoon, Korea) have shown promise as a treatment for MGD. These nanoemulsions are considered more stable and transparent than normal emulsions. Results of the trial indicate that the group receiving cyclosporine nanoemulsions experienced significant improvement in dry eye disease secondary to MGD compared to the control group. After one month of treatment, the cyclosporine nanoemulsion group had better corneal staining and increased lipid layer thickness compared to those receiving the conventional cyclosporine formulation [163].

 

DDS for Conjunctivitis

Conjunctivitis is inflammation of the conjunctiva, the clear outer membrane covering the sclera and inner surface of the eyelids. It can result from viral or bacterial infections, allergens, irritants, or a combination thereof. Treatment depends on the cause and severity and may include artificial tears, topical antibiotics, corticosteroids, and immunosuppressants.

 

Nano-based DDS in clinical Studies

In phase III clinical trials, cyclosporine A nanoemulsions are being investigated as a potential treatment option. These cationic emulsions interact with negatively charged ocular surfaces, leading to increased residence time. The formulation has shown promise in improving signs and symptoms of severe vernal keratoconjunctivitis and good biocompatibility, with the exception of instillation site pain [164].

 

Nano-based DDS in preclinical Studies

A biodegradable DDS based on solid lipid nanoparticles has been developed to improve the stability of tacrolimus, a topical immunosuppressant used to treat ocular inflammation, including vernal keratoconjunctivitis. Solid lipid nanoparticles, made of natural fats or oils, can encapsulate lipophilic molecules, improving drug solubility. The nano-based DDS demonstrated thermo-responsive gelation at 32 degrees and showed promising therapeutic effects in vivo compared to conventional eye drops for conjunctivitis treatment [165].

Several novel DDS are being investigated for the treatment of bacterial conjunctivitis to prolong the release of topical antibiotics. Chitosan and PVA nanofibers have been designed to encapsulate ofloxacin, and the linking of the nanofibers by glutaraldehyde vapor has been found to reduce burst release and increase bioavailability. Co-delivery of multiple guest compounds is another important strategy, with hydrogels made from chitosan and poloxamer 407 being invented for the co-delivery of neomycin and betamethasone. These hydrogels have been found to increase the bioavailability of drug guest molecules and reduce the frequency of dosing required for conjunctivitis eye drops. [166, 167]

 

DDS for Keratoconus

Keratoconus is a progressive eye condition that causes the cornea to become thin and cone-shaped, leading to vision distortion, nearsightedness, and irregular astigmatism. Early treatment options, such as rigid contact lenses or corneal crosslinking (CXL), can help slow the disease's progression. CXL involves creating new chemical bonds within the cornea's collagen fibers by performing epithelial debridement with a blade, applying riboflavin drops, and exposing the cornea to ultraviolet light. However, traditional CXL has a limitation in that the cornea must be of a certain thickness to avoid postoperative corneal ectasia. Advanced drug-delivery systems have the potential to eliminate the need for mechanical epithelial debridement, reducing the risk of complications and making the procedure safer, especially in patients with thin corneal thickness. Nano-sized DDS can penetrate the cornea and directly target the photosensitizing agent to the cornea's deeper layers.

To improve the effectiveness of riboflavin delivery in corneal crosslinking for keratoconus treatment, nanocarriers have been studied for their ability to penetrate the tear film and corneal epithelium and reach the corneal stroma. Among these, nanostructured lipid carriers (NLCs) have shown improved stability and loading capacity compared to solid lipid nanoparticles. NLCs loaded with riboflavin have demonstrated sustained release and enhanced penetration compared to conventional eye drops and solid lipid nanoparticle formulations. Additionally, a thermoresponsive gel consisting of poloxamer 407 and hydroxypropyl methylcellulose has been developed for co-delivery of dexamethasone and riboflavin, exhibiting therapeutic potential in increasing corneal thickness and fibroblast cells associated with keratoconus [168, 169].

To enhance the therapeutic efficacy of peptides for keratoconus treatment, appropriate drug delivery systems (DDS) are required. The rate of diffusion and residence time of peptides in the cornea are major barriers to their effectiveness. One solution is the use of copolymeric nanoparticles synthesized from chitosan-tripolyphosphate and chitosan-Sulfobutyletherβ-cyclodextrin for the delivery of lactoferrin, a peptide that can promote corneal healing. These nanoparticles display superior mucoadhesive properties, enabling them to achieve an ocular retention time of more than 240 minutes [170].

 

DDS for Keratitis

Keratitis is a condition that causes inflammation of the cornea, and it can be caused by a range of factors, from infections to autoimmune diseases. In severe cases, keratitis can lead to corneal melting, perforation, or scarring, which can result in severe vision loss. Therefore, prompt and proper treatment is essential. Treatment options for keratitis depend on the underlying cause and can include topical corticosteroids, antibiotics, and immunomodulatory agents.

To treat keratitis, topical delivery of drugs is commonly used. A gel formulation synthesized from sodium hydroxide, mannitol, and benzalkonium chloride has been approved as a polymeric drug delivery system for ganciclovir. This gel formulation solubilizes ganciclovir better than hydrophobic emulsions and increases the drug’s contact time within the eye. However, it needs to be applied five times a day. To improve the ocular retention and bioavailability of ganciclovir and reduce the need for frequent administration, non-mucoadhesive nanocarriers have been studied.

 

Nano-based DDS in preclinical Studies

Jain et al. developed an in situ gel from hydroxypropyl methylcellulose and sodium alginate to increase the precorneal residence time of levofloxacin, a broad-spectrum antibiotic used to treat infectious keratitis. The hydrogels spontaneously self-assemble at corneal pH and displayed higher permeation compared to QuixinTM eye drops, with minimal in vivo toxicity [174].

Recently developed microneedles made from poly(vinylpyrrolidone) and polyvinyl alcohol offer an improved solution for the ocular delivery of amphotericin B, a polyene antibiotic. The microneedles do not contain deoxycholate, which eliminates the painful side effects associated with current options. In comparison to liposomal amphotericin B formulations, microneedles were more effective in targeting Candida species. Another important DDS has been synthesized using hydroxypropyl methylcellulose with PEG and Poly(vinylpyrrolidone) for the delivery of moxifloxacin. The in situ gel formation prolonged the adhesion of the drug to the cornea and enabled better drug permeation compared to current commercial forms. Additionally, carboxymethyl-alphacyclodextrin conjugated with chitosan has been shown to increase the biocompatibility and aqueous stability of econazole, an antifungal medication, resulting in a 29-fold increase in relative ocular bioavailability compared to conventional eye drop controls [175-177].

 

DDS for Cataracts

Cataract surgery involves the replacement of the diseased lens with a synthetic intraocular lens, and while it is commonly performed with a high success rate, it can carry risks and complications, including corneal edema, cystoid macular edema, endophthalmitis, and retinal detachment. The FDA has approved topical NSAIDs for the prevention of postoperative cystoid macular edema. Although the use of pharmacological compounds as an alternative to cataract surgery is still under development, various strategies aim to combat lens opacification by enhancing the bioavailability of antioxidants in the lens. This is because oxidative stress caused by reactive oxygen species and free radicals is a significant factor in the onset of cataracts.

Silver moieties have been used to synthesize nanoparticles, which can enhance the topical delivery of drugs, including antioxidants, for the treatment of cataracts [180,181]. Although silver nanoparticles have a high surface-area-to-volume ratio and are easy to manufacture, they have been linked to increased reactive oxygen species in the target tissue [182]. Mesoporous silica nanoparticles loaded with CeCl3 have also been developed to potentially reduce reactive oxygen species around the lens, but the formulations were designed for systemic injections, and the non-biodegradable nature of silica would result in the persistence of toxic metabolites in the blood [183,184]. As a result, biodegradable polymers are emerging as DDS applications for the treatment of cataracts, as they have a predictable release profile and increased biocompatibility.

Liu et al. recently developed a PLGA-based nanoformulation by combining curcumin and cerium oxide nanoparticles. This formulation exhibited effective antioxidant and anti-glycation potential to protect lens epithelial cells. Notably, it showed lower in vivo toxicity and increased cerium nanoparticle bioavailability in the rat eye compared to subcutaneous injections. Similarly, low molecular weight chitosan-coated mPEG-PLGA nanoparticles were used to deliver baicalin, another antioxidant. The nanoparticles had a small size and resulted in increased cellular uptake compared to the solution group. Additionally, in vivo tests demonstrated the nanoparticles' ability to improve precorneal residence time and significantly enhance the activities of catalase, superoxide dismutase, and glutathione peroxidase, which neutralize reactive oxygen species [185-186].

Chitosan-NAC nanoparticles have been developed as a biodegradable nanocarrier for drug delivery to the anterior segment, using hydroxypropyl β-CD to encapsulate and deliver quercetin for cataract treatment. This approach, developed by Lan et al., has shown enhanced permeability of quercetin and deeper delivery into the corneal epithelium.

1.1. DDS for Dry Eye Disease

Biodegradable gels offer an attractive DDS for cataracts due to their prolonged contact with the target membrane, resulting in higher permeation of the drug at the site of administration while maintaining its bioactive form. Bodoki et al. used biodegradable nanoparticles composed of zein and PLGA to deliver the antioxidant Lutein for preventing cataract progression. In vivo experiments demonstrated a significant reduction in cataract severity in rats treated topically with lutein-loaded NPs compared to the positive control [188].

Dry eye disease (DED), also known as keratoconjunctivitis sicca, is a multifactorial condition characterized by insufficient or poor-quality tears that result in discomfort, visual disturbances, and instability of the tear film. This can lead to inflammation of the eye surface and cause damage to the ocular surface. It is often accompanied by an increased osmolarity in the tear film. Dry eye disease can be caused by a number of factors, including aging, certain medical conditions such as Sjogren’s syndrome, medications, environmental factors, lifestyle habits, and hormonal changes. Pharmacologic therapies for DED can range from mild cases, such as artificial tears and ointments, to more severe cases requiring topical corticosteroids, immunosuppressants, and autologous tear therapies. The pharmacological treatment options for dry eye disease (DED) vary depending on the severity of the condition. Mild cases may be managed with artificial tears and ointments, while more severe cases may require the use of topical steroids, immunosuppressants, or autologous tear therapy. Each of these treatments has its own limitations and drawbacks. For example, artificial tears need to be applied multiple times per day and rely on the compliance of the patient. Long-term use of topical steroids can cause side effects such as increased intraocular pressure and cataracts, and autologous tear therapy is both costly and involves multiple visits to a healthcare setting for blood draws. Moreover, DED itself can affect ocular drug delivery by reducing the residence time of topically applied drugs and increasing the risk of systemic absorption. DED can also increase the rate of tear turnover which can further reduce the efficacy of topical medications. To maintain a healthy ocular surface and improve drug delivery, other therapeutic strategies have been developed.

 

Currently, nanoemulsions encapsulating cyclosporine A such as CyclokatTM and RestasisTM have also been approved for dry eye disease due to their highly solubilized state and their stability improvement. The delivery of the drug to ocular tissue remains hampered by its high molecular weight and its higher affinity with the oil phase of the nanoemulsion. Recently, the use of CequaTM, a nanomicelle solution containing cyclosporine A, has been shown to treat dry eye diseases. After 84 days of treatment, patients have reported increased tear production and improved ocular surface integrity [1]. CequaTM nanomicelles are amphiphilic surfactants that can increase the dissolution of the hydrophobic cyclosporine A, and its penetration through the tear film and other anatomical barriers of the eye. Recently, KPI-121, a mucin-penetrating particle (MPP) for the delivery of loteprednol etabonate has been approved by the FDA for the treatment of dry eye disease. The nanosuspension (roughly 300 nm) was developed by a milling procedure containing loteprednol etabonate and Pluronic F127 polymer. This delivery system showed a significant advantage over the conventional loteprednol formulation in a New Zealand white rabbit model. KPI-121 achieved a higher ocular exposure with peak concentrations of approximately threefold higher in ocular tissues than the conventional formulation with a single topical delivery [2][3]. These nanoparticles have a low molecular weight and can evade entrapment by mucin and have a reduced clearance rate compared to conventional eye drops. The polymer used is reported to have a longer hydrophobic poly(propylene oxide) chain, that can provide strong hydrophobic absorption on its surface and may further improve drug loading. KPI-121 has shown minimal toxicity in clinical trials [4]. The phase III clinical trial conducted a 2-week course of treatment in approximately 2700 patients and has demonstrated a successful reduction in signs and symptoms of dry eye disease [5]. The F127 polymers form nanomicelle structures and have the ability to form hexagonal morphologies at higher temperatures, which are thought to preserve their overall size and improve the stability of the system [6].
Several novel biodegradable nano-sized DDS have recently been investigated in clinical trials. They aim to reduce the frequent administration times of currently used DDS and to increase the bioavailability of guest drugs at the target site of action. To achieve long-term controlled drug delivery of cyclosporine A, Mun et al. (2019) have synthesized cholesterol-hyaluronate nanomicelles. Crosslinking the nanomicelles using ethylene glycol dimethacrylate and hydroxyethyl methacrylate resulted in the formation of contact lenses that showed a prolonged therapeutic effect on a dry eye disease rabbit model [7]. Novel nanomicelle formulations of cyclosporine A that are based on mPEG-PLA copolymers have been developed. These nanomicelles can be lyophilized and demonstrate increased stability and prolonged shelf life.
Rebamipide has been demonstrated to increase mucin and lipid layers of the tear film and reduce ocular surface dryness. Clinically, rebamipide eye drops have been found to treat tear deficiency and corneal epithelial damage caused by a lack of mucin. Novel drug-delivery systems are being investigated to evade nasolacrimal clearance and increase drug compliance by altering its opaque and turbid appearance. Copolymeric nanoparticles have been developed by Nagai et al., from 2-hydroxypropyl-β-cyclodextrin and methylcellulose and had a more sustained release compared to the commercially available formulation. The use of nanoparticles allows for improved delivery to the goblet cells and meibomian glands, leading to increased stimulation of mucin and lipid production [8]. Another formulation is composed of hydrogenated soybean phospholipids and high-purity cholesterol multilamellar nanoliposomes. They exhibited an equivalent therapeutic effect observed by fluorescein staining compared to the commercially available rebamipide formulation which was several times more concentrated than the nanoliposomes. The nanoliposomes improved drug retention and allowed for sufficient drug concentration at the cornea and aqueous humor, reducing the frequency of administration and the adverse effects [9].
Recently, Wang et al. have reported the synthesis of rapamycin nanospheres based on 3- hydroxybutyrate-co-3-hydroxyvalerate copolymers. Unlike the currently available rapamycin ocular formulations, these nanospheres can penetrate the tear film barrier effectively. They have been shown to increase tear meniscal height, decrease tear break-up time, and improve Schirmer’s test scores, suggesting that they may be advantageous for Sjögren-associated dry eye disease [10]. However, the results of this research are preliminary and further research is needed to determine the long-term safety and efficacy of the nanospheres.
Luo et al. synthesized a novel thermo-responsive in situ gel by functionalizing poly(N-isopropylacrylamide) with mucoadhesive gelatin and helix pomatia. One-time use of the gel in a rabbit dry eye disease model increased the drug (epigallocatechin gallate) bioavailability on the ocular surface beyond the therapeutic level for 14 days [11].
Mucolytic agents are a class of drugs that typically function by reducing mucus viscosity and inhibiting inflammatory cascades. Typically, mucolytic agents are synthetic polymers that have a thiol group, enabling them to break the disulfide bonds in mucoprotein complexes. Other types of mucolytic agents include enzymes such as papain or bromelain, which have been used as they can cleave the cross-links of mucus glycoproteins. By modifying nanocarriers with mucolytic agents, a controlled drug release, enhanced permeation, and improved mucoadhesion can be achieved. Although there has been research on the development of mucolytic enzyme-loaded nanoparticles for penetrating intestinal mucous layers, studies for ocular delivery are currently limited [12].
N-acetylcysteine (NAC) is a mucolytic agent that has been used to treat various anterior segment diseases including cataracts, DED, and filamentous keratitis. NAC is administered via intracorneal injections and is associated with side effects including edema, sloughing, and corneal haze due to the rapid mucolytic activity of NAC. Therefore, integrating them with biodegradable polymers (thiolated polymers) may improve this by achieving a controlled, sustained release. For example, the functionalization of NAC with chitosan has been an attractive strategy for forming highly mucoadhesive copolymers for ocular drug-delivery systems. By optimizing the concentration of NAC on the surface of chitosan, the thiol groups of NAC can form covalent bonds with cysteine-rich mucosal glycoproteins [13]. Nepp et al. (2020) studied the effects of chitosan-NAC eye drops (LacrimeraTM) for patients with dry eye disease and found a sustained improvement over a 1-month period of treatment. This was indicated by an increase in intact corneas by 64%, an increase in Schirmer’s score by 68%, and an increase in tear break-up time by 50%. Thiolated polymers also have the advantage of being able to bind with positively charged glucosamine as well as negatively charged carboxylic acids in mucosal proteins. This is because they can form amidine bonds in the case of cationic targets as well as sulfhydryl bonds in the case of anionic targets [14]. This makes thiolated polymers highly advantageous over other non-thiolated mucoadhesive polymers by significantly improving adhesion to the ocular mucus layer and therefore improving contact time with the drug. This approach was used by Sheng et al. (2022) to synthesize nanomicelles for the delivery of flurbiprofen to reduce inflammation in the context of DED. The nanomicelles demonstrated a strong binding capacity with mucin in vitro and they increased the fluidity of the ocular membranes which was presumed to be due to the ability of the NAC thiol groups to reduce intermolecular interactions between neighboring lipid molecules. The nanomicelles successfully increased the bioavailability of flurbiprofenin, an in vivo rabbit eye model [15]. However, a practical barrier with mucoadhesive nanocarriers is that rabbit models, which are most commonly used for in vivo studies, may not bring clinically translatable results given that rabbit eyes have superior bioadhesion and higher mucus production compared to human eyes [16].
In short, there are several novel drug-delivery systems (DDS) that have been developed to treat dry eye disease. Among these DDS, the nanoemulsions encapsulating cyclosporine A (RestasisTM) and its nanomicelle form (CequaTM) are the two most used topical medications by ophthalmologists in North America. Overall, these novel DDS offer promising results in increasing drug bioavailability and reducing the need for frequent administration. This translates clinically into improved symptom management, greater compliance, and fewer side effects.

1.2. DDS for Meibomian Gland Dysfunction (MGD)

Meibomian gland dysfunction (MGD) is a condition characterized by decreased secretion or blockage of the meibomian glands. This disruption of meibomian gland function can negatively impact both the quality and quantity of the meibum secreted, leading to changes in tear film composition, particularly the lipid layer of the tear film, and subsequent issues such as increased tear evaporation, hyperosmolarity, inflammation, and damage to the ocular surface. Currently, the main treatment strategies for MGD involve a combination of heat therapy, massage, and lid margin hygiene. Artificial tears and topical steroids can provide relief for symptoms of dry eye and ocular irritation, but their effectiveness may be limited by low patient compliance.
Chronic inflammation and oxidative stress play a critical role in the development and progression of MGD [17]. Thus, preservative-free fluorometholone eyedrops can be considered for the administration of drugs to treat MGD. However, multiple installations would be required, and they have the potential for adverse effects if used without DDS [18]. Therefore, Choi et al. developed polyhydroxyethyl methacrylate-based contact lenses embedded with cerium oxide nanoparticles for the scavenging of reactive oxygen species. The contact lenses enhanced the viabilities of human conjunctival epithelial cells and human meibomian gland epithelial cells even in media with high H2O2 concentrations. Moreover, in vivo experiments demonstrated that contact lenses had protective effects in a mouse model when 3% H2O2 eyedrops were administered [19].
Recently, nanoemulsions encapsulating cyclosporine A (nano-cyclosporine; Cyporin NTM, Taejoon, Korea) have been investigated in Phase 3 clinical trials for the treatment of MGD. Nanoemulsions maintain optical transparency and are considered more thermodynamically stable compared to normal emulsions. The trial concludes that cyclosporine nanoemulsions show significant improvement in dry eye disease progression secondary to MGD compared to the control group. The group receiving cyclosporine nanoemulsions had better corneal staining and increased lipid layer thickness after one month of treatment compared to the group receiving the conventional cyclosporine formulation [20].

2. DDS for Conjunctivitis

Conjunctivitis is an inflammation of the conjunctiva, the clear outer membrane that covers the sclera of the eye and the inner surface of the eyelids. This condition can be caused by viral infections, bacterial infections, allergens, irritants, or a combination of these factors. Treatment for conjunctivitis depends on the underlying cause and severity of the condition. Options can include, but are not limited to, artificial tears, topical antibiotics, corticosteroids, and immunosuppressants.

2.1. Clinical Studies

Cyclosporine A nanoemulsions are currently being investigated in phase III clinical trials. These nanocarriers, being cationic emulsions, have the advantage of interacting with the negatively charged ocular surfaces, resulting in increased residence time. The formulation showed improved signs and symptoms of severe vernal keratoconjunctivitis, as well as good biocompatibility, except for instillation site pain [21].

2.2. Preclinical Studies

Tacrolimus is another topical immunosuppressant clinically used to treat ocular inflammatory conditions, including vernal keratoconjunctivitis. A nano-based biodegradable DDS that can increase the stability of tacrolimus in aqueous solutions has been developed from solid lipid nanoparticles. These nanoscale particles made of solid lipids (natural fats or oils) are advantageous for encapsulating lipophilic molecules inside the lipid matrix, which improves drug solubility. The solid lipid nanoparticle in situ gels demonstrated thermo-responsive gelation at 32 degrees and had advantageous therapeutic effects in vivo compared to conventional conjunctivitis eye drops [22].
To prolong the release of topical antibiotics in the treatment of bacterial conjunctivitis, several novel DDS are being investigated in vitro and in vivo. Chitosan and PVA nanofibers have been designed to encapsulate ofloxacin. The linking of the nanofibers by glutaraldehyde vapor could reduce the burst release of ofloxacin and significantly increase its bioavailability compared to the currently available suspensions [23]. Another important strategy is to co-deliver multiple guest compounds to better target the underlying disease mechanisms. Deepthi et al. invented a copolymeric hydrogel from chitosan and poloxamer 407 for the co-delivery of neomycin (an antibiotic) and betamethasone (an anti-inflammatory compound). The hydrogels increased the bioavailability of the drug guest molecules and can reduce the frequency of dosing that is currently required for conjunctivitis eye drops [24].

3. DDS for Keratoconus

Keratoconus is a progressive eye condition in which the normally round cornea becomes thin and cone-shaped. This shape change can lead to distorted vision, nearsightedness, and irregular astigmatism. Early treatment, such as rigid contact lenses or corneal crosslinking (CXL), can help slow the disease process. Corneal crosslinking (CXL) is a surgical procedure that aims to strengthen the cornea by creating new chemical bonds within the cornea’s collagen fibers. It involves performing an epithelial debridement with a blade, applying riboflavin drops to the eye, and subsequently exposing the cornea to ultraviolet light. The traditional CXL technique has a limitation in that the cornea must be of a certain thickness to avoid making the cornea even thinner during the epithelial debridement step, which can lead to postoperative corneal ectasia. Fortunately, advanced drug-delivery systems can potentially eliminate the need for mechanical epithelial debridement, reducing the risk of complications and making the procedure safer, especially in patients with thin corneal thickness. In fact, the advanced nano-sized DDS can penetrate the cornea and target the photosensitizing agent directly to the cornea’s deeper layers.

Preclinical Studies

Nanocarriers loaded with riboflavin have been studied for their ability to penetrate the tear film and corneal epithelium and reach the corneal stroma. Nanostructured lipid carriers, consisting of a solid lipid matrix with liquid lipid, have advantages over solid lipid nanoparticles, such as improved stability and loading capacity. These nanostructured lipid carriers have been loaded with riboflavin and displayed advantageous sustained release compared to eye drops and solid lipid nanoparticle formulations [25]. Another thermo-responsive gel for the co-delivery of dexamethasone and riboflavin has been developed from poloxamer 407 and hydroxypropyl methylcellulose. The gel displayed a therapeutic role in the increasing thickness of keratoconus and corneal fibroblast cells [26].
The delivery of certain peptides might be important for modifying keratoconus disease mechanisms. However, with the lack of appropriate DDS, the rate of diffusion and residence time of peptides in the cornea are the major barriers to their therapeutic efficacy. Copolymeric nanoparticles from chitosan-tripolyphosphate and chitosan-Sulfobutylether-β-cyclodextrin have been synthesized for the delivery of lactoferrin, a peptide that can potentially promote corneal healing. The nanoparticles displayed advantageous mucoadhesive properties that allowed them to achieve an ocular retention time of more than 240 min [27].

4. DDS for Keratitis

Keratitis is an inflammation of the cornea. The causes of keratitis can range from infectious origins (e.g., bacterial, fungal, viral infections) to autoimmune etiologies (e.g., peripheral ulcerative keratitis secondary to rheumatoid arthritis). In severe cases, it can lead to corneal melting, perforation, or scarring resulting in severe vision loss, making prompt and proper treatment important. The treatment of keratitis varies according to its etiology, with options including but not limited to topical corticosteroids, antibiotics, and immunomodulatory agents.
The only polymeric DDS approved for the treatment of keratitis is a gel formulation synthesized from sodium hydroxide, mannitol, and benzalkonium chloride for the delivery of ganciclovir [28]. The gel formulation allows for the solubilization of ganciclovir better than hydrophobic emulsions and increases the drug’s contact time within the eye [29]. This allows for ganciclovir to achieve its inhibitory concentration against the herpes simplex virus in the cornea. Nevertheless, the formulation must be applied five times a day. Non-mucoadhesive nanocarriers have the capacity to increase the ocular retention and bioavailability of ganciclovir, potentially reducing its frequent administration [30].

Preclinical Studies

Levofloxacin is a broad-spectrum antibiotic used to treat infectious keratitis. To enhance its precorneal residence time, Jain et al. designed an in situ gel from hydroxypropyl methylcellulose and sodium alginate. The hydrogels spontaneously self-assemble at corneal pH and had a higher permeation compared to marketed QuixinTM eye drops with minimal in vivo toxicity [31].
Amphotericin B is a polyene antibiotic that can self-aggregate, resulting in reduced bioavailability and reduced biocompatibility. Poly(vinylpyrrolidone) and polyvinyl alcohol microneedles have recently been developed for the ocular delivery of amphotericin B. Microneedles offer an improved solution for amphotericin B ocular treatment as they do not contain deoxycholate, eliminating the painful side effects associated with current options. Moreover, the microneedles were more effective in targeting Candida species compared to the liposomal amphotericin B formulation [32]. Another important DDS has been synthesized using hydroxypropyl methylcellulose with PEG and Poly(vinylpyrrolidone) for the delivery of moxifloxacin. The in situ gel formation prolonged the adhesion of the drug to the cornea and enabled better drug permeation compared to current commercial forms [33]. Finally, Li et al. have demonstrated the advantages of carboxymethyl-alpha-cyclodextrin conjugated with chitosan to increase the biocompatibility and aqueous stability of the econazole (an antifungal medication). The polymeric matrix increased the relative ocular bioavailability by 29 times compared to the conventional eye drop controls [34].

5. Nano-Based DDS for Cataracts

Cataract surgery, the replacement of the diseased lens with a synthetic intraocular lens, remains the treatment of choice for cataracts. It is a commonly performed procedure with a high success rate. However, like all surgical procedures, it can carry certain risks and complications, such as corneal edema, cystoid macular edema, endophthalmitis, and retinal detachment. The FDA has approved the use of topical NSAIDs for the prevention of postoperative cystoid macular edema [35]. However, the use of pharmacological compounds as an alternative to cataract surgery remains under development. To combat lens opacification in cataracts, various strategies aim to enhance the bioavailability of antioxidants in the lens [36]. This is because a significant factor in the onset of cataracts is the oxidation of lenticular proteins by reactive oxygen species and free radicals.

Preclinical Studies

The use of silver moieties in the synthesis of nanoparticles has been explored for enhancing the topical delivery of drugs, including antioxidants. This approach aims to improve the bioavailability of the antioxidants, thereby potentially offering a new avenue for the treatment of cataracts [37][38]. This is due to their large surface-area-to-volume ratio and relative ease of manufacturing. However, silver nanoparticles have been thought to contribute to increased reactive oxygen species in their target tissue [39]. Another group has developed mesoporous silica nanoparticles loaded with CeCl3 that can potentially reduce the reactive oxygen species around the lens. Mesoporous silica nanoparticles have several advantages in drug-delivery applications due to their highly tunable pore characteristic. However, the formulations were designed as systemic injections and the non-biodegradable nature of silica would result in the persistence of toxic metabolites in the blood [40][41]. Therefore, emerging DDS applications for the treatment of cataracts rely on biodegradable polymers that have a predictable release profile and increased biocompatibility.
A PLGA-based nanoformulation was recently prepared by Liu et al., to combine antioxidant curcumin and cerium oxide nanoparticles. The prepared nanoformulation could have effective antioxidant and anti-glycation potential to protect lens epithelial cells. Interestingly, the nanoformulations showed lower in vivo toxicity and increased cerium nanoparticle bioavailability in the rat eye compared to subcutaneous injections [42]. Another similar formulation from low molecular weight chitosan-coated mPEG-PLGA nanoparticles was developed for the delivery of another antioxidant, baicalin. The nanoparticles had an overall small size between 148 and 219 nm and resulted in increased cellular uptake compared to the solution group. Furthermore, in vivo tests demonstrate the ability of the nanoparticles to improve precorneal residence time and significantly enhance the activities of catalase, superoxide dismutase, and glutathione peroxidase, which can neutralize the reactive oxygen species [43].
Recently, chitosan conjugated with NAC has been used as a biodegradable nanocarrier for the delivery of drugs to the anterior segment. Lan et al. have developed nanoparticles that incorporate chitosan-NAC with hydroxypropyl β-CD. The inclusion complexes of β-CD were used to encapsulate and deliver quercetin, which has been used in the treatment of cataracts. The nanoparticles enhanced the permeability of quercetin and allowed for its delivery deeper into the corneal epithelium [44].
The use of biodegradable gels is also an attractive DDS for cataracts due to their prolonged contact with the target membrane allowing for the build-up of significantly higher amounts of permeated drug at the site of administration while maintaining the drug in its bioactive form. Bodoki et al. have used biodegradable nanoparticles composed of zein and PLGA to deliver the antioxidant Lutein to prevent the progression of cataract disease. In vivo experiments showed a significant reduction in cataract severity in rats topically treated with lutein-loaded NPs compared to the positive control [45][46][47].

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